Chemistry of the Retinoid (Visual) Cycle

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [107] Muehlbacher M., 1988, Biochemistry source
• ?Not checked — no full text of the sourcecites [108] Toteva M. M., 1997, Bioorg. Chem. source
• ?Not checked — no full text of the sourcecites [109] Wouters J., 2003, J. Biol. Chem. source
• Disputed

  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.

  cites [110] Durbecq V., 2001, EMBO J. sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [125] Moise A. R., 2004, J. Biol. Chem. source
• Supported

  The introductory passage identifies mouse RetSat as the enzyme that saturates the C13–C14 double bond of all-trans-retinol and produces all-trans-13,14-dihydroretinol, consistent with no isomerization. The Scheme 1 discussion reports that mouse RetSat produces the (R) enantiomer by comparison with a synthetic standard. No page numbers are provided in our copy. (LLM, conf=0.92)

  cites [206] Moise A. R., 2008, J. Am. Chem. Soc. source

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [137] Salyers K. L., 1993, Biochim. Biophys. Acta source
• Partly supported

  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)

  cites [138] Ross A. C., 2011, Annu. Rev. Nutr. sourceExperimental — accuracy not yet measured

In the paper

“However, most eubacteria utilize the MEP pathway.99”

What the sources say

• Supported

  The section “Which Microbes Use the MEP Pathway?” states that the overwhelming majority of eubacteria use it. This directly supports the citing sentence’s “most eubacteria” claim. (LLM, conf=0.95)

  cites [99] Odom A. R., 2011, PLoS Pathog. source

In the paper

“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”

What the sources say

• Supported

  The introduction (p. 1) describes a second route to IPP through condensation of pyruvate and glyceraldehyde-3-phosphate. The paper calls it the recently discovered DXP pathway, describes it as prevalent in eubacteria, and reports its use in plants (pp. 1–2). (LLM, conf=0.91)

  cites [90] Lange B. M., 2000, Proc. Natl. Acad. Sci. U.S.A. source
• ?Not checked — no full text of the sourcecites [91] Rohmer M., 1999, Nat. Prod. Rep. source
• Partly supported

  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)

  cites [92] Schwender J., 1996, Biochem. J. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [93] Flesch G., 1988, Eur. J. Biochem. source
• ?Not checked — no full text of the sourcecites [94] Rohmer M., 1996, J. Am. Chem. Soc. source

In the paper

“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”

What the sources say

• Partly supported

  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)

  cites [145] Ruiz A., 1999, J. Biol. Chem. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [146] MacDonald P. N., 1988, Biochem. Biophys. Res. Commun. source
• ?Not checked — no full text of the sourcecites [147] Batten M. L., 2004, J. Biol. Chem. source
• ?Not checked — no full text of the sourcecites [148] Moiseyev G., 2003, Biochemistry source

In the paper

“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”

What the sources say

• Partly supported

  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)

  cites [163] Golczak M., 2010, Methods Mol. Biol. sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [164] Rosenheim O., 1925, Biochem. J. source
• Supported

  The citation to this paper is attached to the sentence about the blue color’s lifetime. In “Colour Reactions Attributed to Vitamin A,” the paper reports that antimony trichloride in chloroform gives a brilliant blue that does not perceptibly change for three minutes. (LLM, conf=0.93)

  cites [165] Carr F. H., 1926, Biochem. J. source
• ?Not checked — no full text of the sourcecites [166] Blatz P. E., 1972, Anal. Chem. source

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [126] Cunningham F. X., 1994, Plant Cell source
• ?Could not verify

  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)

  cites [127] Cunningham F. X., 1993, FEBS Lett. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [128] Hornero-Mendez D., 2002, FEBS Lett. source

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [135] Chambon P., 1996, FASEB J. source
• Partly supported

  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)

  cites [136] Kumar S., 2012, Biochim. Biophys. Acta sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [87] Walter M. H., 2011, Nat. Prod. Rep. source
• ?Not checked — no full text of the sourcecites [122] Matthews P. D., 2003, J. Exp. Bot. source
• Supported

  The paper’s opening passage states that bacteria use a single enzyme, CrtI, to convert phytoene toward lycopene, whereas plants require two desaturases and two isomerases. The subsequent passages identify the plant enzymes as PDS, ZDS, Z-ISO, and CrtISO. (LLM, conf=0.94)

  cites [123] Chen Y., 2010, Plant Physiol. source

In the paper

“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”

What the sources say

• Partly supported

  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)

  cites [98] Hunter W. N., 2007, J. Biol. Chem. sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• Partly supported

  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)

  cites [167] Schwieter U., 1969, Pure Appl. Chem. sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• Partly supported

  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)

  cites [211] Vopalensky P., 2012, Proc. Natl. Acad. Sci. U.S.A. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [212] Arendt D., 2009, Philos. Trans. R. Soc. London, B: Biol. Sci. source
• ?Not checked — no full text of the sourcecites [213] Nilsson D. E., 2008, Curr. Biol. source
• ?Not checked — no full text of the sourcecites [214] Loosli F., 2001, Development source
• Partly supported

  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)

  cites [215] Arendt D., 2003, Int. J. Dev. Biol. sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [169] Pienta N. J., 1992, J. Am. Chem. Soc. source
• Partly supported

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

  cites [171] McBee J. K., 2000, Biochemistry sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• Partly supported

  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)

  cites [182] Hubbard R., 1952, J. Gen. Physiol. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [183] Kropf A., 1970, Photochem. Photobiol. source
• ?Not checked — no full text of the sourcecites [184] Brown P. K., 1956, J. Biol. Chem. source

In the paper

“The photosensitive active retinoid, 11-cis-retinal, is produced in the RPE and delivered to the photoreceptors.”

