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Cited by 353Retinoids in leukemia and cellular processesPhotoreceptor and optogenetics researchRetinal Development and Disorders

Chemistry of the Retinoid (Visual) Cycle

Open access
Kiser, Philip D., Golczak, Marcin, Palczewski, Krzysztof·2014·Chemical Reviews
DOI 10.1021/cr400107qPMC PMC3858459
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Abstract

Review of retinoid support of rod and cone photoreceptor function and the enzymatic reactions of the visual cycle.

Integrity signals

Registry

Crossref · 10.1021/cr400107q

Cites

579 of 579 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

230 of 530 cited sources checked · 103 supported · 2 flagged · accuracy not yet measured

  • Premisecitation

    Only retinol dehydrogenases contribute to vision-related retinoid metabolism.

    “However, only RDH’s contribute to vision-related metabolism of retinoids.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [287] Kiser P. D., 2012, Biochim. Biophys. Acta source

      Section 3 says RDHs catalyze two reactions in the visual retinoid cycle, but the claim's 'only' is contrary to the paper. Section 2.4 calls LRAT indispensable to that cycle and says LRAT and RPE65 are required for 11-cis-retinoid production in the RPE. Page numbers are unavailable in our copy. (LLM, conf=0.94)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Carotenoid uptake is mediated and regulated by SR-BI.

    “Unlike retinyl esters, which are hydrolyzed to retinol in the small intestine followed by rapid absorption by enterocytes, uptake of carotenoids is mediated and regulated by scavenger receptor class-B type-I (SR-BI).131,132”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [131] During A., 2007, J. Lipid Res. source
    • cites [132] van Bennekum A., 2005, Biochemistry source
  • Premisecitation

    β-carotene undergoes oxidative cleavage by BCMO1 to produce two molecules of all-trans-retinal.

    “Upon absorption by enterocytes, β,β-carotene undergoes oxidative cleavage catalyzed by β,β-carotene 15,15′-monooxygenase (BCMO1).133,134 This symmetric split of the carotenoid produces two molecules of all-trans-retinal that subsequently enter vitamin A metabolic pathways (Figure 5).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [133] von Lintig J., 2000, J. Biol. Chem. source
    • cites [134] Hessel S., 2007, J. Biol. Chem. source

      The paper’s introductory passage (labeled Abstract in our copy; page unavailable) says CMO1 converts β-carotene to retinaldehyde by oxidative cleavage at the central C15,C15′ bond. It does not explicitly specify the yield of two molecules or identify the product as all-trans-retinal. (LLM, conf=0.81)

      Experimental — accuracy not yet measured
  • Premisecitation

    Mammals use preformed vitamin A as all-trans-retinyl esters and pro-vitamin A carotenoids, mainly β-carotene, to sustain the body pool of vitamin A.

    “Mammals efficiently utilize both preformed vitamin A in the form of all-trans-retinyl esters and pro-vitamin A carotenoids (mainly β,β-carotene) to sustain the body pool of vitamin A.130”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [130] Paik J., 2004, J. Nutr. source

      The introductory passage labeled Abstract says dietary vitamin A comes from preformed retinol and retinyl esters or from provitamin A carotenoids, and describes conversion of carotenoids to retinoids. It does not specify all-trans-retinyl esters as the form of preformed vitamin A, identify β-carotene as the main provitamin A carotenoid, or establish that mammals use both efficiently. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Premisecitation

    All-trans-retinal is first reduced to all-trans-retinol by SDR or alcohol dehydrogenase.

    “Instead, all-trans-retinal is first reduced to all-trans-retinol by short-chain dehydrogenase/reductase (SDR) or alcohol dehydrogenase enzymes.136,143,144”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [136] Kumar S., 2012, Biochim. Biophys. Acta source

      The Introduction (page not provided) says all-trans-retinaldehyde can be reduced to all-trans-retinol and identifies some short-chain dehydrogenase/reductase-family enzymes, such as RDH12, that catalyze this reduction. It describes alcohol dehydrogenases as catalyzing the reverse reaction—oxidation of retinol to retinaldehyde—but does not identify them as enzymes that reduce retinaldehyde. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [143] Rattner A., 2000, J. Biol. Chem. source
    • cites [144] Haeseleer F., 1998, J. Biol. Chem. source

      The Abstract identifies reduction of all-trans-retinal as the first step in visual-pigment regeneration and describes retSDR1 as a short-chain dehydrogenase/reductase. The results report that retSDR1 produced all-trans-retinol. Our copy does not establish alcohol dehydrogenase as an alternative enzyme for this reaction; it mentions that enzyme family only in comparisons with SDRs. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • May combine two claims. 130
  • Classified as probably not a substantial claim. 52
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    Type I IDI catalysis involves a metal-binding Glu transferring a proton to IPP to form a carbocation, and an active-site Cys abstracting a proton to form DMAPP.

    “Biochemical and crystallographic analyses of type I IDI indicate that an active site, metal-binding Glu residue transfers a proton to the alkene π bond of IPP, generating a tertiary carbocation or carbocation-like intermediate.107,108 Abstraction of a proton from C2 of the isoprene skeleton by an active site Cys residue regenerates the alkene forming DMAPP.109,110”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [107] Muehlbacher M., 1988, Biochemistry source
    • cites [108] Toteva M. M., 1997, Bioorg. Chem. source
    • cites [109] Wouters J., 2003, J. Biol. Chem. source
    • cites [110] Durbecq V., 2001, EMBO J. source

      The Results and discussion passage assigns the catalytic roles in the opposite direction: C67 initiates protonation of IPP’s double bond, while metal-coordinated E116 deprotonates the carbocation to form DMAPP. The supplied passage has no page number. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The mouse CrtIso-related enzyme accepts all-trans-retinol, saturates the 13-14 double bond, and yields (R)-all-trans-13,14-dihydroretinol without isomerization.

    “Instead, the mouse CrtIso-related enzyme accepts all-trans-retinol as a substrate in carrying out the saturation of the retinoid 13–14 double bond.125,206 However, in contrast to plant CrtIso, this reaction is not accompanied by isomerization of the retinoid, yielding (R)-all-trans-13,14-dihydroretinol as a final product (Figure 11).206”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [125] Moise A. R., 2004, J. Biol. Chem. source
    • cites [206] Moise A. R., 2008, J. Am. Chem. Soc. source

  • May combine two claims.

    Premisecitation

    All-trans-retinoic acid formation is irreversible, and excess is cleared by CYP26 oxidation and/or UGT glucuronidation.

    “Because all-trans-retinoic acid formation is irreversible, an excess of this active retinoid can be cleared only by its further conversion to more polar metabolites through oxidation by cytochrome P450 (CYP26) and/or glucuronidation by UDP-glucuronosyl transferases (UGTs).137,138”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [137] Salyers K. L., 1993, Biochim. Biophys. Acta source
    • cites [138] Ross A. C., 2011, Annu. Rev. Nutr. source

      The Introduction’s “Initial Studies on Retinoic Acid Oxidation” section describes CYP26 oxidation of all-trans-retinoic acid to polar metabolites followed by UDP-glucuronosyl transferase conjugation. Our copy does not state that formation of all-trans-retinoic acid is irreversible, and the “Other CYP Families” section describes additional CYP enzymes capable of oxidizing it, so the claim’s exclusivity is not supported. No page numbers were available for these passages. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Most eubacteria use the MEP pathway.

    “However, most eubacteria utilize the MEP pathway.99”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [99] Odom A. R., 2011, PLoS Pathog. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A second route for IPP synthesis, the MEP or nonmevalonate pathway, uses d-glyceraldehyde 3-phosphate and pyruvate and was discovered in eubacteria and plants.

    “Research in eubacteria and plants then revealed a second metabolic route for IPP synthesis referred to as the methylerythritol 4-phosphate (MEP) or nonmevalonate pathway, which utilizes the triose derivative, d-glyceraldehyde 3-phosphate along with pyruvate as starting materials90−94”
    Quote in the paperNot a substantial claim2 of 5 sources checked
    • cites [90] Lange B. M., 2000, Proc. Natl. Acad. Sci. U.S.A. source
    • cites [91] Rohmer M., 1999, Nat. Prod. Rep. source
    • cites [92] Schwender J., 1996, Biochem. J. source

      The Discussion describes a non-mevalonate route to IPP in eubacteria and the green alga Scenedesmus that uses glyceraldehyde 3-phosphate and a pyruvate-derived unit. It presents the route’s occurrence in higher plants as a hypothesis, rather than a finding established by this study. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [93] Flesch G., 1988, Eur. J. Biochem. source
    • cites [94] Rohmer M., 1996, J. Am. Chem. Soc. source

  • May combine two claims.

    Premisecitation

    Esterification of all-trans-retinol mainly by LRAT provides a major storage form of retinoids and a direct substrate for RPE65-dependent isomerization.

    “Subsequent esterification of all-trans-retinol, mainly by lecithin/retinol acyltransferase (LRAT), provides both a major storage form of retinoids in the body and a direct substrate for RPE65-dependent enzymatic isomerization of the retinoid polyene chain.145−148”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [145] Ruiz A., 1999, J. Biol. Chem. source

      The introductory passage labeled Abstract (page unavailable) says LRAT converts retinol to all-trans-retinyl esters, which are presumptive vitamin A storage forms and substrates for an isomerohydrolase in the RPE visual cycle. It does not identify that enzyme as RPE65 or establish that these esters are a major storage form throughout the body; its storage description is qualified as presumptive. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [146] MacDonald P. N., 1988, Biochem. Biophys. Res. Commun. source
    • cites [147] Batten M. L., 2004, J. Biol. Chem. source
    • cites [148] Moiseyev G., 2003, Biochemistry source

  • May combine two claims.

    Premisecitation

    UV/Vis detection offers retinoid quantification at low picomolar range through most photodiode array detectors and linearity over 2-1500 pmol.

    “UV/Vis detection offers a limit of retinoid quantification at a low picomolar range through most photodiode array detectors and provides excellent linearity over a wide range of concentrations (2–1500 pmol) (Figure 6C).163”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [163] Golczak M., 2010, Methods Mol. Biol. source

      The Introduction reports quantification down to approximately 2 pmol by HPLC with photodiode-array detection and excellent standard-curve linearity over 2–1500 pmol. It does not establish that this applies to most photodiode-array detectors, and pmol (an amount) is not the same as a picomolar concentration. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Vitamin A-containing solutions with Brønsted and Lewis acids change color from pale yellow to brilliant blue; the blue color is semistable with lifetime up to about 3 min in chloroform.

    “In the 1920s two groups164,165 made the discovery that vitamin A-containing solutions, in the presence of Brønsted and Lewis acids, undergo a color change from pale yellow (λmax ∼ 325 nm) to brilliant blue (λmax ∼ 600 nm). The blue color is semistable with an effective lifetime of up to ∼3 min when chloroform is used as a solvent.166”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [164] Rosenheim O., 1925, Biochem. J. source
    • cites [165] Carr F. H., 1926, Biochem. J. source
    • cites [166] Blatz P. E., 1972, Anal. Chem. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Lycopene is transformed into β-carotene by lycopene-β-cyclase, which depends on NADPH.

    “Lycopene, a compound with a red hue conferred by a set of 11 conjugated double bonds, is transformed into β,β-carotene by an enzyme known as lycopene-β-cyclase.126,127 Although not a reaction that involves net redox changes, the cyclization performed by lycopene-β-cyclase is dependent on an NAPDH cofactor.128”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [126] Cunningham F. X., 1994, Plant Cell source
    • cites [127] Cunningham F. X., 1993, FEBS Lett. source

      Citation 128 is attached to the NADPH-dependence claim, not the preceding conversion claim. The Introduction and Discussion describe lycopene cyclase converting lycopene to β-carotene, but the passages found when searching for NADPH, reducing cofactors, and cofactor requirements do not address whether that reaction depends on NADPH. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
    • cites [128] Hornero-Mendez D., 2002, FEBS Lett. source

  • May combine two claims.

    Premisecitation

    Oxidation of all-trans-retinal by RALDHs produces all-trans-retinoic acid, a ligand for RARs that with RXRs bind RAREs and regulate transcription.

    “Oxidation of all-trans-retinal catalyzed by retinaldehyde dehydrogenases (RALDHs) leads to formation of all-trans-retinoic acid, a ligand for nuclear retinoic acid receptors (RARs) that, coupled with retinoid X receptors (RXRs), bind to retinoic acid response elements on the promoter region of target genes and regulate their transcription.135,136”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [135] Chambon P., 1996, FASEB J. source
    • cites [136] Kumar S., 2012, Biochim. Biophys. Acta source

      The Introduction states that RALDHs oxidize retinaldehyde to retinoic acid, that RARs bind all-trans-retinoic acid, and that RAR–RXR heterodimers bind DNA and regulate gene transcription. It does not specify that they bind retinoic acid response elements in the promoter regions of target genes. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In bacteria, CrtI converts phytoene to lycopene; in plants, PDS, ZDS, ξ-carotene isomerase, and CrtIso together convert phytoene to lycopene.

