Chemistry of the Retinoid (Visual) Cycle

In the paper

“However, only RDH’s contribute to vision-related metabolism of retinoids.”

What the sources say

• Disputed

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

  Checked by a reasoning model — may be wrong.

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

In the paper

“Unlike retinyl esters, which are hydrolyzed to retinol in the small intestine followed by rapid absorption by enterocytes, uptake of carotenoids is mediated and regulated by scavenger receptor class-B type-I (SR-BI).131,132”

What the sources say

• Supported

  The Results section reports that SR-BI knockdown decreased uptake of three carotenoids in Caco-2 cells, with uptake inhibition similar in extent to the knockdown. The Discussion identifies SR-BI as the apical transporter whose inhibition affected carotenoid uptake, supporting the claim that SR-BI mediates and regulates uptake in this cell model. (LLM, conf=0.90)

  cites [131] During A., 2007, J. Lipid Res. source
• ?Not checked — no full text of the sourcecites [132] van Bennekum A., 2005, Biochemistry source

In the paper

“Upon absorption by enterocytes, β,β-carotene undergoes oxidative cleavage catalyzed by β,β-carotene 15,15′-monooxygenase (BCMO1).133,134 This symmetric split of the carotenoid produces two molecules of all-trans-retinal that subsequently enter vitamin A metabolic pathways (Figure 5).”

What the sources say

• ?Not checked — no full text of the sourcecites [133] von Lintig J., 2000, J. Biol. Chem. source
• Partly supported

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

  cites [134] Hessel S., 2007, J. Biol. Chem. sourceExperimental — accuracy not yet measured

In the paper

“Mammals efficiently utilize both preformed vitamin A in the form of all-trans-retinyl esters and pro-vitamin A carotenoids (mainly β,β-carotene) to sustain the body pool of vitamin A.130”

What the sources say

• Partly supported

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

  cites [130] Paik J., 2004, J. Nutr. sourceExperimental — accuracy not yet measured

In the paper

“Instead, all-trans-retinal is first reduced to all-trans-retinol by short-chain dehydrogenase/reductase (SDR) or alcohol dehydrogenase enzymes.136,143,144”

What the sources say

• Partly supported

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

  cites [136] Kumar S., 2012, Biochim. Biophys. Acta sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [143] Rattner A., 2000, J. Biol. Chem. source
• Partly supported

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

  cites [144] Haeseleer F., 1998, J. Biol. Chem. sourceExperimental — accuracy not yet measured

In the paper

“Animal homologues of the plant enzyme are inactive toward prolycopene.125,205”

What the sources say

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

  The Discussion (page unavailable) identifies animal RetSat as related to plant CRTISO and says CRTISO isomerizes prolycopene. The paper reports RetSat activity with retinol substrates, but the passages found do not test or state whether animal homologues are inactive toward prolycopene (searched: prolycopene and RetSat substrate activity). (LLM, conf=0.73)

  cites [205] Moise A. R., 2007, Biochemistry sourceExperimental — accuracy not yet measured

In the paper

“Rhabdomeric and ciliary photoreceptors also employ fundamentally different mechanisms for regeneration of their visual pigments following light stimulation.”

What the sources say

• Supported

  The section “Implications of the nature of the regeneration of 11-cis-retinaldehyde” explicitly says that protostome rhabdomeric and vertebrate ciliary photoreceptors use “fundamentally different approaches” to regenerate visual pigment after light absorption. It describes light-driven photoreversal for rhabdomeric opsins and a dark retinoid cycle for the vertebrate ciliary system. No page number is provided in the supplied copy. (LLM, conf=0.95)

  cites [233] Lamb T. D., 2009, Philos. Trans. R. Soc. London, B: Biol. Sci. source

In the paper

“in bacteria they function as cation and anion pumps,217−223”

What the sources say

• ?Not checked — no full text of the sourcecites [217] Nagel G., 2005, Biochem. Soc. Trans. source
• Partly supported