What the sources say

• ?Not checked — no full text of the sourcecites [59] McBee J. K., 2001, Prog. Retinal Eye Res. source
• ?Not checked — no full text of the sourcecites [64] Travis G. H., 2007, Annu. Rev. Pharmacol. Toxicol. source
• Supported

  The Introduction (page not provided) describes conversion of retinol to 11-cis-retinal in the RPE as part of the visual cycle that replenishes chromophore in photoreceptors. Section 3 (page not provided) likewise identifies production of 11-cis-retinal in the RPE. Together, these passages support its production there and delivery to photoreceptors. (LLM, conf=0.89)

  cites [68] Parker R. O., 2010, Exp. Eye Res. source
• Supported

  Section 3.1, “Classic visual cycle” (page not provided), states that 11-cis retinal is generated in the RPE and transported to photoreceptors. It adds that both rods and cones receive it from the RPE. (LLM, conf=0.95)

  cites [69] Tang P. H., 2013, Prog. Retinal Eye Res. source
• ?Not checked — no full text of the sourcecites [71] Lamb T. D., 2004, Prog. Retinal Eye Res. source
• Supported

  The “Visual chromophore recycling” section states that 11-cis-retinol is oxidized to 11-cis-retinal in the RPE, then transported across the interphotoreceptor matrix into photoreceptor outer segments. It also identifies 11-cis-retinal as the visual chromophore. (LLM, conf=0.94)

  cites [83] von Lintig J., 2010, Trends Biochem. Sci. source
• ?Not checked — no full text of the sourcecites [278] Kuksa V., 2003, Vision Res. source
• ?Not checked — no full text of the sourcecites [279] Rozanowska M., 2005, Photochem. Photobiol. source
• Supported

  Section 1.2, “The retinoid (visual) cycle” (page not provided), states that 11-cis-retinol is oxidized to 11-cis-retinal and transported from the RPE back to photoreceptors. This supports the attributed claim. (LLM, conf=0.94)

  cites [284] Kiser P. D., 2010, Prog. Retinal Eye Res. source
• ?Not checked — no full text of the sourcecites [285] Saari J. C., 2012, Annu. Rev. Nutr. source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [278] Kuksa V., 2003, Vision Res. source
• Partly supported

  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)

  cites [282] Imanishi Y., 2004, J. Cell Biol. sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [283] Imanishi Y., 2007, Biochemistry sourceExperimental — accuracy not yet measured

In the paper

“Because retinols and retinyl esters (but not retinals) are intrinsically fluorescent, their transformation can be followed by fluorescence induced by two-photon excitation.”

What the sources say

• ?Not checked — no full text of the sourcecites [278] Kuksa V., 2003, Vision Res. source
• Partly supported

  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)

  cites [282] Imanishi Y., 2004, J. Cell Biol. sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [283] Imanishi Y., 2007, Biochemistry sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [289] Imanishi Y., 2010, Methods Mol. Biol. sourceExperimental — accuracy not yet measured
• Partly supported

  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)

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

  The Introduction states that only retinol and retinyl esters among the retinoid metabolites show intrinsic fluorescence, excluding retinals. It also says the authors used two-photon microscopy to monitor changes in vitamin A and its metabolites in the intact mouse eye; the Results report fluorescence changes tracking retinyl ester formation. Page numbers were not supplied. (LLM, conf=0.93)

  cites [291] Imanishi Y., 2004, J. Cell Biol. source
• ?Not checked — no full text of the sourcecites [292] Wu Q., 2006, Biophys. J. source
• Partly supported

  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)

  cites [293] Koutalos Y., 2010, Methods Mol. Biol. sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [59] McBee J. K., 2001, Prog. Retinal Eye Res. source
• ?Not checked — no full text of the sourcecites [63] Moise A. R., 2005, Trends Plant Sci. source
• ?Not checked — no full text of the sourcecites [64] Travis G. H., 2007, Annu. Rev. Pharmacol. Toxicol. source
• Supported