    “In bacteria, a single enzyme called carotene desaturase (CrtI) is responsible for conversion of phytoene into lycopene. In plants, two desaturase enzymes called phytoene desaturase (PDS) and ξ-carotene desaturase (ZDS)122 and two isomerases called ξ-carotene isomerase123 and carotenoid isomerase (CrtIso)124 together convert phytoene into lycopene.87”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [87] Walter M. H., 2011, Nat. Prod. Rep. source
    • cites [122] Matthews P. D., 2003, J. Exp. Bot. source
    • cites [123] Chen Y., 2010, Plant Physiol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Metazoans, fungi, and archaea use only the mevalonate pathway for isoprenoid biosynthesis, while cyanobacteria and algae use only the MEP pathway.

    “Metazoans, fungi, and archaea rely exclusively on the mevalonate pathway for isoprenoid biosynthesis, whereas cyanobacteria and algae make sole use of the MEP pathway.98”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [98] Hunter W. N., 2007, J. Biol. Chem. source

      The Abstract (page not provided) says the mevalonate pathway supplies isoprenoid precursors in all mammals, archaea, and fungi, and that the MEP pathway occurs in algae and cyanobacteria. It does not establish that each group uses its listed pathway exclusively; the claim’s “sole use” qualifier is unsupported. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The Carr-Price reaction using antimony trichloride was a primary means of retinol detection before chromatography.

    “This color change, when initiated using antimony trichloride as the Lewis acid, is known as the Carr–Price reaction and was a primary means of retinol detection and quantification prior to the advent of chromatographic methods.167”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [167] Schwieter U., 1969, Pure Appl. Chem. source

      The opening passage (indexed as Abstract; page unavailable) says the Carr–Price reaction, including its antimony trichloride form, was a main tool for routine analysis and remained an analytical method for vitamin A. It does not establish retinol quantification, and its example is analysis of chromatographic fractions—not use before chromatography existed. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Drosophila eye has 10 different cells, while humans have 400, with parallel development of retinal circuitry.

    “For example, whereas Drosophila melanogaster eye has 10 different cells, that number has grown to 400 in humans, with a parallel development of retinal circuitry.211−215”
    Quote in the paperNot a substantial claim2 of 5 sources checked
    • cites [211] Vopalensky P., 2012, Proc. Natl. Acad. Sci. U.S.A. source

      The Discussion describes the amphioxus frontal-eye circuit as a simple precursor that might have given rise to more complex vertebrate circuits through expansion, duplication, and divergence. It does not give the claimed counts of 10 cell types in the Drosophila eye or 400 in humans, or establish that retinal circuitry developed in parallel with those counts. (LLM, conf=0.79)

      Experimental — accuracy not yet measured
    • cites [212] Arendt D., 2009, Philos. Trans. R. Soc. London, B: Biol. Sci. source
    • cites [213] Nilsson D. E., 2008, Curr. Biol. source
    • cites [214] Loosli F., 2001, Development source
    • cites [215] Arendt D., 2003, Int. J. Dev. Biol. source

      The ‘Quest for the proto-eye’ section discusses cell types in insect ommatidia and the vertebrate retina, and ‘Diversification of cell types in the vertebrate retina’ describes further retinal subtypes. Neither section gives the claimed counts of 10 in Drosophila and 400 in humans or describes a parallel development of retinal circuitry (pages unavailable in our copy). (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The retinol hydroxyl group is a much better leaving group than typical aliphatic alcohols because of its location relative to the conjugated polyene chain, and the resulting retinylic cation is stabilized by delocalization with a nanosecond half-life.

    “The special location of the retinol hydroxyl group with respect to the conjugated polyene chain makes it a much better leaving group than is typical for regular aliphatic alcohols. Upon dissociation, the resulting retinylic cation is stabilized by extensive delocalization along the polyene chain with a half-life on the nanosecond time scale.169,171”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [169] Pienta N. J., 1992, J. Am. Chem. Soc. source
    • cites [171] McBee J. K., 2000, Biochemistry source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Photolysis of dilute ethanolic all-trans-retinal produces about 50% cis-retinals, with 11-cis-retinal representing 25%.

    “In contrast, early work by Wald indicated that photolysis of dilute ethanolic solutions of all-trans-retinal resulted in the formation of about 50% cis-retinals, with an exceptionally high contribution of 11-cis-retinal representing 25% of the mixture.182−184”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [182] Hubbard R., 1952, J. Gen. Physiol. source

      The Retinene Isomerate section (pp. 283–284) describes irradiating all-trans retinene in ethyl alcohol and reports about 50% active isomers at 0.1 mg/ml. It does not identify that figure as the total cis-retinal fraction or report that 11-cis-retinal makes up 25% of the mixture; the authors say their isomer names are arbitrary pending determination of their configurations (p. 283). (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [183] Kropf A., 1970, Photochem. Photobiol. source
    • cites [184] Brown P. K., 1956, J. Biol. Chem. source

  • May combine two claims.

    Premisecitation

    11-cis-retinal is produced in the RPE and delivered to photoreceptors.

    “The photosensitive active retinoid, 11-cis-retinal, is produced in the RPE and delivered to the photoreceptors.”
    Quote in the paperNot a substantial claim4 of 10 sources checked
    • cites [59] McBee J. K., 2001, Prog. Retinal Eye Res. source
    • cites [64] Travis G. H., 2007, Annu. Rev. Pharmacol. Toxicol. source
    • cites [68] Parker R. O., 2010, Exp. Eye Res. source
    • cites [69] Tang P. H., 2013, Prog. Retinal Eye Res. source
    • cites [71] Lamb T. D., 2004, Prog. Retinal Eye Res. source
    • cites [83] von Lintig J., 2010, Trends Biochem. Sci. source
    • cites [278] Kuksa V., 2003, Vision Res. source
    • cites [279] Rozanowska M., 2005, Photochem. Photobiol. source
    • cites [284] Kiser P. D., 2010, Prog. Retinal Eye Res. source
    • cites [285] Saari J. C., 2012, Annu. Rev. Nutr. source

  • May combine two claims.

    Premisecitation

    LRAT catalyzes formation of retinyl esters that are sequestered into retinosomes, shifting the mass action ratio to favor retinoid uptake from photoreceptors and the choroidal circulation.

    “LRAT, through its ability to catalyze the formation of retinyl esters that are readily sequestered by aggregation into lipid droplets called retinosomes, changes the mass action ratio to favor retinoid uptake from both photoreceptors and the choroidal circulation.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [278] Kuksa V., 2003, Vision Res. source
    • cites [282] Imanishi Y., 2004, J. Cell Biol. source

      In “Formation and utilization of retinosomes in transgenic mice” (page unavailable), the paper says LRAT esterifies all-trans-retinol and is poised to trap it as retinyl esters; it also describes ester clustering in retinosomes. Figure 3 shows retinol entering RPE from the interphotoreceptor space or choroidal circulation. The paper does not state that sequestration changes a mass-action ratio to favor uptake, and it presents clustering as a proposed mechanism rather than an established one. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [283] Imanishi Y., 2007, Biochemistry source

      The Abstract (page not given) says LRAT esterifies retinol arriving from photoreceptors and the choroidal circulation, and that retinyl esters accumulate in retinosomes. It suggests that esterification may trap photoreceptor-derived retinol in the RPE, but does not state that aggregation into lipid droplets changes the mass-action ratio to favor uptake from both sources. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Retinols and retinyl esters, but not retinals, are intrinsically fluorescent, so their transformation can be followed by two-photon excitation.

    “Because retinols and retinyl esters (but not retinals) are intrinsically fluorescent, their transformation can be followed by fluorescence induced by two-photon excitation.”
    Quote in the paperNot a substantial claim6 of 8 sources checked
    • cites [278] Kuksa V., 2003, Vision Res. source
    • cites [282] Imanishi Y., 2004, J. Cell Biol. source

      The section on retinosome imaging (page unavailable) describes intrinsic vitamin A fluorescence used with two-photon microscopy and identifies retinosome fluorescence with retinyl esters. The Conclusions (page unavailable) say the method monitors regeneration without external fluorophores. Our copy does not state that retinals are nonfluorescent, so it does not support that exclusion. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [283] Imanishi Y., 2007, Biochemistry source

      The passages labeled Abstract (no page supplied) identify retinol and retinyl esters as endogenous fluorophores and describe using two-photon excitation to follow retinol processing and retinyl-ester accumulation. They do not state that retinals are nonfluorescent, so that exclusion is unsupported by our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [289] Imanishi Y., 2010, Methods Mol. Biol. source

      The Introduction states that retinols and retinyl esters are intrinsically fluorescent and describes using two-photon microscopy to monitor retinyl ester dynamics and trafficking. It does not state that retinals are not intrinsically fluorescent, so the parenthetical exclusion is unsupported by our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [290] Imanishi Y., 2008, J. Biol. Chem. source

      The section on aggregation of newly synthesized all-trans-retinyl esters (page unavailable) says two-photon microscopy monitored changes in retinyl ester fluorescence after light exposure. Our copy does not establish that retinols are intrinsically fluorescent or that retinals are not; searches for those fluorescence properties found no such passage. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [291] Imanishi Y., 2004, J. Cell Biol. source
    • cites [292] Wu Q., 2006, Biophys. J. source
    • cites [293] Koutalos Y., 2010, Methods Mol. Biol. source

      The Introduction states that retinol fluorescence can be excited with two-photon light, and describes the conversion of retinol to retinyl ester. It does not say that retinyl esters fluoresce, that retinals do not, or that the transformation can be followed by two-photon fluorescence. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The RPE expresses key metabolic enzymes needed to produce 11-cis-retinal and is an integral part of the retinoid cycle.

    “the RPE expresses key metabolic enzymes required for production of the visual chromophore, 11-cis-retinal, and thus comprises an integral part of the retinoid cycle.”
    Quote in the paperNot a substantial claim3 of 10 sources checked
    • cites [59] McBee J. K., 2001, Prog. Retinal Eye Res. source
    • cites [63] Moise A. R., 2005, Trends Plant Sci. source
    • cites [64] Travis G. H., 2007, Annu. Rev. Pharmacol. Toxicol. source
    • cites [65] Palczewski K., 2010, Trends Pharmacol. Sci. source
    • cites [68] Parker R. O., 2010, Exp. Eye Res. source
    • cites [69] Tang P. H., 2013, Prog. Retinal Eye Res. source
    • cites [71] Lamb T. D., 2004, Prog. Retinal Eye Res. source
    • cites [72] Rando R. R., 1991, Biochemistry source
    • cites [73] Pepperberg D. R., 1993, Mol. Neurobiol. source
    • cites [74] Wolf G., 2002, Nutr. Rev. source

  • May combine two claims.

    Premisecitation

    Postmitotic rod and cone photoreceptors undergo daily renewal in which about 10% of outer segment volume is shed, phagocytosed by adjacent RPE cells, and replaced by new outer segments.

    “postmitotic rod and cone photoreceptor cells undergo a daily regeneration process wherein ∼10% of their OS volume is shed, subsequently phagocytosed by adjacent RPE cells268 and replaced with newly formed outer segments.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [268] Kevany B. M., 2010, Physiology (Bethesda) source

  • May combine two claims.

    Premisecitation

    The opsin binding pocket modulates the photosensitivity of the 11-cis-retinylidene chromophore, producing visual pigments with different wavelength maxima and enabling color discrimination.

    “The extreme photosensitivity of the 11-cis-retinylidene chromophore is modulated by the chemical environment of the opsin chromophore binding pocket, yielding different visual pigments that respond maximally to light at different wavelengths, causing the so-called “opsin shift” that allows us to discern differences in color.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [235] Mustafi D., 2009, Prog. Retinal Eye Res. source
    • cites [248] Nakanishi K., 1980, J. Am. Chem. Soc. source

  • May combine two claims.

    Premisecitation

    DES-1 produces mainly 9-cis- and 13-cis-retinoids rather than 11-cis-retinoids from all-trans-retinol, which is unexpected given the abundance of 11-cis-retinoids in chicken retina.

    “DES-1 produces mainly 9-cis- and 13-cis-retinoids rather than 11-cis-retinoids from all-trans-retinol, which is unexpected given the abundance of 11-cis-retinoids in the chicken retina.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [308] Kaylor J. J., 2013, Nat. Chem. Biol. source

  • May combine two claims.

    Premisecitation

    Rhodopsin is the main protein of ROS disk and plasma membranes, making up 90% and 75% of their protein content respectively.