  The Introduction (page not available) describes proton-translocating bacteriorhodopsins and chloride-translocating halorhodopsins, supporting the cation- and anion-pump functions. But it identifies these as archaeal rhodopsins, not opsins functioning as both types of pump in bacteria. (LLM, conf=0.86)

  cites [218] Zhai Y., 2001, Biochim. Biophys. Acta sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [219] Pedros-Alio C., 2006, Int. Microbiol.
• ?Not checked — no full text of the sourcecites [220] Kennis J. T., 2007, Curr. Opin. Struct. Biol. source
• Partly supported

  Section 4.4, “Bacteriorhodopsin” (page unavailable), describes bacteriorhodopsin as a light-driven pump that transports protons, which are cations, across a cell membrane. It does not describe anion pumping, so it supports only the cation part of the claim. (LLM, conf=0.88)

  cites [221] Rossle S. C., 2009, Front. Biosci. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [222] Davies W. L., 2010, Photochem. Photobiol. Sci. source
• ?Not checked — no full text of the sourcecites [223] Purschwitz J., 2006, Curr. Opin. Microbiol. source

In the paper

“the chromophores are retinals bound to opsin via a Schiff base (retinylidene) group with a transmembrane domain (TMD) Lys residue.”

What the sources say

• ?Not checked — no full text of the sourcecites [60] Okada T., 2001, Trends Biochem. Sci. source
• ?Not checked — no full text of the sourcecites [61] Filipek S., 2003, Annu. Rev. Physiol. 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 [84] Palczewski K., 2006, Annu. Rev. Biochem. source
• Supported

  The Introduction describes a Schiff base linkage between the retinal chromophore and K7.43[296]. Its residue-numbering explanation identifies K7.43 as a lysine in helix 7, one of rhodopsin’s transmembrane helices. (LLM, conf=0.94)

  cites [224] Filipek S., 2003, Annu. Rev. Biophys. Biomol. Struct. 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
• ?Not checked — no full text of the sourcecites [227] Okada T., 2001, Curr. Opin. Struct. Biol. source
• ?Not checked — no full text of the sourcecites [228] Rao V. R., 1996, Annu. Rev. Biophys. Biomol. Struct. source

In the paper

“Cyanobacterial and plant CrtIso catalyze the isomerization of (7Z,9Z,9′Z,7′Z)-tetra-cis-lycopene (prolycopene) to all-trans-lycopene.200−203 This enzyme-mediated isomerization employing redox cofactors occurs through a reversible saturation–desaturation reaction of the cis-double bonds.204”

What the sources say

• Partly supported

  In “CRTISO Orthologs and Isomerase Activity in Vitro,” the paper reports that plant CRTISO increased all-trans-lycopene while decreasing poly-cis carotenoids. It identifies a homologous cyanobacterial sequence but does not demonstrate cyanobacterial enzyme activity. In “Carotenoid Isomerization,” it treats prolycopene as a possible substrate and describes electron holding as consistent with the enzyme’s structure, not a proven reversible saturation–desaturation mechanism. (LLM, conf=0.87)

  cites [200] Park H., 2002, Plant Cell sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [201] Isaacson T., 2002, Plant Cell source
• Partly supported

  The paper’s Abstract reports that expressing the Synechocystis gene sll0033 promotes formation of all-E lycopene and identifies it as a carotene isomerase, supporting the enzyme-mediated isomerization underlying the sentence cited as 204. It does not establish that this reaction uses redox cofactors or proceeds by reversible saturation–desaturation of cis double bonds; the Abstract says further experiments are needed to determine how the protein acts. No page number is available in our copy. (LLM, conf=0.84)

  cites [202] Breitenbach J., 2001, Z. Naturforsch., C sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [203] Masamoto K., 2001, Plant Cell Physiol. source
• Partly supported

  The ‘Carotenoid Biosynthesis in Plants Follows the cis-Desaturation Pathway’ section reports that tomato CRTISO converted prolycopene to all-trans-lycopene in vitro. The paper identifies a cyanobacterial CrtISO ortholog but does not show that it performs this conversion. In ‘CRTISO Activity Requires a Redox Mechanism,’ reversible reduction and reoxidation of the cis-double bond is proposed as a possible mechanism, not established as fact; page numbers are unavailable in our copy. (LLM, conf=0.87)

  cites [204] Isaacson T., 2004, Plant Physiol. sourceExperimental — accuracy not yet measured