  The “Phototransduction and the retinoid cycle” section (page not supplied) says the cycle operates in the RPE and identifies RPE65 as a key enzyme there. It also describes conversion to 11-cis-retinal by retinoid-metabolizing enzymes, supporting both parts of the claim. (LLM, conf=0.94)

  cites [65] Palczewski K., 2010, Trends Pharmacol. Sci. source
• Supported

  The Introduction describes the RPE as a site of enzymatic reactions in the visual cycle, including conversion of 11-cis retinol to 11-cis retinal by RDHs. Section 3 identifies RDH5 and RDH11 as enzymes involved in that RPE reaction. The provided passages do not specify page numbers. (LLM, conf=0.93)

  cites [68] Parker R. O., 2010, Exp. Eye Res. source
• Supported

  Section 3.2 identifies RPE65 as an abundant RPE enzyme involved in producing 11-cis retinoids and reports that loss of RPE65 prevents 11-cis-retinal generation. The Introduction describes synthesis and transport of 11-cis retinal between the RPE and photoreceptors as part of retinoid cycling. Together, these passages support the RPE’s integral role in the cycle. (LLM, conf=0.93)

  cites [69] Tang P. H., 2013, Prog. Retinal Eye Res. source
• ?Not checked — no full text of the sourcecites [71] Lamb T. D., 2004, Prog. Retinal Eye Res. source
• ?Not checked — no full text of the sourcecites [72] Rando R. R., 1991, Biochemistry source
• ?Not checked — no full text of the sourcecites [73] Pepperberg D. R., 1993, Mol. Neurobiol. source
• ?Not checked — no full text of the sourcecites [74] Wolf G., 2002, Nutr. Rev. source

In the paper

“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.”

What the sources say

• Supported

  The RPE section states that photoreceptors shed about 10% of their volume daily and that adjacent RPE cells phagocytose the shed material. It also says the outer segments regenerate roughly the same volume each day, supporting the renewal described in the citing sentence. (LLM, conf=0.92)

  cites [268] Kevany B. M., 2010, Physiology (Bethesda) source

In the paper

“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.”

What the sources say

• Supported

  Section 2.2 states that differences in the retinal-binding pocket produce a blue shift in S-cone opsin. Section 1.1 reports that the three human cone pigments have different wavelength maxima and underlie trichromatic color vision. Together, these passages support the attributed mechanism and its role in color discrimination; page numbers are unavailable in our copy. (LLM, conf=0.90)

  cites [235] Mustafi D., 2009, Prog. Retinal Eye Res. source
• ?Not checked — no full text of the sourcecites [248] Nakanishi K., 1980, J. Am. Chem. Soc. source

In the paper

“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.”

What the sources say

• Supported

  The Results section (DES1 Catalyzes Equilibrium Isomerization of Retinol; page not provided) reports much faster production of 9-cis- and 13-cis-retinol than 11-cis-retinol from all-trans-retinol. The retinal measurements (DES1 Expression in Rod- and Cone-dominant Retinas; page not provided) show that 9-cis-retinaldehyde accounts for only about 7% of chicken visual chromophore, consistent with the citing sentence’s contrast with abundant 11-cis-retinoids. Calling that contrast ‘unexpected’ is the citing authors’ interpretation. (LLM, conf=0.90)

  cites [308] Kaylor J. J., 2013, Nat. Chem. Biol. source

In the paper

“Rhodopsin is the main component of disk and plasma membranes of ROS, accounting for 90 and 75% of their protein content.”

What the sources say

• ?Not checked — no full text of the sourcecites [61] Filipek S., 2003, Annu. Rev. Physiol. source
• ?Not checked — no full text of the sourcecites [66] Palczewski K., 2012, J. Biol. Chem. source
• ?Not checked — no full text of the sourcecites [79] Hofmann K. P., 2009, Trends Biochem. Sci. source
• ?Not checked — no full text of the sourcecites [225] Menon S. T., 2001, Physiol. Rev. source
• ?Not checked — no full text of the sourcecites [226] Sakmar T. P., 2002, Annu. Rev. Biophys. Biomol. Struct. source
• Partly supported

  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)

  cites [235] Mustafi D., 2009, Prog. Retinal Eye Res. sourceExperimental — accuracy not yet measured
• ?Could not verify

  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)

  cites [321] Farrens D. L., 2010, Photochem. Photobiol. Sci. sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [322] Park P. S., 2008, Annu. Rev. Pharmacol. Toxicol. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [323] Ridge K. D., 2007, J. Biol. Chem. source
• ?Could not verify

  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)

  cites [324] Vogel R., 2007, Photochem. Photobiol. sourceExperimental — accuracy not yet measured

In the paper

“Retinosomes are located close to the RPE plasma membrane and are essential components for 11-cis-retinal production.”

What the sources say

• Partly supported

  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)

  cites [282] Imanishi Y., 2004, J. Cell Biol. sourceExperimental — accuracy not yet measured
• Partly supported

  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)

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

  The Abstract says retinosomes are located close to the RPE plasma membrane and accumulate fatty acid–esterified retinol essential for 11-cis-retinal production. The Discussion likewise places retinosomes close to the plasma membrane. No page numbers are supplied in our copy. (LLM, conf=0.90)

  cites [313] Palczewska G., 2010, Nat. Med. source

In the paper

“The determined molecular envelope accommodated two rhodopsin molecules together with one transducin heterotrimer, indicating a heteropentameric structure for the photoactivated rhodopsin–transducin complex.”