    “Rhodopsin is the main component of disk and plasma membranes of ROS, accounting for 90 and 75% of their protein content.”
    Quote in the paperNot a substantial claim4 of 10 sources checked
    • cites [61] Filipek S., 2003, Annu. Rev. Physiol. source
    • cites [66] Palczewski K., 2012, J. Biol. Chem. source
    • cites [79] Hofmann K. P., 2009, Trends Biochem. Sci. source
    • cites [225] Menon S. T., 2001, Physiol. Rev. source
    • cites [226] Sakmar T. P., 2002, Annu. Rev. Biophys. Biomol. Struct. source
    • cites [235] Mustafi D., 2009, Prog. Retinal Eye Res. source

      Section 2.2 states that rhodopsin comprises approximately 90% of the protein in rod disc membranes. It does not give the claimed 75% figure for rod outer-segment plasma membranes (page not provided). (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [321] Farrens D. L., 2010, Photochem. Photobiol. Sci. source

      The Abstract identifies rhodopsin as a photoreceptor membrane protein, while the ‘Helix 6 in rhodopsin moves upon light activation’ section discusses structural changes rather than ROS membrane composition (page numbers unavailable). Searches for disk and plasma membranes and for the 90% and 75% figures found no passage stating rhodopsin’s share of their protein content. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [322] Park P. S., 2008, Annu. Rev. Pharmacol. Toxicol. source

      The ‘Oligomerization of GPCRs’ passage (page unavailable) describes a highly concentrated distribution of rhodopsin in rod outer-segment disc membranes, supporting its abundance there. It does not give the claimed 90% figure or address rhodopsin’s share of plasma-membrane protein, including the claimed 75%. (LLM, conf=0.77)

      Experimental — accuracy not yet measured
    • cites [323] Ridge K. D., 2007, J. Biol. Chem. source
    • cites [324] Vogel R., 2007, Photochem. Photobiol. source

      The Introduction (page unavailable) identifies rhodopsin as a rod-cell visual pigment and describes experiments in native disk membranes. It does not state that rhodopsin is the main protein of either disk or plasma membranes, or give the claimed 90% and 75% figures. Searches for those percentages and for rod outer segment membrane abundance found no supporting passage. (LLM, conf=0.73)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Retinosomes lie close to the RPE plasma membrane and are essential for 11-cis-retinal production.

    “Retinosomes are located close to the RPE plasma membrane and are essential components for 11-cis-retinal production.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [282] Imanishi Y., 2004, J. Cell Biol. source

      Figure 1 in the section on retinoid compartmentalization places retinosomes close to the RPE plasma membrane, and Figure 3 in the transgenic-mice section says their retinyl esters are used to produce 11-cis-retinal. The latter section says retinosomes *appear* to be essential for retaining esterified vitamin A to support chromophore formation; the claim states their necessity without that qualification. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [312] Orban T., 2011, J. Biol. Chem. source

      The paper reports that retinosomes lie close to the RPE plasma membrane, and its imaging results describe them near cell plasma membranes. It says several lines of evidence *suggest* they are essential for 11-cis-retinal regeneration; the citing sentence presents that proposed role as established fact (Abstract and TPM imaging section; page not provided). (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [313] Palczewska G., 2010, Nat. Med. source

  • May combine two claims.

    Interpretationcitation

    The molecular envelope accommodated two rhodopsin molecules and one transducin heterotrimer, indicating that the photoactivated rhodopsin-transducin complex is a heteropentamer.

    “The determined molecular envelope accommodated two rhodopsin molecules together with one transducin heterotrimer, indicating a heteropentameric structure for the photoactivated rhodopsin–transducin complex.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [334] Jastrzebska B., 2011, J. Struct. Biol. source

  • May combine two claims.

    Premisecitation

    The RPE also accumulates retinal condensation products, which can be detected by TPM and monitored independently from other retinoids because of their unique spectral properties.

    “The RPE also accumulates other retinoids, including retinal condensation products.314,315 These metabolites also can be detected by TPM, and since they are characterized by unique spectral properties, the intracellular accumulation and distribution of these compounds can be monitored independently from other retinoids”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [314] Sparrow J. R., 2010, J. Lipid Res. source

      The sections on RPE lipofuscin and the all-trans-retinal dimer series describe retinal condensation products accumulating in RPE. “Spectroscopic properties” reports their absorbance and fluorescence characteristics. The passages do not establish that TPM detects these compounds or can monitor their intracellular distribution independently of other retinoids (page numbers unavailable). (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [315] Sparrow J. R., 2012, Adv. Exp. Med. Biol. source

      The All-Trans-Retinal Dimer Series section (page unavailable) describes retinal condensation products in RPE lipofuscin and gives their distinct absorbance wavelengths. The paper does not establish that TPM detects them or that their intracellular accumulation and distribution can be monitored independently from other retinoids. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [313] Palczewska G., 2010, Nat. Med. source

  • May combine two claims.

    Premisecitation

    The minimal building block of rhodopsin is a dimer in which only one monomer is activated under normal lighting conditions.

    “Physiologically, the minimal building block of rhodopsin is a dimer in which only one monomer is activated under normal lighting conditions”
    Quote in the paperNot a substantial claim4 of 6 sources checked
    • cites [330] Fotiadis D., 2003, Nature source
    • cites [331] Vahedi-Faridi A., 2013, J. Electron Microsc. (Tokyo) source

      The Materials and methods section reports rhodopsin arranged in rows of dimers in native disk membranes and describes a rhodopsin dimer in the rhodopsin–transducin complex. It does not establish that the dimer is the physiological minimal building block or that only one monomer is activated under normal lighting conditions. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [332] Jastrzebska B., 2013, FASEB J. source

      The Discussion (page unavailable) says rhodopsin forms dimers in native membranes and that, in the studied light-activated rhodopsin–transducin complex, only one monomer is stabilized in the active Meta II state. It does not establish that only one monomer is activated under normal lighting conditions; it says the physiological role of the asymmetry remains unclear. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [333] Orban T., 2012, Structure source

      The Discussion (page unavailable) says GPCR oligomerization warrants considering at least a dimer and that a single photoactivated rhodopsin can activate transducin. It does not establish that a dimer is rhodopsin’s physiological minimal building block or that only one monomer in each dimer is activated under normal lighting conditions. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [334] Jastrzebska B., 2011, J. Struct. Biol. source

      The Introduction (page not provided) describes rhodopsin dimers in native membranes and a proposed Rho*–Rho functional unit. The Results and Discussion (page not provided) support a complex containing two rhodopsin molecules and one transducin, but do not establish that only one monomer is activated under normal lighting conditions. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [335] Jastrzebska B., 2004, J. Biol. Chem. source

  • May combine two claims.

    Premisecitation

    Rhodopsin activation involves geometric cis/trans isomerization of the chromophore, deprotonation of the Schiff linkage, and reorganization of water molecules within the transmembrane domain.

    “This activation is accomplished through geometric cis/trans isomerization of the chromophore,182 deprotonation of the Schiff linkage,339 and reorganization of water molecules within the TMD of this receptor.”
    Quote in the paperNot a substantial claim5 of 6 sources checked
    • cites [182] Hubbard R., 1952, J. Gen. Physiol. source
    • cites [339] Wald G., 1957, J. Gen. Physiol. source

      The Summary (p. 633) identifies the retinal precursor as an 11-cis isomer, and Fig. 3 (p. 631) describes its light-induced isomerization. But that experiment uses retinene in solution; the paper does not establish that chromophore isomerization activates rhodopsin. The Schiff-linkage and water-molecule clauses carry separate citations and are not judged here. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [333] Orban T., 2012, Structure source

      Citation 339 follows the claim about deprotonation of the Schiff linkage. The Introduction describes retinal cis-to-trans isomerization, and the Discussion addresses internal water during activation, but no passage in our copy states that the Schiff linkage deprotonates (searched: Schiff, Schiff base deprotonation, protonated Schiff base). (LLM, conf=0.73)

      Experimental — accuracy not yet measured
    • cites [340] Angel T. E., 2009, Proc. Natl. Acad. Sci. U.S.A. source
    • cites [341] Angel T. E., 2009, Proc. Natl. Acad. Sci. U.S.A. source

      The paper reports activation-dependent changes in bound waters in the transmembrane region and suggests that water reorganization helps transmit the activation signal. The citing sentence attributes this source to the water-reorganization component, but states its mechanistic role as established, whereas the paper presents that role as a proposed explanation. The cis/trans isomerization and Schiff-linkage clauses have separate citations. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [342] Orban T., 2010, Biochemistry source

  • May combine two claims.

    Premisecitation

    Noninvasive TPM showed that retinosomes are elongated structures about 8 μm long and 1 μm wide, with their long axis perpendicular to the RPE basal surface.

    “noninvasive TPM revealed that retinosomes are elongated structures approximately 8 μm long and 1 μm wide with their long axis oriented perpendicularly to the RPE basal surface”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [291] Imanishi Y., 2004, J. Cell Biol. source

      The Results section (“Identification of retinyl ester storage particles in wild-type RPE”; page unavailable) reports that two-photon microscopy showed elongated structures perpendicular to the RPE cell layer, with a diameter of 0.8 ± 0.2 μm. It gives their length as 6.9 ± 1.1 μm, rather than approximately 8 μm; the claim also substitutes “RPE basal surface” for the paper’s “cell layer.” (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    CRALBP is expressed in Müller cells, which supports the hypothesis that Müller cells produce visual chromophore.

    “the 11-cis-retinol-binding protein, cellular retinaldehyde-binding protein (CRALBP), is known to be expressed in Müller cells, providing additional support for the above hypothesis.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [306] Bok D., 1984, Invest. Ophthalmol. Vis. Sci.
    • cites [307] Fleisch V. C., 2008, J. Neurosci. source

  • May combine two claims.

    Premisecitation

    Condensation products increase with age because they are delivered from photoreceptors by daily phagocytosis, with at least the first steps occurring in ROS.

    “They also increase with age because they are delivered from photoreceptors (at least the first steps of condensation reaction occur in ROS) by daily phagocytosis.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [270] Sparrow J. R., 2012, Prog. Retinal Eye Res. source
    • cites [314] Sparrow J. R., 2010, J. Lipid Res. source

  • May combine two claims.

    Premisecitation

    RDH8 localizes to ROS/COS; its transport there is mediated by a C-terminal signaling sequence, and its membrane anchoring is achieved by fatty acylation of conserved Cys residues.

    “An interesting case is RDH8, which localizes to ROS/COS. Efficient transport to the ROS/COS is mediated by a signaling sequence at the C-terminus of this enzyme whereas membrane anchoring is achieved by fatty acylation of conserved Cys residues.389”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [389] Luo W., 2004, J. Neurosci. source

  • May combine two claims.

    Premisecitation

    In SDR catalysis, the deprotonated Tyr phenolic group hydrogen bonds to the alcohol hydroxyl and acts as a base to remove a proton from the substrate hydroxyl.

    “Here, the deprotonated phenolic group of Tyr initially forms a hydrogen bond with the alcohol hydroxyl group and the deprotonated Tyr residue acts as a catalytic base to extract a proton from the substrate’s hydroxyl group.”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [378] Chang Y. H., 2007, J. Biol. Chem. source

      The Discussion (page not available) describes Tyr155 deprotonating to a tyrosinate anion and abstracting a proton from androsterone’s 3-hydroxyl group. Our copy does not state that the deprotonated Tyr initially forms a hydrogen bond with the substrate hydroxyl, so that specific step is not supported. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [379] Ensor C. M., 1991, Biochem. Biophys. Res. Commun. source
    • cites [380] Obeid J., 1992, Biochem. Biophys. Res. Commun. source

      The Results (page unavailable) propose that Tyr-179’s deprotonated phenolic group may remove a proton from the steroid’s hydroxyl group. They do not describe an initial hydrogen bond, and they present proton removal as a possible mechanism rather than an established step of SDR catalysis. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [381] Kavanagh K. L., 2008, Cell. Mol. Life Sci. source

      The Structural and mechanistic aspects of SDR enzymes section describes a hydroxyl-tyrosinate ion that abstracts a proton from the substrate, supporting Tyr’s catalytic-base role. It does not specify that Tyr initially hydrogen-bonds to the alcohol hydroxyl; the section also notes that some SDRs use distinct mechanisms. Page numbers are unavailable in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    All-trans-retinyl ester is not easily accommodated in the RPE65 active site, whereas 11-cis- and 13-cis-retinyl esters are.

    “all-trans-retinyl ester could not easily be accommodated in the RPE65 active site whereas 11-cis- and 13-cis-retinyl esters could.467”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [467] Chander P., 2012, J. Biol. Chem. source

      The paper’s docking simulations support this comparison for the relatively closed RPE65 substrate cleft (p. 1). The claim omits that condition: the Discussion (p. 7) proposes that all-trans-retinyl ester enters an open conformation before the cleft closes. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    LRAT is a 25 kDa bitopic integral ER membrane protein with a single C-terminal membrane-spanning helix and a potential membrane-interacting N-terminal domain.

    “Localized in the endoplasmic reticulum (ER), LRAT is a 25 kDa bitopic integral membrane protein with a single membrane-spanning helix localized at the C-terminus406 and a potential membrane-interacting N-terminal domain.407”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [406] Moise A. R., 2007, J. Biol. Chem. source

      The ER-localization section (page unavailable) supports a single C-terminal membrane-spanning helix and an N-terminal domain that faces the cytoplasm. Figure 1 describes the N-terminal region as hydrophobic, but the paper does not establish that it interacts with the membrane; a later section says it is not involved in membrane anchoring. The 25 kDa description is attached to a different citation in the citing sentence. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [407] Bussieres S., 2012, Langmuir source

  • May combine two claims.

    Premisecitation

    Under physiological conditions the NAD/NADH ratio is near 1000, so RDHs binding this cofactor mainly contribute to retinol oxidation.