In the paper

“several lines of evidence indicate that cone photoreceptors might have access to a special source of visual chromophore not available to rods85”

What the sources say

• Supported

  Section 3, “The cone-specific retina visual cycle” (page not provided), describes several lines of evidence for a second, cone-specific source of recycled chromophore. It contrasts that proposed pathway with the RPE cycle, which supplies both rods and cones, matching the claim’s qualified wording. (LLM, conf=0.93)

  cites [85] Wang J. S., 2011, Prog. Retinal Eye Res. source

In the paper

“after equal levels of bleaching, cones dark-adapt faster than rods by a factor of ∼10.”

What the sources say

• Partly supported

  Section IV (pp. 840–841) says cone dark adaptation is nearly complete in 4–5 minutes, while rod adaptation takes about ten times as long. The paper compares adaptation after exposure to light, but does not establish that rods and cones had equal levels of bleaching, so that condition is unsupported. (LLM, conf=0.87)

  cites [299] Hecht S., 1937, J. Gen. Physiol. sourceExperimental — accuracy not yet measured

In the paper

“The number and types of cones that collect photons in ambient light differ dramatically, from less than 1% in rats to more than 95% in the ground squirrel.”

What the sources say

• ?Not checked — no full text of the sourcecites [251] Szel A., 1993, Invest. Ophthalmol. Vis. Sci.
• Partly supported

  The “Rods and cones” section reports that cones make up 2.8% of mouse photoreceptors, and the Discussion compares mouse and primate photoreceptor populations. Our copy does not give the claimed percentages for rats or ground squirrels, or establish the stated range of cone types. (LLM, conf=0.78)

  cites [252] Jeon C. J., 1998, J. Neurosci. sourceExperimental — accuracy not yet measured

In the paper

“Several potentially toxic byproducts are condensation compounds derived from all-trans-retinal.”

What the sources say

• Supported

  Section 5.2 (page unavailable) describes all-trans-retinal reacting to form bis-retinoids, including A2PE and its derivative A2E. Section 5.4 reports more than 20 bis-retinoids and studies suggesting A2E can be toxic. The paper also notes that 11-cis-retinal may be another source, but that does not negate the claimed pathway. (LLM, conf=0.88)

  cites [69] Tang P. H., 2013, Prog. Retinal Eye Res. source
• Supported

  Section 3.2 describes A2E and A2PE forming through reactions involving two molecules of all-trans-retinal, while Section 3.4 says two all-trans-retinal molecules condense to form a dimer and related conjugate. Section 5 reports that these bisretinoids can produce damaging photoproducts, supporting the claim’s cautious description of them as potentially toxic. Page numbers are not provided in our copy. (LLM, conf=0.91)

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

In the paper

“Dysfunction of such processes as phagocytosis, lysosomal degradation, and removal of waste products by the RPE can lead to severe retinopathies, including age-related macular degeneration (AMD).”

What the sources say

• Partly supported

  Section 7.7 links RPE bisretinoid lipofuscin photooxidation to processes that may predispose the macula to AMD. But section 1 does not identify failed phagocytosis, lysosomal degradation, or waste removal as causes of retinopathy; it specifically argues against inhibited lysosomal enzymes as the explanation for lipofuscin accumulation. The claimed causal chain is therefore broader than the paper supports. (LLM, conf=0.82)

  cites [270] Sparrow J. R., 2012, Prog. Retinal Eye Res. sourceExperimental — accuracy not yet measured
• ?Not matched

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

  cites [271] Pagon R. A., 1993
• ?Not matched

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

  cites [272] Weleber R. G., 1993
• Partly supported

  Section 9.4 links compromised lysosomal/autophagic protein degradation to early AMD-like changes in mice, and Section 13 proposes that inadequate removal of oxidatively damaged molecules contributes to RPE injury and drusen formation. Section 2 identifies phagocytosis as an essential RPE function, but the paper does not establish that dysfunctional RPE phagocytosis causes AMD or the broader category of severe retinopathies. Page numbers were not available in our copy. (LLM, conf=0.84)

  cites [273] Handa J. T., 2012, Mol. Aspects Med. sourceExperimental — accuracy not yet measured
• ?Could not verify