What the sources say

• Supported

  The Introduction states that the three-dimensional molecular envelope accommodates one rhodopsin dimer and one transducin heterotrimer. It also reports a measured stoichiometry of two rhodopsin molecules per transducin heterotrimer, supporting the described heteropentameric structure. (LLM, conf=0.94)

  cites [334] Jastrzebska B., 2011, J. Struct. Biol. source

In the paper

“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”

What the sources say

• Partly supported

  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)

  cites [314] Sparrow J. R., 2010, J. Lipid Res. sourceExperimental — accuracy not yet measured
• Partly supported

  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)

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

  The Discussion (page not provided) says retinal condensation products accumulate in the RPE and that TPM excitation at about 910 nm primarily detects their fluorescence, while about 730 nm images retinosomes. It also describes distinct fluorescence spectra and cellular distributions; the introductory passage explicitly says these products can be spectrally resolved from retinyl esters to monitor them independently. (LLM, conf=0.94)

  cites [313] Palczewska G., 2010, Nat. Med. source

In the paper

“Physiologically, the minimal building block of rhodopsin is a dimer in which only one monomer is activated under normal lighting conditions”

What the sources say

• ?Not checked — no full text of the sourcecites [330] Fotiadis D., 2003, Nature source
• Partly supported

  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)

  cites [331] Vahedi-Faridi A., 2013, J. Electron Microsc. (Tokyo) sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [332] Jastrzebska B., 2013, FASEB J. sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [333] Orban T., 2012, Structure sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [334] Jastrzebska B., 2011, J. Struct. Biol. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [335] Jastrzebska B., 2004, J. Biol. Chem. source

In the paper

“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.”

What the sources say

• Supported

  Citation 182 is attached to the chromophore’s cis/trans isomerization, not to Schiff-linkage deprotonation or water reorganization. In the Discussion (p. 303), the paper says retinene enters rhodopsin in one configuration and emerges from bleaching primarily or wholly all-trans; the discussion on p. 308 likewise places the transition to all-trans during bleaching. (LLM, conf=0.91)

  cites [182] Hubbard R., 1952, J. Gen. Physiol. source
• Partly supported

  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)

  cites [339] Wald G., 1957, J. Gen. Physiol. sourceExperimental — accuracy not yet measured
• ?Could not verify

  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)

  cites [333] Orban T., 2012, Structure sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [340] Angel T. E., 2009, Proc. Natl. Acad. Sci. U.S.A. source
• Partly supported

  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)

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

  The cited source is offered for the water-reorganization part of the sentence; the other two mechanisms have separate citations. In §3, “Footprinting of a model GPCR – rhodopsin” (page not provided), the paper attributes a change upon activation to the altered positioning of an internal water molecule near the Schiff base. (LLM, conf=0.88)

  cites [342] Orban T., 2010, Biochemistry source

In the paper

“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”

What the sources say

• Partly supported

  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)

  cites [291] Imanishi Y., 2004, J. Cell Biol. sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [306] Bok D., 1984, Invest. Ophthalmol. Vis. Sci.
• Supported

  The Introduction states that CRALBP expression in Müller glia cells suggests a role in cone visual pigment regeneration. The expression-results section confirms that Cralbp b protein is expressed in zebrafish Müller glia cells, supporting the cited hypothesis. Page numbers are not provided in our copy. (LLM, conf=0.93)

  cites [307] Fleisch V. C., 2008, J. Neurosci. source

In the paper

“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.”

What the sources say

• Supported

  Section 1 says RPE lipofuscin amasses with age and originates largely from ingestion of shed photoreceptor outer segments. Sections 3.1–3.2 describe the initial bisretinoid-forming reactions in those outer segments, while section 7.6 says bisretinoids accumulate in RPE cells with age because the cells cannot metabolize them. The copy does not specify the daily frequency of phagocytosis, but supports the attributed process. (LLM, conf=0.88)

  cites [270] Sparrow J. R., 2012, Prog. Retinal Eye Res. source
• Supported

  The section on phosphatidyl-bisretinoid species says bisretinoids form in photoreceptors and are transferred to RPE cells in phagocytosed outer-segment material as the segments are shed and replaced. The paper also describes their accumulation in RPE cells with age and the initiation of the bisretinoid pathway in photoreceptor membranes. The indexed passages do not specify page numbers. (LLM, conf=0.90)

  cites [314] Sparrow J. R., 2010, J. Lipid Res. source

In the paper

“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”

What the sources say

• Supported

  The Abstract and Discussion (page numbers unavailable) report that prRDH localizes to rod and cone outer segments, that its C-terminal sequence supports efficient targeting there, and that fatty acylation of conserved C-terminal cysteines mediates membrane association. (LLM, conf=0.90)

  cites [389] Luo W., 2004, J. Neurosci. source

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [378] Chang Y. H., 2007, J. Biol. Chem. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [379] Ensor C. M., 1991, Biochem. Biophys. Res. Commun. source
• Partly supported

  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)

  cites [380] Obeid J., 1992, Biochem. Biophys. Res. Commun. sourceExperimental — accuracy not yet measured
• Partly supported

  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)

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

In the paper

“all-trans-retinyl ester could not easily be accommodated in the RPE65 active site whereas 11-cis- and 13-cis-retinyl esters could.467”

What the sources say

• Partly supported

  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)

  cites [467] Chander P., 2012, J. Biol. Chem. sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• Partly supported

  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)

  cites [406] Moise A. R., 2007, J. Biol. Chem. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [407] Bussieres S., 2012, Langmuir source

In the paper

“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.”