    “Under physiological conditions the ratio between NAD/NADH is close to 1000;287 thus, RDH’s that bind this cofactor can contribute significantly only to retinol oxidation.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [287] Kiser P. D., 2012, Biochim. Biophys. Acta source

      The citation is attached to the physiological NAD/NADH ratio of approximately 1000. Section 3 (Retinol dehydrogenases) discusses NAD-dependent reactions and retinol oxidation, but neither the supplied passages nor searches for the ratio and its proposed effect found a physiological NAD/NADH value in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    ARAT may contribute to intestinal retinyl ester formation and thereby facilitate retinoid uptake and packaging into chylomicrons.

    “On the basis of this evidence, ARAT may contribute to retinyl ester formation within the intestine and thus facilitate retinoid uptake and packaging into chylomicrons.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [402] O’Byrne S. M., 2005, J. Biol. Chem. source

  • May combine two claims.

    Premisecitation

    HRASLS proteins cannot use all-trans-retinol as an acyl acceptor and lack specificity for the sn-1 ester cleavage site; instead they catalyze lipid hydrolysis and acyl transfer onto enzyme-specific substrates such as lyso-phospholipids or phosphatidylethanolamine.

    “Importantly, despite their highly conserved catalytic domains, HRASLS proteins cannot employ all-trans-retinol as an acyl acceptor and they lack specificity toward the sn-1 ester cleavage site as well.411 Instead, they catalyze both lipid hydrolysis and acyl transfer onto a variety of enzyme-specific substrates, such as lyso-phospholipids or phosphatidylethanolamine (PE).411,419−422”
    Quote in the paperNot a substantial claim1 of 5 sources checked
    • cites [411] Golczak M., 2012, J. Biol. Chem. source
    • cites [419] Jin X. H., 2007, J. Biol. Chem. source
    • cites [420] Shinohara N., 2011, J. Lipid Res. source
    • cites [421] Uyama T., 2009, Biochim. Biophys. Acta source
    • cites [422] Uyama T., 2009, J. Lipid Res. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    LRAT is the main enzyme for retinyl ester formation in most tissues, except adipocytes, which use acyl-CoA-dependent ARAT activity from an unidentified protein.

    “LRAT is the main enzyme that catalyzes retinyl ester formation in most tissues,147,402,403 with the exception being adipocytes that instead exhibit acyl-CoA-dependent transferase activity of a protein (acyl-CoA:retinol acyltransferase or ARAT) yet to be identified.404”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [147] Batten M. L., 2004, J. Biol. Chem. source
    • cites [402] O’Byrne S. M., 2005, J. Biol. Chem. source

      The Discussion (page unavailable) says LRAT is the most physiologically significant enzyme for retinyl ester synthesis and that ARAT activity can occur in adipose tissue. But it also identifies intestine and mammary tissue as sites of alternative activity, and proposes the named enzyme DGAT1 as a likely physiologically significant ARAT. Thus the claim overstates adipocytes as the exception and omits the paper’s DGAT1 candidate, although its identity in vivo was not established. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [403] Liu L., 2005, J. Biol. Chem. source

  • May combine two claims.

    Premisecitation

    Isotopically labeled retinol substrates showed stereochemical inversion at carbon 15 and loss of the 15-hydroxy oxygen, replaced by water-derived oxygen during isomerization.

    “It was found that a stereochemical inversion of carbon 15 occurs477,478 and that the 15-hydroxy oxygen is lost171 and replaced by bulk water-derived oxygen during the isomerization.452”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [477] Law W. C., 1988, Biochemistry source
    • cites [478] Jang G. F., 2000, J. Biol. Chem. source
    • cites [171] McBee J. K., 2000, Biochemistry source

      The Results report that cis-retinols produced from oxygen-labeled retinol lost or exchanged the oxygen label. The Discussion proposes that elimination of water is followed by hydration to form cis-retinol, supporting water as the replacement source. It does not show that the replacement oxygen was traced experimentally to bulk water; the claim presents that proposed mechanism as a demonstrated finding. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    All vertebrate RDHs can use retinol or retinal, but some have broad substrate specificity and retinoids are not their preferred physiological substrates.

    “Although all RDH’s identified in vertebrates can utilize retinol or retinal, some have wide substrate specificities, and retinoids are not their preferred physiological substrates.374,390”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [374] Duester G., 2000, Eur. J. Biochem. source
    • cites [390] Liden M., 2006, J. Biol. Chem. source

      The introduction (p. 1) says that about 20 identified enzymes display retinol dehydrogenase activity, but cautions that whether all function as RDHs in vivo remains to be determined. “Two Families of Mammalian Retinol Dehydrogenases” (p. 1) says some RDHs also oxidize steroids, while describing broad substrate range chiefly for ADHs. The paper does not establish that retinoids are not the preferred physiological substrates of some vertebrate RDHs. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    CRBP I and CRBP II have about 50% sequence identity depending on species and show differential tissue expression.

    “Two isoforms of the protein, CRBP I and CRBP II with ∼50% sequence identity depending on the species, exhibit differential tissue expression.494”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [494] Noy N., 2000, Biochem. J. source

  • May combine two claims.

    Interpretationcitation

    ATP-dependent transporters such as ABCA4 or the channel-like property of STRA6 could facilitate retinoid transport.

    “But this process could be facilitated by ATP-dependent transporters such as ABCA476,485−487 or the channel-like property of STRA6.488−492”
    Quote in the paperNot a substantial claim5 of 9 sources checked
    • cites [76] Tsybovsky Y., 2010, Adv. Exp. Med. Biol. source
    • cites [485] Molday R. S., 2006, Adv. Exp. Med. Biol. source
    • cites [486] Molday R. S., 2010, Prog. Lipid Res. source
    • cites [487] Molday R. S., 2009, Biochim. Biophys. Acta source
    • cites [488] Kawaguchi R., 2007, Science source
    • cites [489] Isken A., 2008, Cell Metab. source
    • cites [490] Kim Y. K., 2008, J. Biol. Chem. source

      The STRA6 section and Discussion (page unavailable) describe STRA6-mediated retinol uptake and speculate that STRA6 may act as a bidirectional retinol transporter. They support a possible role in retinoid transport, but do not establish the claimed channel-like property. The ABCA4 portion has separate citations in the citing sentence and is not attributed to this paper. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [491] Hu J., 2010, Methods Mol. Biol. source
    • cites [492] Amengual J., 2012, J. Biol. Chem. source

      The Discussion (p. 7) describes STRA6 as a receptor that facilitates retinol uptake, supporting its proposed role in transport. The cited paper does not describe STRA6 as channel-like. The ABCA4 clause has separate citations and is not attributed to this source. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CRALBP is a founding member of the CRAL-TRIO protein family, whose members share a common three-dimensional architecture.

    “CRALBP is one of the founding members of the CRAL-TRIO protein family, members of which share a common three-dimensional architecture.505−507”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [505] Punta M., 2012, Nucleic Acids Res. source

      The Introduction and Concluding Remarks (pages unavailable) describe Pfam families generally and say homologous proteins are more likely to share structural features. Searches for CRALBP and CRAL-TRIO found no passage identifying CRALBP as a founding member or describing that family's three-dimensional architecture. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [506] Sha B., 1998, Nature source
    • cites [507] He X. Q., 2009, Proc. Natl. Acad. Sci. U.S.A. source

      The paper says CRALBP contains conserved CRAL-TRIO domains (introductory text, page unavailable) and describes its prototypical SEC14-like structure and structural similarity to another family member (Results and Discussion, page unavailable). This supports the shared-architecture point, but our copy does not identify CRALBP as a founding member of the family. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Retinoids are readily oxidized and isomerized.

    “Finally retinoids are readily oxidized and isomerized; thus, a set of binding proteins evolved to protect them from these undesirable reactions as well as defend surrounding molecules from retinoid (photo)reactivity.59,73,171,279,285”
    Quote in the paperSubstantial claim1 of 5 sources checked
    • cites [59] McBee J. K., 2001, Prog. Retinal Eye Res. source
    • cites [73] Pepperberg D. R., 1993, Mol. Neurobiol. source
    • cites [171] McBee J. K., 2000, Biochemistry source

      The Abstract describes enzymatic isomerization of retinol and oxidation of 11-cis-retinol to 11-cis-retinal. The Results also report that all-trans-retinol is unstable under acid treatment. These passages support that retinoids can undergo both reactions, but they do not establish that retinoids generally undergo oxidation and isomerization readily. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [279] Rozanowska M., 2005, Photochem. Photobiol. source
    • cites [285] Saari J. C., 2012, Annu. Rev. Nutr. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Holo-RBP4 has an eight-stranded β-barrel core containing a single retinol-binding site.

    “The main structural feature of holo-RBP4, determined crystallographically in the early 1980s, is an eight-stranded β-barrel core containing a single retinol-binding site (Figure 32).495”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [495] Newcomer M. E., 1984, EMBO J. source

  • May combine two claims.

    Premisecitation

    CRBP I is expressed in many tissues including the eye, whereas CRBP II expression is restricted to the intestine.

    “CRBP I is expressed in many tissues, including the eye, whereas CRBP II expression is restricted to the intestine.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [494] Noy N., 2000, Biochem. J. source

      The Functions of CRBPs section says CRBP-I is expressed in multiple tissues, including pigment epithelium cells in the eye. It says CRBP-II is restricted to the small intestine in adults, but also reports transient expression in the fetal liver and expression in the yolk sac. The claim omits that developmental qualification. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Retinol orientation in the CRBP pocket is reversed relative to holo-RBP4, with β-ionone near the pocket mouth and the hydroxyl group hydrogen bonding to a Glu residue at the cavity base.

    “However, the orientation of retinol in the binding pocket is reversed in relation to that in holo-RBP4 with the β-ionone nearest the mouth of the pocket and the hydroxyl group hydrogen bonding with a Glu residue at the base of the cavity.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [495] Newcomer M. E., 1984, EMBO J. source

      The Results and Discussion (page unavailable) place the β-ionone ring deepest in RBP’s pocket and the isoprene tail near the protein surface, supporting the RBP side of the comparison. The paper does not describe retinol’s orientation in CRBP or a hydroxyl-group hydrogen bond to Glu at the cavity base. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationreasoning

    A set of binding proteins evolved to protect retinoids from oxidation and isomerization and to protect surrounding molecules from retinoid reactivity.

    “thus, a set of binding proteins evolved to protect them from these undesirable reactions as well as defend surrounding molecules from retinoid (photo)reactivity.59,73,171,279,285”
    Quote in the paperSubstantial claim1 of 5 sources checked
    • cites [59] McBee J. K., 2001, Prog. Retinal Eye Res. source
    • cites [73] Pepperberg D. R., 1993, Mol. Neurobiol. source
    • cites [171] McBee J. K., 2000, Biochemistry source

      The Results and Discussion (page unavailable) show that retinoid-binding proteins affect which retinol isomers are produced, but do not say they evolved to protect retinoids from oxidation or unwanted isomerization. Searches for protective effects and retinoid (photo)reactivity found no passage saying the proteins shield surrounding molecules. (LLM, conf=0.73)

      Experimental — accuracy not yet measured
    • cites [279] Rozanowska M., 2005, Photochem. Photobiol. source
    • cites [285] Saari J. C., 2012, Annu. Rev. Nutr. source

  • May combine two claims.

    Premisecitation

    All-trans-retinol is oriented in the RBP4 binding pocket with its hydroxyl group facing solvent and its retinyl moiety bound by nonpolar residues, explaining high specificity for the all-trans isomer.

    “all-trans-Retinol is oriented in the binding pocket with its hydroxyl group facing the solvent and the retinyl moiety snuggly bound by a number of nonpolar residues in a highly complementary fashion, explaining the high binding specificity toward the all-trans isomer.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [495] Newcomer M. E., 1984, EMBO J. source

      The Results and Discussion describe all-trans-retinol in a complementary pocket lined by hydrophobic or uncharged residues, with its ionone ring deepest and its tail extending toward the protein surface. But they say retinol is essentially inaccessible to water, not that its hydroxyl group faces solvent. They also do not establish high specificity for the all-trans isomer; instead, they note that RBP may bind various retinyl derivatives. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    IRBP binds several isomeric forms of retinol and retinal but prefers all-trans and 11-cis-retinoids.

    “The protein can also bind several isomeric forms of retinol and retinal but has a preference for all-trans and 11-cis-retinoids.510,511”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [510] Shaw N. S., 2001, Exp. Eye Res. source
    • cites [511] Gonzalez-Fernandez F., 2007, BMC Biochem. source

      The Results section (pages not provided), particularly Table 3, shows that Xenopus IRBP binds all-trans retinol and 11-cis retinaldehyde. It does not establish binding to several isomeric forms of both retinol and retinal or a preference for those retinoids over other isomers; the reported selectivity is limited to module 2's preference for all-trans retinol over 11-cis retinaldehyde. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    CRALBP is expressed predominantly in RPE and Müller glial cells and plays a key role in visual chromophore regeneration by binding 11-cis-retinoids, protecting them from esterification or isomerization, and facilitating intracellular transport.

    “CRALBP is expressed predominantly in two retinal locations, the RPE and Müller glial cells, where it plays a key role in visual chromophore regeneration by binding 11-cis-retinoids, protecting them from esterification or from photo- or thermal isomerization and facilitating their intracellular transport.476,500,501”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [476] Stecher H., 1999, J. Biol. Chem. source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [500] Futterman S., 1977, Invest. Ophthalmol. Vis. Sci.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [501] Bunt-Milam A. H., 1983, J. Cell Biol. source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Newly liberated all-trans-retinal is reduced to all-trans-retinol by all-trans-RDHs, mainly RDH8 in mouse retina, which associate with the cytoplasmic side of the disk bilayer.