  Section 4.3.3 describes RPE phagocytosis in the formation of lipofuscin, while Sections 4.1 and 6 link RPE65-related retinopathy to a block in the visual cycle. Searches for lysosomal degradation, waste removal, and age-related macular degeneration found no passage linking dysfunction of the processes named in the claim to retinopathy or AMD. The cited copy therefore does not address the claim's causal point. (LLM, conf=0.75)

  cites [274] Cideciyan A. V., 2010, Prog. Retinal Eye Res. sourceExperimental — accuracy not yet measured

In the paper

“these retinoid ester products then coalesce into lipid droplets termed retinosomes, which are found in vertebrate RPE.”

What the sources say

• Supported

  The Results section identifies retinyl ester storage particles in mouse RPE as “RESTs, or retinosomes.” The Discussion says esterified retinoids are trapped in RESTs, and the Results describe the structures as lipid droplet-like; mice are vertebrates. Page numbers were not available in our copy. (LLM, conf=0.88)

  cites [291] Imanishi Y., 2004, J. Cell Biol. source

In the paper

“Key residues in rhodopsin’s active site are Lys296, Glu113, and Glu181”

What the sources say

• ?Not checked — no full text of the sourcecites [60] Okada T., 2001, Trends Biochem. Sci. source
• ?Not checked — no full text of the sourcecites [139] Palczewski K., 2000, Science source
• ?Not checked — no full text of the sourcecites [226] Sakmar T. P., 2002, Annu. Rev. Biophys. Biomol. Struct. source
• ?Not checked — no full text of the sourcecites [227] Okada T., 2001, Curr. Opin. Struct. Biol. source
• Partly supported

  Section 6, “Retinal binding site” (page unavailable), identifies Lys-296 at the retinal Schiff-base linkage and Glu-113 nearby as a possible counterion. The available text does not identify Glu-181 as a key residue in that site, so only two of the three named residues are supported. (LLM, conf=0.85)

  cites [240] Stenkamp R. E., 2002, Biochim. Biophys. Acta sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [350] Bourne H. R., 2000, Science source
• ?Not checked — no full text of the sourcecites [351] Meng E. C., 2001, Trends Pharmacol. Sci. source
• ?Not checked — no full text of the sourcecites [352] Sakmar T. P., 2002, Curr. Opin. Cell Biol. source
• ?Not checked — no full text of the sourcecites [353] Stenkamp R. E., 2002, ChemBioChem source
• ?Not checked — no full text of the sourcecites [354] Okada T., 2004, J. Mol. Biol. source

In the paper

“On the basis of structural mass spectrometry techniques, we found that the transition of ground state rhodopsin to its photoactivated state causes a structural relaxation that then tightens upon transducin binding.”

What the sources say

• Partly supported

  The Abstract (page not provided) says the authors used structural mass spectrometry and that their measurements suggest rhodopsin relaxes with photoactivation and tightens upon transducin (Gt) coupling. The citing sentence presents that inferred structural sequence as a finding that definitively occurs, omitting the source’s uncertainty. (LLM, conf=0.84)

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

In the paper

“These esters can be minor or major components of lipid droplets that along with phospholipids total about 160 molecular species including other fatty acid esters, triglycerides, cholesterol, cholesterol esters, and various proteins.”