What the sources say

• ?Could not verify

  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)

  cites [287] Kiser P. D., 2012, Biochim. Biophys. Acta sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

  The Discussion reports retinyl ester formation in the intestines of LRAT-deficient mice and finds those esters in chylomicrons. The paper further suggests that an acyl-CoA-dependent enzyme acts as a physiologically significant ARAT; its Results report dietary retinoid uptake despite the absence of LRAT. This supports the citing sentence’s qualified claim that ARAT may contribute to ester formation, uptake, and chylomicron packaging. (LLM, conf=0.86)

  cites [402] O’Byrne S. M., 2005, J. Biol. Chem. source

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [411] Golczak M., 2012, J. Biol. Chem. source
• ?Not checked — no full text of the sourcecites [419] Jin X. H., 2007, J. Biol. Chem. source
• ?Not checked — no full text of the sourcecites [420] Shinohara N., 2011, J. Lipid Res. source
• ?Not checked — no full text of the sourcecites [421] Uyama T., 2009, Biochim. Biophys. Acta source
• Partly supported

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

  cites [422] Uyama T., 2009, J. Lipid Res. sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [147] Batten M. L., 2004, J. Biol. Chem. source
• Partly supported

  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)

  cites [402] O’Byrne S. M., 2005, J. Biol. Chem. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [403] Liu L., 2005, J. Biol. Chem. source

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [477] Law W. C., 1988, Biochemistry source
• ?Not checked — no full text of the sourcecites [478] Jang G. F., 2000, J. Biol. Chem. source
• Partly supported

  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)

  cites [171] McBee J. K., 2000, Biochemistry sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [374] Duester G., 2000, Eur. J. Biochem. source
• Partly supported

  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)

  cites [390] Liden M., 2006, J. Biol. Chem. sourceExperimental — accuracy not yet measured

In the paper

“Two isoforms of the protein, CRBP I and CRBP II with ∼50% sequence identity depending on the species, exhibit differential tissue expression.494”

What the sources say

• Supported

  The Functions of CRBPs section reports 56% sequence identity between rat CRBP-I and CRBP-II and notes that each protein is highly conserved across species. The same section describes their strikingly different tissue distributions: CRBP-I occurs in multiple adult tissues, whereas adult CRBP-II is restricted to the small intestine. (LLM, conf=0.91)

  cites [494] Noy N., 2000, Biochem. J. source

In the paper

“But this process could be facilitated by ATP-dependent transporters such as ABCA476,485−487 or the channel-like property of STRA6.488−492”

What the sources say

• Supported

  Section 5.1 identifies retinal and N-retinylidene-PE as proposed transported substrates of ABCA4, and section 5.2 describes ATP-dependent translocation. Section 5.4 specifically suggests that ABCA4 may accelerate retinal clearance across the disk membrane, matching the claim’s tentative wording. The STRA6 clause has separate citations and is not attributed to this paper. (LLM, conf=0.92)

  cites [76] Tsybovsky Y., 2010, Adv. Exp. Med. Biol. source
• ?Not checked — no full text of the sourcecites [485] Molday R. S., 2006, Adv. Exp. Med. Biol. source
• Supported

  The ABCA4 citation supports the ATP-dependent transporter part of the sentence. Section 2.8 describes ABCA4 as using ATP hydrolysis to move a retinoid-containing lipid across the photoreceptor disc membrane. STRA6 has a separate citation group and is not attributed to this source. (LLM, conf=0.92)

  cites [486] Molday R. S., 2010, Prog. Lipid Res. source
• Supported

  The ABCA4 citation supports the ABCA4 portion of the sentence; separate citations accompany the STRA6 portion. Sections 4.2 and 5 describe a retinoid-derived substrate binding to ABCA4 and an ATP-dependent proposed transport mechanism. Section 8 notes that direct transport across disc membranes had not yet been demonstrated, consistent with the citing sentence’s tentative “could.” (LLM, conf=0.90)

  cites [487] Molday R. S., 2009, Biochim. Biophys. Acta source
• ?Not checked — no full text of the sourcecites [488] Kawaguchi R., 2007, Science source
• ?Not checked — no full text of the sourcecites [489] Isken A., 2008, Cell Metab. source
• Partly supported

  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)

  cites [490] Kim Y. K., 2008, J. Biol. Chem. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [491] Hu J., 2010, Methods Mol. Biol. source
• Partly supported

  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)

  cites [492] Amengual J., 2012, J. Biol. Chem. sourceExperimental — accuracy not yet measured