    “The next step in the visual cycle is reduction of newly liberated all-trans-retinal to all-trans-retinol by all-trans-RDHs (mainly RDH8 in mouse retina), which associate with the cytoplasmic side of the disk bilayer.64,400”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [64] Travis G. H., 2007, Annu. Rev. Pharmacol. Toxicol. source
    • cites [400] Maeda A., 2007, Proc. Natl. Acad. Sci. U.S.A. source

      The Results report that RDH8 was the main contributor to all-trans-RDH activity in mouse retina, and the paper describes these enzymes reducing all-trans-retinal to all-trans-retinol. The Discussion places RDH8 in photoreceptor outer segments, but our copy does not specify that the enzymes associate with the cytoplasmic side of the disk bilayer. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Study design and conductcitation

    The overall topological model for ABCA4 is supported by glycosylation sites in both ECD domains and phosphorylation sites in CD1.

    “The overall topological model for ABCA4 is supported by multiple glycosylation sites identified in both ECD domains, whereas CD1 hosts multiple phosphorylation sites.76,521,522”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [76] Tsybovsky Y., 2010, Adv. Exp. Med. Biol. source

      Section 4.3 says glycosylation studies support the placement of both exocytoplasmic domains, and section 4.4 reports eight glycosylation sites across those domains. But section 4.3 describes ABCA4 phosphorylation only as a possibility needing further study; it does not identify multiple phosphorylation sites in CD1. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [521] Tsybovsky Y., 2011, Biochemistry source
    • cites [522] Bungert S., 2001, J. Biol. Chem. source

      The Discussion reports four N-linked glycosylation sites in each of ABCR’s two ECD domains and says this organization supports the topological model (page unavailable in our copy). It does not report multiple phosphorylation sites in CD1; searches for CD1 phosphorylation and related terms found no supporting passage. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Lipofuscin granules contain several chromophores absorbing UV, blue, and green light, while A2E accepts energy from their photoexcited states and dissipates it mainly by thermal deactivation and partly by fluorescence.

    “Lipofuscin granules contain several chromophores absorbing UV, blue, and green light whereas A2E acts as an acceptor of energy from their photoexcited states and dissipates that energy mainly by thermal deactivation and partly by emitting fluorescence.544”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [544] Haralampus-Grynaviski N. M., 2003, Proc. Natl. Acad. Sci. U.S.A. source

      The Abstract reports several blue-absorbing chromophores and a low fluorescence quantum yield for A2E. Results and Discussion says A2E becomes excited largely by energy transfer and contributes to lipofuscin fluorescence. The passages do not establish several chromophores absorbing UV and green light or identify thermal deactivation as A2E’s main route of energy dissipation; page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Protonated N-ret-PE is the common precursor in biosynthesis of these fluorophores and undergoes spontaneous tautomerization via an H-shift [1,6] to generate phosphatidyl analogs of enamine.

    “The common precursor in the biosynthesis of these fluorophores is protonated N-ret-PE, that undergoes spontaneous tautomerization via an H-shift [1,6] generating phosphatidyl analogs of enamine.536,537”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [536] Ben-Shabat S., 2002, J. Biol. Chem. source
    • cites [537] Kaufman Y., 2011, J. Biol. Chem. source

      The Discussion (page not available) describes a retinaldehyde–phosphatidylethanolamine Schiff base as a precursor to A2E and ATR-dimer and says it can form enamines. It does not specify a protonated precursor or establish spontaneous tautomerization: it proposes either a (1,5) hydrogen shift or deprotonation, not the claimed [1,6] shift. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Human ABCA4 is an integral membrane protein of 2273 residues forming two homologous but nonidentical parts, each with six membrane-spanning helices, a cytoplasmic domain containing a nucleotide-binding site with Walker A and B motifs, and an exocytoplasmic domain.

    “Human ABCA4 is an integral membrane protein with 2273 residues that form two homologous but nonidentical parts. Each carries six membrane-spanning helices that constitute a TMD, a soluble cytoplasmic domain (CD) that hosts a canonical nucleotide-binding site (NBD) with Walker A and Walker B motifs characteristic of ATP-processing enzymes, and an exocytoplasmic (intradiscal) domain (ECD) (Figure 33”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [76] Tsybovsky Y., 2010, Adv. Exp. Med. Biol. source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Alternatively, nucleophilic carbon 20 of the N-ret-PE tautomer can react with carbon 13 of all-trans-retinal via [1,4] conjugate addition, and Mannich condensation leads to the RALdi precursor.

    “Alternatively, the nucleophilic carbon 20 of the N-ret-PE tautomer can react with carbon 13 of all-trans-retinal via [1,4] conjugate addition. Consequent Mannich condensation then leads to the RALdi precursor (Figure 35).534”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [534] Fishkin N. E., 2005, Proc. Natl. Acad. Sci. U.S.A. source

  • May combine two claims.

    Findingcitation

    In chloroform/methanol (2:1), N-ret-PE formation has a bimolecular rate constant of about 3.75 × 10-2 M-1 s-1 and its hydrolysis rate is about 7.9 × 10-6 s-1.

    “In a test tube, the formation of N-ret-PE in a mixture of chloroform/methanol (2:1) occurs with a bimolecular rate constant of about 3.75 × 10–2 M–1 s–1 while the rate of its hydrolysis is about 7.9 × 10–6 s–1.528”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [528] Plack P. A., 1969, Biochem. J. source

      Table 1 reports formation and reverse-reaction rate constants for synthetic phosphatidylethanolamine and retinal in chloroform/ethanol (2:1), so it supports the reaction and solvent attributed to the source. Its values for that mixture are 0.161 mM⁻¹ h⁻¹ and 0.0226 h⁻¹—about 4.47 × 10⁻² M⁻¹ s⁻¹ and 6.28 × 10⁻⁶ s⁻¹—not the two rates claimed. The table is in the section headed “25° in the reactions…”; our copy provides no page number. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Retinal samples from Stargardt patients show elevated levels of N-retinylidene-PE and overaccumulation of A2E in the RPE.

    “Consequently, retinal samples collected from these patients revealed elevated levels of N-retinylidene-PE and overaccumulation of A2E in the RPE.529”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [529] Mata N. L., 2000, Proc. Natl. Acad. Sci. U.S.A. source

      The Results section on human FFM and STGD1 tissues (page unavailable) reports elevated A2E in patient RPE compared with controls. It reports elevated retinal phosphatidylethanolamine (PE), not N-retinylidene-PE (APE); the APE comparison in Table 1 concerns mice, not patient samples. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    The formation and hydrolysis of N-ret-PE is reversible and highly dependent on the presence of water.

    “This reversible reaction is highly dependent on the presence of water.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [528] Plack P. A., 1969, Biochem. J. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingcitation

    A2E can be further metabolized by horseradish peroxidase, but there is no evidence that this process occurs in vivo.

    “A2E was shown to be further metabolized by horseradish peroxidase,543 but there is yet no evidence that this process occurs in vivo.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [543] Wu Y., 2011, J. Am. Chem. Soc. source

  • May combine two claims.

    Findingcitation

    All-trans-retinal and its phosphatidylethanolamine conjugate N-ret-PE are preferred substrates for ATP hydrolysis by ABCA4, although numerous lipids stimulate it.

    “Although numerous lipids stimulate ATP hydrolysis by ABCA4, all-trans-retinal or its phosphatidylethanolamine (PE) conjugate, N-retinylidene-PE (N-ret-PE) are the preferred substrates.524,525”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [524] Sun H., 1999, J. Biol. Chem. source

      The Abstract and ‘Kinetic Analysis of ATPase Stimulation’ report that all-trans-retinal stimulates ABCR ATPase and suggest that it is a transport substrate. The paper does not establish N-ret-PE as a preferred substrate. Its ‘Factors Affecting’ section says certain lipids support retinal-stimulated activity as a membrane environment, not that numerous lipids themselves stimulate ATP hydrolysis. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [525] Quazi F., 2012, Nat. Commun. source

      The Discussion (page unavailable) identifies N-retinylidene-PE as an ABCA4 substrate and mentions retinal-stimulated ATPase activity. But it explicitly says N-retinylidene-PE, not free all-trans-retinal, is the true transport substrate; the passages examined also do not establish that numerous lipids stimulate ATP hydrolysis. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Lipofuscin bodies provide a fluorescent marker for quantification in the living eye and can serve as long-lasting evidence of excessive past accumulation of all-trans-retinal.

    “These bodies provide a useful fluorescent marker for lipofuscin quantification in the living eye, which can serve as long-lasting evidence of excessive past accumulation of all-trans-retinal.539−541”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [539] Sparrow J. R., 2003, Vision Res. source

      The Introduction (page unavailable) says RPE lipofuscin produces fundus fluorescence, can be monitored in the living eye, and accumulates because it cannot be enzymatically degraded. Section 2 (page unavailable) links increased availability of all-trans-retinal to formation of a lipofuscin precursor. The paper does not establish that the fluorescence specifically identifies excessive past accumulation of all-trans-retinal, rather than lipofuscin formed through ordinary visual-cycle activity. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [540] Rozanowski B., 2008, Photochem. Photobiol. source
    • cites [541] Rozanowski B., 2008, Invest. Ophthalmol. Vis. Sci. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingcitation

    Retinal G protein-coupled receptor expressed in the RPE provides light-dependent modulation of all-trans-retinyl ester synthesis and degradation and influences RPE65 activity in mice.

    “Despite early work showing that retinal G protein-coupled receptor, expressed in the RPE, provides light-dependent modulation of all-trans-retinyl ester synthesis and degradation as well as influences RPE65 activity in mice,576”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [576] Radu R. A., 2008, J. Biol. Chem. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The structure of RPE65 provided an incentive for obtaining structures of other membrane-associated proteins including LRAT and RDHs.

    “The structure of RPE65452,455 definitely provided an incentive for obtaining structures of other membrane associated proteins including LRAT and RDHs.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [452] Kiser P. D., 2009, Proc. Natl. Acad. Sci. U.S.A. source
    • cites [455] Kiser P. D., 2012, Proc. Natl. Acad. Sci. U.S.A. source

  • May combine two claims.

    Findingcitation

    Retinylamine and other primary amines buffer the toxic effect of all-trans-retinal by inhibiting the visual cycle or by chemically trapping excess all-trans-retinal as a Schiff base when it cannot be cleared by reduction to all-trans-retinol.

    “Retinylamine and other primary amines were employed to buffer the toxic effect of all-trans-retinal either by inhibiting the visual cycle or by chemically trapping an excess of all-trans-retinal in the form of a Schiff base when it could not be effectively cleared from photoreceptor cells by reduction to all-trans-retinol (Figure 36).318,572,573”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [318] Maeda A., 2009, J. Biol. Chem. source

      The Discussion (page not available in our copy) identifies free all-trans-retinal as the cause of acute light-induced retinopathy, and the section on A2E and other condensation products proposes inhibiting its production or removing excess retinal as possible therapies. The paper does not say that retinylamine or other primary amines were employed for this purpose, nor does it describe trapping retinal as a Schiff base when reduction to retinol is insufficient. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [572] Maeda A., 2012, Nat. Chem. Biol. source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [573] Golczak M., 2008, J. Biol. Chem. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Lack of a functional ABCA4 transporter causes Stargardt disease, a juvenile form of macular degeneration, whereas some other changes are associated with AMD.

    “Here, lack of a functional transporter causes Stargardt disease,545,558,559 a juvenial form of macular degeneration, whereas some other changes were demonstrated to be associated with AMD.560,561”
    Quote in the paperNot a substantial claim1 of 5 sources checked
    • cites [545] Allikmets R., 1997, Nat. Genet. source
    • cites [558] Cideciyan A. V., 2009, Hum. Mol. Genet. source

      The Discussion links ABCA4 mutations to Stargardt disease (STGD), but describes a spectrum of disease rather than saying that complete loss of transporter function specifically causes STGD. It associates likely complete loss of function with some of the more severe retinal disease and notes that STGD can progress beyond the macula. The AMD clause has separate citations in the citing sentence, so it is not attributed to this source. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [559] Allikmets R., 1997, Nat. Genet.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [560] Allikmets R., 1999, Eur. J. Ophthalmol. source
    • cites [561] Allikmets R., 2000, Am. J. Hum. Genet. source

  • May combine two claims.

    Findingcitation

    Full-length IRBP observed by negative stain electron microscopy adopts a flexible rod-shaped structure and undergoes major conformational changes in the presence of retinoids.

    “Full-length IRBP, as observed by negative stain electron microscopy, adopts a rod-shaped structure that is flexible and undergoes major conformational changes in the presence of retinoids.513”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [513] Adler A. J., 1987, J. Biol. Chem. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    IRBP can bind nonretinoid hydrophobic ligands.

    “IRBP can also bind a number of nonretinoid, hydrophobic ligands, but the physiological significance of this capability is not currently understood.512”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [512] Gonzalez-Fernandez F., 2008, Exp. Eye Res. source

  • May combine two claims.