What the sources say

• Partly supported

  The “Chemical Makeup of Retinosomes and Lipid Droplets” section reports triglycerides, cholesterol, and cholesterol esters in purified bovine retinosomes, and Figure 7 describes proteins localized to them. But the approximately 160 molecular species refers specifically to the phospholipid composition of lipid droplets in a study the paper discusses, not to a count of all retinosome components, including proteins. (LLM, conf=0.88)

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

In the paper

“A candidate protein responsible for the alternative retinoid isomerization (all-trans-retinol to 11-cis-retinol) activity found in chicken retinas was identified as dihydroceramide desaturase-1 (DES-1)”

What the sources say

• Supported

  The paper states that it identified the protein responsible for isomerase-2 activity in chicken retinas, which acts on all-trans-retinol. The Discussion identifies DES1 and reports that DES1-expressing chicken Müller cells convert all-trans-retinol to 11-cis-retinol. (LLM, conf=0.93)

  cites [308] Kaylor J. J., 2013, Nat. Chem. Biol. source
• ?Not checked — no full text of the sourcecites [309] Shanklin J., 2009, J. Biol. Chem. source

In the paper

“We found that each of the dimeric rhodopsin monomers contributed differently to the pentameric complex, indicating a functional distinction between rhodopsin monomers in their oligomeric”

What the sources say

• Supported

  The Abstract states that the two rhodopsin monomers contribute unequally to the pentameric complex and have a functional distinction in their oligomeric form. The Discussion likewise reports different conformational properties for the two monomers in the rhodopsin–transducin complex. No page numbers are supplied in our copy. (LLM, conf=0.95)

  cites [332] Jastrzebska B., 2013, FASEB J. source

In the paper

“The dimeric structure of rhodopsin in the complex was confirmed using succinylated concanavalin A as a labeling probe.”

What the sources say

• Supported

  The Abstract says that visualization of sConA–Rho*–Gt complexes demonstrated an assembly in which a photoactivated rhodopsin dimer binds transducin. The Discussion says images of the sConA-labeled complexes further demonstrated the native arrangement of the rhodopsin dimer. (LLM, conf=0.94)

  cites [345] Jastrzebska B., 2013, J. Struct. Biol. source

In the paper

“These condensation products accumulate most prominently in mice lacking the ABCA4 transporter and retinol dehydrogenase 8 (RDH8)”

What the sources say

• Supported

  The Results section (“Abca4−/−Rdh8−/− mice accumulate high levels of A2E”; page not provided) states that mice lacking both genes accumulate large amounts of A2E and other all-trans-retinal condensation products, with brighter images than wild-type mice. (LLM, conf=0.94)

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

In the paper

“Retinosomes recruit proteins such as caveolin-1, perilipins PLIN1-3, sterol carrier protein-2, structural proteins, chaperone proteins, and redox enzymes.”

What the sources say

• Partly supported

  The Discussion identifies Adfp as a component of retinosomes, but the Expression Profiles section reports Tip47 mainly in the RPE cytoplasm and did not detect perilipin in the RPE (page numbers unavailable). The paper therefore does not establish recruitment of PLIN1–3 as a group; the searched passages also do not establish recruitment of caveolin-1, sterol carrier protein-2, chaperones, or redox enzymes. Its mention of cytoskeletal proteins concerns lipid droplets generally, not demonstrated recruitment to retinosomes. (LLM, conf=0.88)

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

  The Discussion (page unavailable) reports PLIN1–3 in the retinosome fraction and corroborates the presence of caveolin-1 and sterol carrier protein-2. Its analysis of proteins identified from retinosomes also includes structural proteins, heat-shock proteins and dehydrogenases, supporting the broader protein categories in the claim. (LLM, conf=0.88)

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

In the paper

“An integral part of the retinoid cycle is the interconversion of retinals and retinols.”

What the sources say

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

  The Introduction describes reduction of retinal to retinol as the first step of the retinoid cycle. It also identifies oxidation of 11-cis-retinol to 11-cis-retinal as another important reaction in the cycle. (LLM, conf=0.94)

  cites [287] Kiser P. D., 2012, Biochim. Biophys. Acta source

In the paper

“it is believed that a switch in the counterion occurs from Glu113 to Glu181.”