In the paper

“CRALBP is one of the founding members of the CRAL-TRIO protein family, members of which share a common three-dimensional architecture.505−507”

What the sources say

• ?Could not verify

  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)

  cites [505] Punta M., 2012, Nucleic Acids Res. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [506] Sha B., 1998, Nature source
• Partly supported

  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)

  cites [507] He X. Q., 2009, Proc. Natl. Acad. Sci. U.S.A. sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [59] McBee J. K., 2001, Prog. Retinal Eye Res. source
• ?Not checked — no full text of the sourcecites [73] Pepperberg D. R., 1993, Mol. Neurobiol. source
• Partly supported

  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)

  cites [171] McBee J. K., 2000, Biochemistry sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [279] Rozanowska M., 2005, Photochem. Photobiol. source
• ?Not checked — no full text of the sourcecites [285] Saari J. C., 2012, Annu. Rev. Nutr. source

In the paper

“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”

What the sources say

• Supported

  The Results and Discussion describe an eight-stranded β-barrel with the retinol molecule inside it and identify the retinol-binding site. The Introduction states that the retinol–RBP complex was crystallized. No page numbers are supplied in our copy. (LLM, conf=0.93)

  cites [495] Newcomer M. E., 1984, EMBO J. source

In the paper

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

What the sources say

• Partly supported

  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)

  cites [494] Noy N., 2000, Biochem. J. sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [495] Newcomer M. E., 1984, EMBO J. sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [59] McBee J. K., 2001, Prog. Retinal Eye Res. source
• ?Not checked — no full text of the sourcecites [73] Pepperberg D. R., 1993, Mol. Neurobiol. source
• ?Could not verify

  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)

  cites [171] McBee J. K., 2000, Biochemistry sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [279] Rozanowska M., 2005, Photochem. Photobiol. source
• ?Not checked — no full text of the sourcecites [285] Saari J. C., 2012, Annu. Rev. Nutr. source

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [495] Newcomer M. E., 1984, EMBO J. sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [510] Shaw N. S., 2001, Exp. Eye Res. source
• Partly supported

  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)

  cites [511] Gonzalez-Fernandez F., 2007, BMC Biochem. sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• Partly supported

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

  cites [476] Stecher H., 1999, J. Biol. Chem. sourceExperimental — accuracy not yet measured
• ?Not matched

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

  cites [500] Futterman S., 1977, Invest. Ophthalmol. Vis. Sci.
• Partly supported

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

  cites [501] Bunt-Milam A. H., 1983, J. Cell Biol. sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [64] Travis G. H., 2007, Annu. Rev. Pharmacol. Toxicol. source
• Partly supported

  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)

  cites [400] Maeda A., 2007, Proc. Natl. Acad. Sci. U.S.A. sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• Partly supported

  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)

  cites [76] Tsybovsky Y., 2010, Adv. Exp. Med. Biol. sourceExperimental — accuracy not yet measured
• Supported

  The Results section (Glycosylation Sites of Native Bovine ABCA4; page not provided) identifies seven glycosylation sites across ECD1 and ECD2 and says their locations are consistent with the topological model. The Discussion (ABCA4 Phosphorylation Sites; page not provided) reports five phosphorylation sites in CD1. (LLM, conf=0.95)

  cites [521] Tsybovsky Y., 2011, Biochemistry source
• Partly supported

  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)

  cites [522] Bungert S., 2001, J. Biol. Chem. sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• Partly supported

  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)

  cites [544] Haralampus-Grynaviski N. M., 2003, Proc. Natl. Acad. Sci. U.S.A. sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• Supported

  The paper’s biosynthesis overview (page unavailable) identifies N-retinylidene-phosphatidylethanolamine as the initial adduct and says it undergoes [1,6]-proton tautomerization to form a phosphatidylethanolamine-retinyl enamine. It describes this pathway as leading to A2-PE and then A2E, with iso-A2E arising by photoisomerization. (LLM, conf=0.89)

  cites [536] Ben-Shabat S., 2002, J. Biol. Chem. source
• Partly supported

  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)

  cites [537] Kaufman Y., 2011, J. Biol. Chem. sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• Partly supported

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

  cites [76] Tsybovsky Y., 2010, Adv. Exp. Med. Biol. sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• Supported

  The Discussion’s proposed pathway (Fig. 10) says C20 of the NRPE tautomer reacts with C13 of free all-trans-retinal in a Michael-type [1,4] addition, followed by a Mannich reaction that closes the ring. The claim describes this proposed route rather than an experimentally established mechanism. (LLM, conf=0.91)

  cites [534] Fishkin N. E., 2005, Proc. Natl. Acad. Sci. U.S.A. source

In the paper

“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”

What the sources say

• Partly supported

  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)

  cites [528] Plack P. A., 1969, Biochem. J. sourceExperimental — accuracy not yet measured

In the paper

“Consequently, retinal samples collected from these patients revealed elevated levels of N-retinylidene-PE and overaccumulation of A2E in the RPE.529”

What the sources say

• Partly supported

  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)

  cites [529] Mata N. L., 2000, Proc. Natl. Acad. Sci. U.S.A. sourceExperimental — accuracy not yet measured

In the paper

“This reversible reaction is highly dependent on the presence of water.”