    Findingcitation

    CRALBP can effectively bind 9-cis-retinoids but not 13-cis-retinoids.

    “It can also effectively bind 9-cis-retinoids as well but not 13-cis-retinoids.502”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [502] Saari J. C., 1987, J. Biol. Chem. source

  • May combine two claims.

    Findingcitation

    Domain A of the IRBP module adopts a ββα-spiral fold, whereas domain B forms an αβα sandwich.

    “Domain A adopts a ββα-spiral fold whereas domain B forms an αβα sandwich.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [514] Loew A., 2002, Structure source

  • May combine two claims.

    Findingcitation

    CRBP I-/- mice accumulate all-trans-retinol in the retina and form fewer retinyl esters in the RPE.

    “This is evidenced by accumulation of all-trans-retinol in the retina and reduced formation of retinyl esters in the RPE.498”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [498] Saari J. C., 2002, Invest. Ophthalmol. Vis. Sci.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    The crystal structure of an isolated X. laevis IRBP module reveals a two-domain architecture.

    “The crystal structure of an isolated module from X. laevis IRBP has been determined, revealing a two-domain architecture.514”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [514] Loew A., 2002, Structure source

  • May combine two claims.

    Findingreasoning

    Aromatization of the dihydropyridine in A2PE-H2 eliminates two hydrogens to yield A2PE, whereas the RALdi precursor rearranges to eliminate the amino group of PE.

    “Aromatization of the dihydropyridine in A2PE-H2 eliminates two hydrogens to yield phosphatidyl-pyridinium bisretinoid (A2PE) whereas the RALdi precursor spontaneously rearranges to eliminate the amino group of PE (Figures 34 and 35, respectively).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    A2E and its oxidation products can be cytotoxic to RPE cells and trigger complement activation and inflammatory signaling in vitro.

    “Yet, A2E also exhibits some minor photoreactivity and several experiments in vitro demonstrated that A2E and its oxidation products can be cytotoxic to RPE cells and trigger complement activation and inflammatory”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [317] Sparrow J. R., 2003, Adv. Exp. Med. Biol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In higher plants, most cytosolic IPP and DMAPP come from the mevalonate pathway, while plastid IPP and DMAPP are made through the MEP pathway.

    “In higher plants, most cytosolic IPP and DMAPP are derived from the mevalonate pathway via enzymes encoded by genomic DNA. By contrast, these isoprene compounds are synthesized through the MEP pathway in plastids of plants as a consequence of the evolutionary relationship of plastids to cyanobacteria.100”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] Farre G., 2010, Plant Sci. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Naturally occurring carotenoids are all synthesized from IPP and DMAPP.

    “Naturally occurring carotenoids are all synthesized from two basic 5-carbon precursors: isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP).87”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] Walter M. H., 2011, Nat. Prod. Rep. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Type II IDIs catalyze the same reaction as type I IDIs but are structurally and evolutionarily unrelated.

    “Type II IDIs are a more recently discovered class of enzymes that catalyze the same reaction as type I IDIs but are structurally and evolutionarily unrelated.105,106”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [105] Kaneda K., 2001, Proc. Natl. Acad. Sci. U.S.A. source
    • cites [106] Berthelot K., 2012, Biochimie source

  • May combine two claims.

    Premisecitation

    Type 1 IDIs require an active-site Cys residue and divalent cations for catalysis.

    “Type 1 IDIs were the first to be characterized and rely on an active site Cys residue as well as divalent cations for their catalytic function.106”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [106] Berthelot K., 2012, Biochimie source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Carotenoid biosynthesis begins with GGPP synthase-catalyzed condensation of DMAPP with three IPP molecules to form GGPP.

    “The biosynthesis of carotenoids from IPP and DMAPP begins with the condensation of one molecule of DMAPP with three molecules of IPP catalyzed by the enzyme geranylgeranyl diphosphate synthase to form geranylgeranyl diphosphate (GGPP) (Figure 4).87”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] Walter M. H., 2011, Nat. Prod. Rep. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CrtIso shares significant sequence homology with CrtI and mammalian RetSat.

    “Interestingly, CrtIso shares significant sequence homology with the carotene desaturase (CrtI) as well as a mammalian enzyme known as retinol desaturase (RetSat).63,125”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [63] Moise A. R., 2005, Trends Plant Sci. source
    • cites [125] Moise A. R., 2004, J. Biol. Chem. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Most carotenoids consumed by humans are synthesized from MEP-derived IPP and DMAPP.

    “Most carotenoids consumed by humans are synthesized from MEP-derived IPP and DMAPP.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Opsins are proteins with molecular masses between 30 and 60 kDa.

    “Such 30–60 kDa proteins were given the name “opsins””
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Ancient photoreceptors composed of light-sensing cells mediated phototaxis with pigmented cells that were precursors of the RPE.

    “Ancient photoreceptors composed of light-sensing cells (proto-eyes) mediated phototaxis with the assistance of pigmented cells, precursors of the retinal pigment epithelium (RPE) in the retina of the eye.209,210”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [209] Pichaud F., 2002, Curr. Opin. Genet. Dev. source
    • cites [210] Pichaud F., 2002, Nature source

  • May combine two claims.

    Premisecitation

    In hexane, illumination leads almost exclusively to 13-cis isomer, while increased solvent polarity produces 11-cis, 9-cis, and 7-cis retinals in ratios 0.19, 0.06, and 0.005.

    “For example, in hexane light illumination led to almost exclusive formation of the 13-cis isomer whereas increased solvent polarity contributed to efficient production of 11-cis, 9-cis, and 7-cis-retinals in 0.19, 0.06, and 0.005 ratios, respectively.192,193”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [192] Deval P., 1988, J. Photochem. Photobiol., A: Chem. source
    • cites [193] Waddell W. H., 1976, J. Am. Chem. Soc. source

  • May combine two claims.

    Premisecitation

    9,13-di-cis is a favored intermediate in isomerization of 9-cis-retinal, while 13-cis-retinal converts directly to all-trans without other intermediates.

    “Interestingly, kinetic studies revealed that the 9,13-di-cis isomer was a favored intermediate in the isomerization of 9-cis-retinal, whereas 13-cis-retinal was directly converted into the all-trans conformation without the contribution of any other isomeric intermediates.181”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [181] Rando R. R., 1983, J. Am. Chem. Soc. source

  • May combine two claims.

    Premisecitation

    Retinol's hydroxyl combines with acids, converting it into a good leaving group; dissociation generates a retinylic cation that can eliminate a proton to form anhydroretinol.

    “Investigation into the mechanism of the reaction underlying the color change revealed that the hydroxyl moiety of retinol readily combines with acids (e.g., protons or antimony), converting it into a good leaving group.166 Hydroxyl dissociation generates a short-lived retinylic cation that can undergo proton elimination to form anhydroretinol (Figure 7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [166] Blatz P. E., 1972, Anal. Chem. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    In higher organisms, opsins are coupled to G proteins and are therefore G protein-coupled receptors.

    “whereas in higher organisms they are coupled to G proteins and therefore are called G protein-coupled receptors (GPCRs).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Light-activated rhabdomeric opsins can return to their ground state by absorbing a second, lower-energy photon in photoreversal.

    “Light-activated rhabdomeric opsins can be restored to their ground state by absorption of a second, lower energy photon in a process known as photoreversal.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Light is focused by the cornea and lens before being absorbed by retinal photoreceptors.

    “First, light is focused by passing through two proteinaceous biological lenses at the front of the eye, namely the cornea and lens.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [242] Rodieck R. W., 1998

  • May combine two claims.

    Premisecitation

    For 11-cis and 7-cis retinal, isomerization also occurs after intersystem crossing to a triplet state, which accounts for up to 50% of observed isomerization.

    “Although the directly formed singlet excited state had a major role in the photoisomerization of either all-trans or 13-cis-retinal, in the case of 11-cis-retinal and 7-cis-retinal, isomerization occurred also after an intersystem crossing to an excited triplet state, so the triplet state was responsible for up to 50% of the observed isomerization with the other half of isomerized retinoid arising”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [188] Rosenfel. T., 1974, J. Phys. Chem. source
    • cites [193] Waddell W. H., 1976, J. Am. Chem. Soc. source
    • cites [197] Ganapathy S., 1990, J. Chem. Soc., Chem. Commun. source
    • cites [198] Rosenfel. T., 1974, Photochem. Photobiol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Rods and cones are the two morphologically distinct ciliated photoreceptor cell types in the human retina.

    “Rods and cones are the two morphologically distinct types of ciliated photoreceptor cells found in human retina”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Retinol dehydratase, a sulfotransferase, catalyzes conversion of retinol to anhydroretinol via retinyl sulfate.

    “Hydroxyl dissociation can also be facilitated by its conjugation with an electron-withdrawing group, for example a sulfo moiety, as occurs catalytically via the enzyme retinol dehydratase. This member of the sulfotransferase family is responsible for the catalytic conversion of retinol into anhydroretinol.172”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [172] Pakhomova S., 2001, Nat. Struct. Biol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Vision begins when photoreceptors absorb light, and rods act as photon counters because they can respond to a single photon under dim illumination.

    “Vision is initiated by absorption of light by photoreceptors, with rod cells acting as photon counters because under dim illumination they can respond to a single photon.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [246] Baylor D. A., 1979, J. Physiol. source
    • cites [247] Baylor D. A., 1987, Invest. Ophthalmol. Vis. Sci.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A mouse ROS about 24 μm long and 1.2 μm wide contains roughly 600-800 stacked membranous disks that increase rhodopsin density for photon absorption.

    “a mouse ROS with a length of ∼24 μm and a diameter of ∼1.2 μm259 contains about 600–800 membranous stacked disks which increase the density of rhodopsin available for photon absorption.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [259] Liang Y., 2004, J. Biol. Chem. source

  • May combine two claims.

    Premisecitation

    The RPE is a monolayer of highly polarized, quasi-hexagonal epithelial cells whose apical membrane lies next to photoreceptor outer segments and whose basal surface faces Bruch's membrane.

    “The RPE is a monolayer of highly polarized, quasi-hexagonal, epithelial cells. The apical membrane of RPE cells lies adjacent to the photoreceptor OS, whereas the RPE cell basal surface faces Bruch’s membrane.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [260] Nag T. C., 2012, Micron source
    • cites [261] Bok D., 1993, J. Cell Sci. Suppl. source
    • cites [262] Booij J. C., 2010, Prog. Retinal Eye Res. source

  • May combine two claims.

    Premisecitation

    Rods are more light-sensitive than cones but saturate at low light levels; at rod saturation, cones still respond but have a very high photon saturation threshold.

    “Rod cells are more light-sensitive than cones but saturate at relatively low levels of light. At the light level at which rods reach saturation, cones generate measurable responses but have an extremely high photon saturation threshold.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [242] Rodieck R. W., 1998

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Rod and cone photoreceptors make up more than 75% of the cells in the highly layered retina.

    “rod and cone photoreceptors constitute more than 75% of the cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Cones operate in bright light without saturating, implying that the rate of visual chromophore delivery to rods and cones must differ substantially.

    “In contrast to rods, cones operate in bright light without saturating, implying that the rate of visual chromophore delivery to these two cell types must be substantially different.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [300] Schnapf J. L., 1990, J. Physiol. source
    • cites [301] Penn R. D., 1972, Biophys. J. source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Vision cannot be sustained without RPE cells.

    “Without RPE cells, our vision would not be sustainable.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Rod and cone cells share the same structural plan: outer segments, an inner segment rich in mitochondria, a soma, and synaptic termini connected by inner fibers.

    “Both rod and cone cells feature the same structural design. The most distal portions, called rod/cone outer segments (ROS/COS), are in close contact with the RPE cell layer. These ciliary structures connect with the soma via an inner segment endowed with a high density of mitochondria that supply energy to the highly metabolically active photoreceptor. The soma in turn connects with synaptic”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Diffusion is likely sufficient for chromophore transfer because the chromophore forms a highly stable covalent complex with opsin, especially in rods, driving retinoid transfer to photoreceptors.

    “Diffusion likely suffices for this process because the chromophore forms, especially in rods, a highly stable covalent complex with opsin, thereby driving the transfer of retinoids to photoreceptors.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    ROS consist of stacked individual disks surrounded by the ROS plasma membrane, while COS have invaginations continuous with the COS plasma membrane.

    “ROS are made up of a stack of individualized disks surrounded by the ROS plasma membrane, whereas COS differ by having a series of invaginations continuously connected with the COS plasma membrane.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The last common ancestor of jawed vertebrates arose about 400 million years ago, with PAX6 playing a key role in eye and sensory organ development.

    “the last common ancestor of all jawed vertebrates evolved ∼400 million years ago with a key role for transcriptional master regulator paired box gene 6 (PAX6) in controlling development of eyes and other sensory organs.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [243] Quiring R., 1994, Science source
    • cites [244] Halder G., 1995, Science source
    • cites [245] Gehring W., 2003, J. Mol. Evol. source

  • May combine two claims.

    Premisereasoning

    Light-induced photochemical reactions in transparent retinal tissue require a balance between renewal and disposal of damaged components; disturbing this balance can cause rapid and massive retinal degeneration.