What the sources say

• Partly supported

  The Introduction identifies Glu113 as the retinal Schiff-base counterion and says its salt bridge breaks during the Meta I–Meta II transition. Neither that passage nor the passages retrieved for “Glu181” say that Glu181 takes over as counterion, so the proposed switch is not supported by our copy. (LLM, conf=0.83)

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

  The paper’s Abstract states that the primary counterion switches from Glu-113 in the dark state to Glu-181 in the Meta I state during rhodopsin photoactivation. The Discussion likewise presents this as the authors’ proposed counterion-switch model, consistent with the citing sentence’s hedging. (LLM, conf=0.94)

  cites [361] Yan E. C., 2003, Proc. Natl. Acad. Sci. U.S.A. source
• ?Not checked — no full text of the sourcecites [362] Ludeke S., 2005, J. Mol. Biol. source
• ?Not checked — no full text of the sourcecites [363] Kapoor N., 2009, J. Mol. Biol. source
• ?Not checked — no full text of the sourcecites [364] Maeda T., 2003, Prog. Retinal Eye Res. source

In the paper

“The crystal structure of opsin,370 an opsin structure with another retinoid bound,371 and mutagenesis studies372 all suggest an escape and entrance route for retinal.”

What the sources say

• ?Not checked — no full text of the sourcecites [370] Scheerer P., 2008, Nature source
• ?Not checked — no full text of the sourcecites [371] Makino C. L., 2010, Biophys. J. source
• Supported

  The Abstract says the opsin crystal structure provides the basis for modeling retinal release and uptake. In Results (‘A channel through opsin’; page unavailable), the authors analyze opsin crystal structures and identify a channel connecting the retinal-binding pocket to two openings. Citation 370 supports the crystal-structure-based route; the other structure and mutagenesis studies have separate citations. (LLM, conf=0.90)

  cites [372] Hildebrand P. W., 2009, PLoS One source

In the paper

“In contrast, SDR’s show a Tyr-based catalytic center with adjacent Ser and Lys residues.378−381”

What the sources say

• Supported

  The Abstract identifies Ser, Tyr, and Lys as catalytically important residues in the SDR family and says Tyr is the most conserved. It also describes Ser114, Tyr155, and Lys159 as an active-site triad in the SDR enzyme studied, supporting the claim's description of a Tyr-based center with nearby Ser and Lys. (LLM, conf=0.92)

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

  The Discussion (page not available in our copy) supports a catalytic role for Tyr-179 and Lys-183 in 11β-hydroxysteroid dehydrogenase and suggests a similar role in related enzymes. It does not identify an adjacent Ser residue in the catalytic center; its mentions of Ser concern a Tyr-to-Ser mutation and a comparison with serine proteases. (LLM, conf=0.87)

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

  The section “Structural and mechanistic aspects of SDR enzymes” states that the vast majority of SDRs have a Tyr-based catalytic center with adjacent Ser and Lys residues. The citing sentence expresses this as a general feature, not a claim that every SDR has it. (LLM, conf=0.91)

  cites [381] Kavanagh K. L., 2008, Cell. Mol. Life Sci. source

In the paper

“Thus, the final sequence of the catalytic tetrad of SDR’s is composed of Asn, Ser, Tyr, and Lys residues (Figure 21).383”

What the sources say

• Supported

  The ‘Reaction Mechanism of 3β/17β-HSD’ passage says the previously identified Ser–Tyr–Lys triad is extended by an essential Asn to form an active-site tetrad. The ‘Role of Conserved Residues in SDR Enzymes’ passage likewise describes the SDR SYK triad as forming a tetrad with conserved Asn-111. Page numbers are not provided in our copy. (LLM, conf=0.94)

  cites [383] Filling C., 2002, J. Biol. Chem. source

In the paper

“The catalytic mechanism of AKR’s, in principle, is similar to that found in SDR’s with an active site Tyr residue and an assisting Lys residue facilitating the deprotonation of the Tyr hydroxyl group.384”

What the sources say

• Partly supported

  The Acid/base Catalysis—Tyr-51 section identifies an active-site Tyr as the likely catalytic acid. But it says that, in AKR2B5, interaction with Lys-80 is not required to lower Tyr-51’s pKa; the Electrostatic stabilization—Lys-80 section instead proposes an electrostatic role for Lys. The cited passages do not establish the stated comparison with SDRs. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  cites [384] Kratzer R., 2006, IUBMB Life sourceExperimental — accuracy not yet measured