What the sources say

• Supported

  Table 1 reports formation and backward-reaction constants for the retinal–phosphatidylethanolamine Schiff base, supporting reversibility. The discussion of equilibrium constants explains that water concentration enters the equilibrium calculation and that the constants vary with solvent water content (page not available in our copy). (LLM, conf=0.89)

  cites [528] Plack P. A., 1969, Biochem. J. source

In the paper

“A2E was shown to be further metabolized by horseradish peroxidase,543 but there is yet no evidence that this process occurs in vivo.”

What the sources say

• Supported

  Citation 543 is attached to the claim that horseradish peroxidase metabolizes A2E. The Discussion states that A2E is a substrate for HRP-mediated oxidation and degradation; the Results report reduced A2E in a cell-free assay. The sentence's separate in-vivo caveat follows the citation and is not attributed to this source. (LLM, conf=0.93)

  cites [543] Wu Y., 2011, J. Am. Chem. Soc. source

In the paper

“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”

What the sources say

• Partly supported

  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)

  cites [524] Sun H., 1999, J. Biol. Chem. sourceExperimental — accuracy not yet measured
• Partly supported

  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)

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

In the paper

“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”

What the sources say

• Partly supported

  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)

  cites [539] Sparrow J. R., 2003, Vision Res. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [540] Rozanowski B., 2008, Photochem. Photobiol. source
• ?Not checked — no full text of the sourcecites [541] Rozanowski B., 2008, Invest. Ophthalmol. Vis. Sci. source

In the paper

“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”

What the sources say

• Supported

  The section “RGR-Opsin Modulates Retinyl Ester Processing Activities” states that RGR-opsin light-modulates all-trans-retinyl ester synthesis and degradation. It also reports that loss of RGR significantly reduces isomerase activity in mice without changing Rpe65 protein levels, supporting the claim that RGR influences Rpe65 activity. (LLM, conf=0.94)

  cites [576] Radu R. A., 2008, J. Biol. Chem. source

In the paper

“The structure of RPE65452,455 definitely provided an incentive for obtaining structures of other membrane associated proteins including LRAT and RDHs.”

What the sources say

• Supported

  The Results and Discussion (page not provided) report that the authors solved the crystal structure of bovine RPE65 and describe its membrane-associated features. The citation identifies that structure; the statement that it inspired work on LRAT and RDHs is the citing authors’ interpretation, not a finding attributed to this paper. (LLM, conf=0.90)

  cites [452] Kiser P. D., 2009, Proc. Natl. Acad. Sci. U.S.A. source
• Supported

  The Abstract reports the crystal structure of RPE65 in a membrane-like environment. The citation identifies that structure; the statement that it provided an incentive to study LRAT and RDHs is the citing authors’ own interpretation. (LLM, conf=0.88)

  cites [455] Kiser P. D., 2012, Proc. Natl. Acad. Sci. U.S.A. source

In the paper

“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”

What the sources say

• Partly supported

  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)

  cites [318] Maeda A., 2009, J. Biol. Chem. sourceExperimental — accuracy not yet measured
• Partly supported

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

  cites [572] Maeda A., 2012, Nat. Chem. Biol. sourceExperimental — accuracy not yet measured
• Partly supported

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

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

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [545] Allikmets R., 1997, Nat. Genet. source
• Partly supported

  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)

  cites [558] Cideciyan A. V., 2009, Hum. Mol. Genet. sourceExperimental — accuracy not yet measured
• ?Not matched

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

  cites [559] Allikmets R., 1997, Nat. Genet.
• ?Not checked — no full text of the sourcecites [560] Allikmets R., 1999, Eur. J. Ophthalmol. source
• ?Not checked — no full text of the sourcecites [561] Allikmets R., 2000, Am. J. Hum. Genet. source

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [513] Adler A. J., 1987, J. Biol. Chem. source

In the paper

“IRBP can also bind a number of nonretinoid, hydrophobic ligands, but the physiological significance of this capability is not currently understood.512”

What the sources say

• ?Not checked — no full text of the sourcecites [512] Gonzalez-Fernandez F., 2008, Exp. Eye Res. source

In the paper

“It can also effectively bind 9-cis-retinoids as well but not 13-cis-retinoids.502”

What the sources say

• ?Not checked — no full text of the sourcecites [502] Saari J. C., 1987, J. Biol. Chem. source

In the paper

“Domain A adopts a ββα-spiral fold whereas domain B forms an αβα sandwich.”

What the sources say

• ?Not checked — no full text of the sourcecites [514] Loew A., 2002, Structure source

In the paper

“This is evidenced by accumulation of all-trans-retinol in the retina and reduced formation of retinyl esters in the RPE.498”

What the sources say

• ?Not matched

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

  cites [498] Saari J. C., 2002, Invest. Ophthalmol. Vis. Sci.