    “Photochemical reactions induced by light in transparent retinal tissue require a delicate balance between protein, lipid, and metabolite renewal and damaged component disposal, which when disturbed can lead to rapid and massive retinal degeneration.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    About 20-40 photoreceptor cells project to one RPE cell; the rod-to-RPE ratio is 29 in the periphery and the cone-to-RPE ratio is 22 in the fovea.

    “About 20–40 photoreceptor cells project toward a single RPE cell. In humans, this ratio depends on the location of these cells in the eye because the gradient of rod/cone cells and also slight differences in the dimension of photoreceptors dictates their packing density. In the periphery, the rod to RPE cell ratio is 29 whereas, in the fovea, the cones to RPE cells ratio is 22.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [263] Gao H., 1992, Invest. Ophthalmol. Vis. Sci.

  • May combine two claims.

    Premisereasoning

    ROS reach the apical RPE and are tightly wrapped by RPE microvilli, increasing contact area for transfer of substances including retinoids.

    “ROS extend up to the apical part of the RPE and are tightly enveloped by microvilli of RPE cells that increase the contact area of these two cell types to facilitate transfer of substances, including retinoids.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    After release from ROS, all-trans-retinal is reduced to all-trans-retinol, which diffuses into the RPE.

    “Once released from ROS, all-trans-retinal is reduced to all-trans-retinol which then diffuses into the RPE.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Photoisomerization of retinal causes a reliable conformational change in rhodopsin to its activated form, which couples with G protein.

    “when photoisomerized causes a reliable change in the conformation of rhodopsin to its activated form that couples with G protein.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    LRAT traps retinol delivered from photoreceptors or the circulation, and retinosomes are absent in Lrat−/− mice that cannot synthesize retinyl esters.

    “The highly efficient enzymatic activity of LRAT traps retinol delivered from the photoreceptors or from the circulation, whereas retinosomes are absent in the eyes of Lrat–/– mice deficient in retinyl ester synthesis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Rhodopsin is not uniformly distributed throughout disks, but its locally high density within each disk enables efficient light absorption.

    “Although rhodopsin is not uniformly distributed throughout disks,84,328 its local high density within each disk allows efficient absorption of light.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [84] Palczewski K., 2006, Annu. Rev. Biochem. source
    • cites [328] Molday R. S., 1998, Invest. Ophthalmol. Vis. Sci.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    The authors postulated that RPE retinosomes function like lipid droplets in other cells and are dynamic tissue-specific organelles whose composition changes with fatty acid, cholesterol, and all-trans-retinol availability.

    “We postulated that retinosomes in RPE cells perform functions similar to those of lipid droplets in other types of cells, suggesting that they are rather dynamic tissue-specific organelles that change their composition in response to fatty acid, cholesterol, and all-trans-retinol”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Retinal condensation products arise from inadequate reduction or clearance of all-trans-retinal and are often seen as small 1 μm deposits scattered through RPE cells.

    “Resulting from inadequate reduction/clearance of all-trans-retinal, they are often detected as small 1 μm deposits scattered throughout RPE cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    The Schiff base between 11-cis-retinal and Lys296 of opsin is protonated, allowing a spectral shift to longer wavelengths at least in rhodopsin, green, and blue pigments.

    “The Schiff base between 11-cis-retinal and Lys296 of opsin is protonated to allow a spectral shift to longer wavelengths (at least in rhodopsin, green and blue pigments).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cultured primary chicken Müller cells convert all-trans-retinol into 11-cis-retinol and 11-cis-retinyl esters, suggesting that Müller cells could produce visual chromophore in vivo.

    “Cultured primary Müller cells from chickens were found to convert all-trans-retinol added to the media into 11-cis-retinol and 11-cis-retinyl esters, suggesting that this cell type could be a site of visual chromophore production in vivo.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [305] Das S. R., 1992, Biochem. J. source

  • May combine two claims.

    Premisereasoning

    A counterion is essential because positively charged groups are extremely rare in the transmembrane domain of membrane proteins.

    “A counterion is essential, as positively charged groups are extremely rare in the TMD of membrane proteins.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    The 11-cis-retinylidene bond is protonated, and Glu113 serves as the counterion for this linkage.

    “The 11-cis-retinylidene bond is protonated, and Glu113 is the counterion of this linkage.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    RDHs form a microsomal SDR group with at least 30% overall sequence similarity, while their catalytic cores are much more homologous and nearly identically folded.

    “The RDH’s represent a microsomal SDR group with an overall sequence similarity of at least 30% (Figure 21) although the catalytic core of these enzymes reveals a much higher homology with nearly identical folding.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Independent verification of the proposed counterion switch and the whole mechanism of chromophore regeneration is still lacking.

    “Although there is convincing evidence for the roles proposed for Glu113 and Glu181, independent verification of this switch and the whole mechanism of chromophore regeneration is still lacking.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    AKRs do not contain the canonical Rossmann fold.

    “By contrast, AKR’s do not contain the canonical Rossmann fold.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Site II is an entrance site, and site III is an exit site occupied by retinal after it leaves site I.

    “Site II is called an entrance site, and the exit site (site III) is occupied by retinal after its release from site I.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    RDH12 is a glycoprotein with an endoglycosidase H-sensitive sugar modification, suggesting a luminal orientation.

    “In contrast to this model, RDH12 was reported to be a glycoprotein carrying an endoglycosidase H-sensitive sugar modification, which suggests a luminal orientation of this enzyme.386”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [386] Janecke A. R., 2004, Nat. Genet. source

  • May combine two claims.

    Premisecitation

    An acidic residue that binds the 2′ and 3′ hydroxyls of the adenine ribose downstream of the Gly-rich motif confers NAD(H) specificity, while a basic residue in the Gly-rich segment dictates NADP(H) binding.

    “An acidic residue binding to the 2′ and 3′ hydroxyls of the adenine ribose and located downstream of the Gly-rich motif confers NAD(H) specificity, whereas NADP(H) binding is dictated by the presence of a basic residue within the Gly-rich segment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [375] Lesk A. M., 1995, Curr. Opin. Struct. Biol. source

  • May combine two claims.

    Premisecitation

    Further relaxation with Schiff base deprotonation produces the signaling form Meta II, which has a maximum absorbance at 382 nm and interacts with G protein-coupled receptor kinase 1 and arrestin.

    “Further relaxation combined with Schiff base deprotonation results in a signaling form called Meta II (λmax = 382 nm)343 which then interacts with G protein-coupled receptor kinase 1 and arrestin.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [343] Choe H. W., 2011, Nature source
    • cites [60] Okada T., 2001, Trends Biochem. Sci. source
    • cites [62] Ridge K. D., 2003, Trends Biochem. Sci. source
    • cites [239] Oprian D. D., 1992, Curr. Opin. Neurobiol. source
    • cites [365] Palczewski K., 1991, Trends Biochem. Sci. source
    • cites [366] Polans A., 1996, Trends Neurosci. source

  • May combine two claims.

    Premisecitation

    The absorption difference at this stage results from chromophore relaxation, with only small changes in the protein moiety.

    “Though the difference in absorption results from relaxation of the chromophore, only small changes in the protein moiety take place at this stage”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [358] Furutani Y., 2003, Biochemistry source
    • cites [359] Nakamichi H., 2006, Angew. Chem., Int. Ed. source
    • cites [360] Schreiber M., 2006, Angew. Chem., Int. Ed. source

  • May combine two claims.

    Premisecitation

    The ADH and RDH oxidoreductase families share a conserved cofactor-binding mode but differ in domain architecture and catalytic mechanism.

    “Despite their conserved mode of cofactor binding, ADH and RDH families of oxidoreductases reveal diverse protein domain architectures and mechanisms of catalysis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [376] Howard E. I., 2004, Proteins source

  • May combine two claims.

    Premisenone given

    Regeneration with 11-cis-retinal requires polarization of the 11-cis-retinal carbonyl, deprotonation of the Lys296 side chain amine, and exclusion of water from the active site.

    “When regeneration with 11-cis-retinal subsequently occurs, formation of the Schiff base requires polarization of the carbonyl group of 11-cis-retinal and deprotonation of the Lys296 side chain amine as well as exclusion of water from the active site”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The Rossmann motif contains a Gly-rich sequence, TGXXXGXG, that maintains structural integrity and binds the diphosphate portion of nucleotide cofactors.

    “This structural motif contains a Gly-rich sequence (TGXXXGXG) responsible for its structural integrity and binding of the diphosphate portion of the nucleotide cofactors.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [375] Lesk A. M., 1995, Curr. Opin. Struct. Biol. source

  • May combine two claims.

    Premisecitation

    ADH enzymes use a catalytic zinc atom in the active site that electrostatically stabilizes the substrate oxygen and increases the acidity of the alcohol proton.

    “ADH’s depend on a catalytic Zn atom bound in the active site, which electrostatically stabilizes the substrate’s oxygen and thus increases the acidity of the alcohol proton.377”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [377] Danielsson O., 1994, Proc. Natl. Acad. Sci. U.S.A. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In the AKR family, preferable NADPH binding occurs within the characteristic (β/α)8 motif.

    “Preferable NADPH binding occurs within the characteristic (β/α)8 motif of this protein family.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [376] Howard E. I., 2004, Proteins source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In ADHs and RDHs, the nucleotide cofactors are bound by a Rossmann fold made of 6-7 parallel β-strands flanked by 3-4 α-helices.

    “In ADH’s and RDH’s they are bound by a Rossmann fold, a classic structural element composed of 6 to 7 parallel β-strands flanked by 3–4 α-helices present in these enzymes”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [375] Lesk A. M., 1995, Curr. Opin. Struct. Biol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    NAD(H) and NADP(H) are the universal redox carriers for these reactions.

    “The universal redox carriers for these reactions are the dinucleotide cofactors NAD(H) and NADP(H).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The Rando mechanism for RPE65 isomerization involves attack of an enzyme-associated nucleophile on C11 of the retinyl ester with simultaneous ester dissociation and double-bond shuffling.

    “The first, proposed by Rando and colleagues, involves the attack of an enzyme-associated nucleophile on C11 of the retinyl ester with simultaneous ester dissociation and shuffling of the double bonds (Figure 29).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    LRAT is critical for retinoid uptake and storage in peripheral tissues, including RPE, where it supplies substrate for visual chromophore regeneration via RPE65.

    “Consequently, LRAT is critical for uptake and storage of retinoids in peripheral tissues, including RPE cells where it plays a pivotal role in providing substrate for visual chromophore regeneration via the enzymatic activity of RPE65.147,148,405”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [147] Batten M. L., 2004, J. Biol. Chem. source
    • cites [148] Moiseyev G., 2003, Biochemistry source
    • cites [405] Jin M., 2005, Cell source

  • May combine two claims.

    Premisereasoning

    ARAT requires a preactivated acyl-CoA, unlike LRAT, which uses phospholipids as acyl donors.

    “In contrast to LRAT, which efficiently utilizes phospholipids as acyl donors, acyl-CoA/retinol acyltransferase (ARAT) requires a preactivated acyl moiety coupled to coenzyme A (Figure 24).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Interpretationreasoning

    Based on preferred substrate geometry and role in the retinoid cycle, retinal RDHs can be classified into all-trans and 11-cis-retinol dehydrogenases.

    “Based on their preferred substrate geometry and role in the retinoid cycle, this group of enzymes can be classified into all-trans and 11-cis-retinol dehydrogenases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The Palczewski mechanism for RPE65 isomerization proposes a carbocation intermediate generated by O-alkyl cleavage, allowing bond rotation and subsequent attack by water or hydroxide at C15.

    “A second mechanism, postulated by Palczewski and colleagues, proposes a key role for a carbocation intermediate in the isomerization reaction (Figure 30). In this reaction involving an SN1′ nucleophilic substitution mechanism, ester dissociation via O-alkyl cleavage removes electrons from the polyene, thereby generating a retinylic cation with reduced carbon–carbon bond order allowing bond rot”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The NADP/NADPH ratio is about 0.005, so enzymes using this dinucleotide reduce retinal to retinol.

    “In contrast, the ratio of NADP to its reduced form is about 0.005,395 such that enzymes utilizing this dinucleotide reduce retinal to retinol.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [395] Merrill D. K., 1981, Brain Res. source

  • May combine two claims.

    Premisecitation

    RPE65 and other CCOs share 20-40% sequence identity and contain four conserved His and three Glu residues involved in binding a required iron cofactor.

    “Sequence identity between RPE65 and other CCO members varies from ∼20 to 40%, but all of these enzymes contain an absolutely conserved set of four His and three Glu residues that are involved in binding of a required iron cofactor448,449 (Figure 25).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [448] Kloer D. P., 2006, Cell. Mol. Life Sci. source
    • cites [449] Moiseyev G., 2006, J. Biol. Chem. source

  • May combine two claims.

    Premisereasoning

    RDH-catalyzed reactions are fully reversible; in vitro the net direction depends on cofactor oxidation state and substrate/product concentration ratio, while in vivo it is determined by enzyme specificity for NAD(H) or NADP(H).