In the paper

“The crystal structure of an isolated module from X. laevis IRBP has been determined, revealing a two-domain architecture.514”

What the sources say

• ?Not checked — no full text of the sourcecites [514] Loew A., 2002, Structure source

In the paper

“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).”

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [317] Sparrow J. R., 2003, Adv. Exp. Med. Biol. source

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [100] Farre G., 2010, Plant Sci. source

In the paper

“Naturally occurring carotenoids are all synthesized from two basic 5-carbon precursors: isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP).87”

What the sources say

• ?Not checked — no full text of the sourcecites [87] Walter M. H., 2011, Nat. Prod. Rep. source

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [105] Kaneda K., 2001, Proc. Natl. Acad. Sci. U.S.A. source
• ?Not checked — no full text of the sourcecites [106] Berthelot K., 2012, Biochimie source

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [106] Berthelot K., 2012, Biochimie source

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [87] Walter M. H., 2011, Nat. Prod. Rep. source

In the paper

“Interestingly, CrtIso shares significant sequence homology with the carotene desaturase (CrtI) as well as a mammalian enzyme known as retinol desaturase (RetSat).63,125”

What the sources say

• ?Not checked — no full text of the sourcecites [63] Moise A. R., 2005, Trends Plant Sci. source
• ?Not checked — no full text of the sourcecites [125] Moise A. R., 2004, J. Biol. Chem. source

In the paper

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

In the paper

“Such 30–60 kDa proteins were given the name “opsins””

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [209] Pichaud F., 2002, Curr. Opin. Genet. Dev. source
• ?Not checked — no full text of the sourcecites [210] Pichaud F., 2002, Nature source

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [192] Deval P., 1988, J. Photochem. Photobiol., A: Chem. source
• ?Not checked — no full text of the sourcecites [193] Waddell W. H., 1976, J. Am. Chem. Soc. source

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [181] Rando R. R., 1983, J. Am. Chem. Soc. source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites [166] Blatz P. E., 1972, Anal. Chem. source

In the paper

“whereas in higher organisms they are coupled to G proteins and therefore are called G protein-coupled receptors (GPCRs).”

In the paper

“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.”

In the paper

“First, light is focused by passing through two proteinaceous biological lenses at the front of the eye, namely the cornea and lens.”

What the sources say

• ?Not checked — no full text of the sourcecites [242] Rodieck R. W., 1998

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [188] Rosenfel. T., 1974, J. Phys. Chem. source
• ?Not checked — no full text of the sourcecites [193] Waddell W. H., 1976, J. Am. Chem. Soc. source
• ?Not checked — no full text of the sourcecites [197] Ganapathy S., 1990, J. Chem. Soc., Chem. Commun. source
• ?Not checked — no full text of the sourcecites [198] Rosenfel. T., 1974, Photochem. Photobiol. source

In the paper

“Rods and cones are the two morphologically distinct types of ciliated photoreceptor cells found in human retina”

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [172] Pakhomova S., 2001, Nat. Struct. Biol. source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [246] Baylor D. A., 1979, J. Physiol. source
• ?Not matched

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

  cites [247] Baylor D. A., 1987, Invest. Ophthalmol. Vis. Sci.

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [259] Liang Y., 2004, J. Biol. Chem. source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [260] Nag T. C., 2012, Micron source
• ?Not checked — no full text of the sourcecites [261] Bok D., 1993, J. Cell Sci. Suppl. source
• ?Not checked — no full text of the sourcecites [262] Booij J. C., 2010, Prog. Retinal Eye Res. source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [242] Rodieck R. W., 1998

In the paper

“rod and cone photoreceptors constitute more than 75% of the cells.”

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [300] Schnapf J. L., 1990, J. Physiol. source
• ?Not checked — no full text of the sourcecites [301] Penn R. D., 1972, Biophys. J. source

In the paper

“Without RPE cells, our vision would not be sustainable.”

In the paper

“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”

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [243] Quiring R., 1994, Science source
• ?Not checked — no full text of the sourcecites [244] Halder G., 1995, Science source
• ?Not checked — no full text of the sourcecites [245] Gehring W., 2003, J. Mol. Evol. source

In the paper

“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.”

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [263] Gao H., 1992, Invest. Ophthalmol. Vis. Sci.

In the paper

“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.”

In the paper

“Once released from ROS, all-trans-retinal is reduced to all-trans-retinol which then diffuses into the RPE.”

In the paper

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

In the paper

“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.”

In the paper

“Although rhodopsin is not uniformly distributed throughout disks,84,328 its local high density within each disk allows efficient absorption of light.”

What the sources say

• ?Not checked — no full text of the sourcecites [84] Palczewski K., 2006, Annu. Rev. Biochem. source
• ?Not checked — no full text of the sourcecites [328] Molday R. S., 1998, Invest. Ophthalmol. Vis. Sci.

In the paper

“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”

In the paper

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

In the paper

“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).”

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [305] Das S. R., 1992, Biochem. J. source

In the paper

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

In the paper

“The 11-cis-retinylidene bond is protonated, and Glu113 is the counterion of this linkage.”

In the paper

“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.”