    “Reactions catalyzed by RDH’s are fully reversible. In a test tube, the net direction of retinoid interconversion depends on the oxidation state of the provided cofactor and the ratio between the concentrations of substrate and product. However, in more complex in vivo systems, the direction of the enzymatic reaction is determined by enzyme specificity for binding either NAD(H) or NADP(H).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Rpe65-/- mice show early onset blindness and ocular retinoid abnormalities consisting of a lack of 11-cis-retinoids and overaccumulation of all-trans-retinyl esters.

    “Rpe65–/– mice, generated in the Redmond laboratory, exhibited early onset blindness and ocular retinoid abnormalities consisting of a lack of 11-cis-retinoids and overaccumulation of all-trans-retinyl esters, indicating an important physiological role for RPE65 in the visual cycle.439”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [439] Redmond T. M., 1998, Nat. Genet. source

  • May combine two claims.

    Premisecitation

    By analogy to HRASLS proteins, LRAT has a papain-like protease structural motif with a four-strand antiparallel β-sheet, three α-helices, and catalytic residues Cys161, His60, and His72 at the active site.

    “By analogy to HRASLS proteins, LRAT’s basic structural motif is largely reminiscent of papain-like proteases and consists of a four-strand antiparallel β-sheet, three α-helices, and conserved catalytic residues Cys161, His60, and His72 that define the active site located at the N-terminus of helix α3 and β-sheets β2 and β3, respectively (Figure 22).411”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [411] Golczak M., 2012, J. Biol. Chem. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    IRBP is a soluble lipoglycoprotein and the second eye-specific retinoid-binding protein.

    “The second eye-specific retinoid-binding protein is a soluble lipoglycoprotein called interphotoreceptor-binding protein (IRBP).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    ABCA4 is predominantly expressed in photoreceptor outer segments, where it is located in the rims of rod disk membranes and cone incisures.

    “ABCA4, a member of the ABCA transporter subfamily, is predominantly expressed in the outer segments of photoreceptor cells where it is located in the rims of rod disk membranes and cone incisures.515−517”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [515] Molday L. L., 2000, Nat. Genet. source
    • cites [516] Sun H., 1997, Nat. Genet. source
    • cites [517] Papermaster D. S., 1982, Vision Res. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    IRBP consists of four homologous modules generated by gene duplication.

    “The protein consists of four homologous “modules” generated by gene duplication.512”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [512] Gonzalez-Fernandez F., 2008, Exp. Eye Res. source

  • May combine two claims.

    Premisenone given

    IRBP is a 136 kDa protein produced by photoreceptors and secreted into the interphotoreceptor matrix, where it is the most abundant extracellular protein.

    “This large, 136 kDa protein is produced by photoreceptors and secreted into the interphotoreceptor matrix, where it is the most abundant extracellular protein.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    CRBP is a compact 15 kDa intracellular lipid-binding protein evolutionarily unrelated to RBP4.

    “A member of the intracellular lipid-binding protein family, this compact 15 kDa protein is evolutionarily unrelated to RBP4.497”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [497] Cowan S. W., 1993, J. Mol. Biol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mutations in the CRALBP gene are associated with several retinal diseases, including retinitis pigmentosa, Newfoundland rod-cone dystrophy, fundus albipunctatus, and Bothnia retinal dystrophy.

    “Mutations in the CRALBP gene are associated with several retinal diseases, including retinitis pigmentosa, Newfoundland rod-cone dystrophy, fundus albipunctatus, and Bothnia retinal dystrophy.509”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [509] Saari J. C., 2005, Exp. Eye Res. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    In the accepted model of ATP-driven transport, substrate binding increases NBD affinity for ATP, nucleotide-induced NBD dimerization drives a conformational change that translocates substrate across the membrane, and ATP hydrolysis returns the transporter to its initial state.

    “On the basis of the accepted model of ATP-driven transport across a lipid membrane, binding of a molecule to be transported increases the affinity of NBDs for ATP. The nucleotide then induces a conformational change of NBDs that come in close contact to form a dimer with the two nucleotide molecules positioned at its interface. This movement is translated onto a TMD that induces the translocation”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    In biological membranes, all-trans-retinal reacts predominantly with PE to form N-ret-PE, which cannot freely flip between the inner and outer leaflets of the lipid bilayer.

    “In the biological membrane environment, all-trans-retinal reacts predominantly with PE to form N-ret-PE that, similar to phospholipids, cannot freely flip between the inner and outer leaflets of the lipid bilayer.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Decay of photoactivated rhodopsin hydrolyzes the opsin-retinylidene Schiff base bond and releases all-trans-retinal into the disk membrane.

    “Decay of photoactivated rhodopsin results in hydrolysis of the opsin-retinylidene Schiff base bond followed by subsequent release of all-trans-retinal into the disk membrane.84”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Palczewski K., 2006, Annu. Rev. Biochem. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    In the absence of substrate, ABC transporters undergo slow ATP hydrolysis by individual NBDs, producing basal ATPase activity.

    “In the absence of substrate, ABC transporters undergo cycles of slow ATP hydrolysis by individual NBDs, resulting in a basal ATPase activity.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Because lipofuscin granules contain potent photosensitizers, quenching of their excited states by A2E may play a protective antioxidant role.

    “Considering that lipofuscin granules contain potent photosensitizers, quenching of excited states of lipofuscin photosensitizers by A2E may play a protective antioxidant role.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    P23H is the most frequent rod opsin mutation and the first identified as causing blindness, accounting for 10% of human cases of autosomal dominant retinitis pigmentosa.

    “The most frequent mutation and the first identified as causing blindness is P23H,553 accounting for 10% of human cases of autosomal dominant RP.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [553] Dryja T. P., 1990, Nature source

  • May combine two claims.

    Premisenone given

    Transport of vitamin A is facilitated by RBP4, and its cellular receptor STRA6 functionally couples with LRAT via CRBP.

    “Transport of vitamin A is facilitated by RBP4, and its cellular receptor, STRA6, functionally couples with LRAT via CRBP.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    It is improper to treat the retinoid cycle as a separate entity because it depends on metabolism of the whole organism.

    “Indeed, it would be improper to treat the retinoid cycle as a separate entity because it is so dependent on the metabolism of the whole organism (Figure 37).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    Newly generated 11-cis-retinal is needed to reform light-sensitive visual pigments.

    “Newly generated 11-cis-retinal is needed to reform light-sensitive visual pigments.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Experimental therapies utilize carotenoids, retinoid precursors that are an integral part of the human macula.

    “Moreover, there are also experimental therapies that utilize carotenoids, retinoid precursors that comprise an integral part of human macula.574”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [574] Kijlstra A., 2012, Prog. Retinal Eye Res. source
160 of 160

  • The paper relies on this without support.

    The retinoid (visual) cycle is required for visual function in vertebrates.

    “A specific enzyme system, called the retinoid (visual) cycle, has evolved to accomplish retinoid isomerization that is required for visual function in vertebrates.”

  • The paper relies on this without support.

    Malfunctions of retinoid cycle processes or other pathological reactions often precipitate severe retinal pathologies.

    “Malfunctions of these processes or other pathological reactions often precipitate severe retinal pathologies.”

  • The paper relies on this without support.

    Retinoids readily isomerize.

    “Retinoids are reactive compounds that readily isomerize.”

  • The paper relies on this without support.

    Cis/trans isomerization of retinals does not occur efficiently in the dark at room temperature.

    “Cis/trans isomerization of retinals does not occur efficiently in the dark at room temperature.”

  • The paper relies on this without support.

    The hydrophobic character of retinoids restricts their diffusion in aqueous environments.

    “The hydrophobic nature of retinoids limits their ability to diffuse in aqueous environments.”

  • The authors state this as an assumption.

    Only a fraction of the total all-trans-retinal is processed by ABCA4.

    “Taking into account the partition of retinals into the lipid bilayer and a relatively slow rate of ATP hydrolysis by ABCA4 equivalent to three enzymatic cycles per second, one can assume that only a fraction of the total all-trans-retinal is processed by ABCA4.530”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In contrast to invertebrates, vertebrates evolved a relatively complex sequence of enzymatic reactions to facilitate thermodynamically unfavorable isomerization of retinoid independently of light.

    “In contrast to invertebrates, in which isomerized visual chromophore does not leave the binding pocket and can be re-isomerized back to 11-cis configuration in situ [82,83], vertebrates evolved a relatively complex sequence of enzymatic reactions to facilitate thermodynamically unfavorable isomerization of retinoid independently of light [3,84].”

    From Molecular Basis for Vitamin A Uptake and Storage in Vertebrates (2016) · cites this paper as [3]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting claims about disease linked to IRBP mutations

    Minor

    One section says no human disease has been attributed to IRBP mutations, while a later section associates mutations in the gene encoding IRBP with progressive retinal degeneration.

1 of 1

Cites

Flagged first, then by citations

1 of the 580 references couldn’t be matched to a known paper.

Research works printed but not linked: 36

  1. Olson J. A., 1967, Pharmacol. Rev., 19, 559
  2. Olson J. A., 1968, Vitam. Horm., 26, 1
  3. Goodman D. S., 1972, Biochem. Soc. Symp., 287
  4. Porter S. B., 1986, Int. J. Vitam. Nutr. Res., 56, 11
  5. Chytil F., 1979, Fed. Proc., 38, 2510
  6. Chytil F., 1978, Vitam. Horm., 36, 1
  7. Green M. H., 1993, Am. J. Physiol., 264, G509
  8. Norum K. R., 1991, Tidsskr. Nor. Laegeforen., 111, 1078
  9. Tseng S. C., 1987, Invest. Ophthalmol. Vis. Sci., 28, 538
  10. Cane D. E., 1999, Isoprenoid Including Carotenoids and Steroids, 1
  11. Cunningham F. X., 1994, Plant Cell, 6, 1107
  12. Bensasson R., 1978, New J. Chem., 2, 503
  13. Arendt D., 2003, Int. J. Dev. Biol., 47, 563
  14. Pedros-Alio C., 2006, Int. Microbiol., 9, 191
  15. Baylor D. A., 1987, Invest. Ophthalmol. Vis. Sci., 28, 34
  16. Szel A., 1993, Invest. Ophthalmol. Vis. Sci., 34, 3641
  17. Gao H., 1992, Invest. Ophthalmol. Vis. Sci., 33, 1
  18. Kevany B. M., 2010, Physiology (Bethesda), 25, 8
  19. Anderson D. H., 1978, Invest. Ophthalmol. Vis. Sci., 17, 117
  20. Pagon R. A., 1993, GeneReviews
  21. Weleber R. G., 1993, GeneReviews
  22. Kuhne, W.On the photochemistry of the retina;Cambridge University Press: 1878; pp1–104.
  23. Rodriguez K. A., 1989, Am. J. Physiol., 256, R255
  24. Bok D., 1984, Invest. Ophthalmol. Vis. Sci., 25, 877
  25. Molday R. S., 1998, Invest. Ophthalmol. Vis. Sci., 39, 2491
  26. Kandori H., 2001, Biochemistry, 66, 1197
  27. Garron L. K., 1963, Trans. Am. Ophthalmol. Soc., 61, 545
  28. Hemati N., 2005, Mol. Vis., 11, 1151
  29. Ma J., 2001, Invest. Ophthalmol. Vis. Sci., 42, 1429
  30. Saari J. C., 2002, Invest. Ophthalmol. Vis. Sci., 43, 1730
  31. Futterman S., 1977, Invest. Ophthalmol. Vis. Sci., 16, 768
  32. Saari J. C., 2009, Mol. Vis., 15, 844
  33. Dryja T. P., 1995, Invest. Ophthalmol. Vis. Sci., 36, 1197
  34. Azam M., 2009, Mol. Vis., 15, 2526
  35. Allikmets R., 1997, Nat. Genet., 17, 122
  36. Travis G. H., 2002, Invest. Ophthalmol. Vis. Sci., 43, U1006

Cited by

Sorted by citations

Related

Authors
Kiser, P. D., Golczak, M., & Palczewski, K.
Affiliations
Case Western Reserve University (US)
Corresponding author
Palczewski, Krzysztof
ORCID
Venue
Chemical Reviews
Publisher
American Chemical Society (ACS)
Published
2013-07-11
Volume
114
Issue
1
Pages
194-232
ISSN
  • 0009-2665 (ISSN-L)
  • 1520-6890
DOI
10.1021/cr400107q
PMC
PMC3858459
OpenAlex
W2076602698
Cited by
353
References
580
Citations by year
2026: 21 · 2025: 28 · 2024: 25 · 2023: 28 · 2022: 28 · 2021: 40 · 2020: 40 · 2019: 23 · 2018: 24 · 2017: 25 · 2016: 28 · 2015: 24 · 2014: 15 · 2013: 3
FWCI
2.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Chemical Reviews (publishedVersion, other-oa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Eye Institute (EY021126, EY009339, R24EY021126, R01EY009339)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Photoreceptor and optogenetics research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
Keywords
retinoid cycle, visual cycle, retinoids, retinol, retinal, retinyl esters, vitamin A, rhodopsin, retinol dehydrogenase, retinal dehydrogenase
MeSH terms
Retinoid Isomerohydrolase, Acyltransferases, Animals, Humans, Mevalonic Acid, Photoreceptor Cells, Retinal Diseases, Retinaldehyde, Retinoids, Retinol-Binding Proteins, Rhodopsin, Coenzyme A-Transferases, cis-trans-Isomerases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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