In the paper

“On the basis of its amino acid sequence and predicted tertiary structure, LRAT is classified as a member of the NlpC/P60 thiol peptidase protein superfamily (Figure 22).409”

What the sources say

• Supported

  The Sequence analysis and detection of novel divergent members section reports that sequence searches recovered LRAT and that its predicted secondary structure agreed with NlpC/P60 forms. The Structural and biochemical features section describes LRAT as a member of the superfamily and discusses its predicted thiol-protease fold. Page numbers are not provided in our copy. (LLM, conf=0.92)

  cites [409] Anantharaman V., 2003, Genome Biol. source

In the paper

“For example, RDH1, RDH3, RDH4, RDH6, and RDH7 reveal 25–60 times higher affinities for androgens than all-trans-retinol.391−393”

What the sources say

• ?Not checked — no full text of the sourcecites [391] Biswas M. G., 1997, J. Biol. Chem. source
• Partly supported

  Table I in the Discussion reports RoDH-4 Kₘ values of 0.14 and 0.22 µM for the androgen-related substrates androsterone and androstane-diol; Table III gives an all-trans-retinol inhibition Kᵢ of 5.8 µM. Those values support an approximately 26–41-fold affinity difference for RoDH-4, but the paper does not establish the claimed 25–60-fold range for RDH1, RDH3, RDH6, and RDH7. (LLM, conf=0.87)

  cites [392] Gough W. H., 1998, J. Biol. Chem. sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (Table III; page not available in our copy) show that CRAD2 acts on both androgen substrates and all-trans-retinol. But the reported K0.5 values—2.2 for 3α-adiol, 0.6 for androsterone, and 6.9 for all-trans-retinol—do not establish a 25–60-fold affinity difference. The paper also does not report that comparison for all five RDH enzymes named in the claim. (LLM, conf=0.87)

  cites [393] Su J., 1998, J. Biol. Chem. sourceExperimental — accuracy not yet measured

In the paper

“certain radical spin-trap compounds, for example N-tert-butyl-α-phenylnitrone (PBN) can inhibit RPE65-mediated isomerization in an uncompetitive manner.481,482”

What the sources say

• Supported

  The supplied passage labeled Abstract explicitly reports that PBN is an effective uncompetitive inhibitor of RPE65 (Ki = 61 μM). It also reports inhibition of RPE65 isomerohydrolase activity by aromatic lipophilic spin traps. (LLM, conf=0.94)

  cites [481] Poliakov E., 2011, Biochemistry source
• Supported

  The Results section (‘Effect of PBN on RPE65 Isomerohydrolase Activity’) reports parallel Lineweaver–Burk lines characteristic of uncompetitive inhibition by PBN. The Discussion identifies PBN as a free-radical spin trap and likewise states that it inhibits RPE65 uncompetitively. (LLM, conf=0.93)

  cites [482] Mandal M. N., 2011, J. Biol. Chem. source

In the paper

“However, studies of LRAT-deficient mice indicate that the intestinal absorption of vitamin A decreased to 50% that of wild type animals challenged with a physiologic dose of retinol.402”

What the sources say

• Supported

  The Lrat section (page not available in our copy) reports that, under the experimental conditions, chylomicron absorption of a physiological retinol dose in LRAT-deficient mice was 50–60% as efficient as in wild-type mice. The cited 50% is the lower end of that reported range. (LLM, conf=0.91)

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

In the paper

“Like other CCOs, RPE65 contains a ferrous iron cofactor within its active site directly coordinated in a distorted octahedral or trigonal bipyramidal fashion by His residues 180, 241, 313, and 527 (bovine and human sequence numbering) with Fe–Nε bond lengths between 2.1 and 2.2 Å.”

What the sources say

• Partly supported

  The Results and Discussion section identifies His180, His241, His313, and His527 as directly coordinating the iron through Nε atoms, and the RPE65 Enzymology subsection says catalytic activity requires ferrous iron. It reports an average Fe–Nε bond length of 2.2 Å, not the claimed range of 2.1–2.2 Å. It describes the coordination geometry as approximately octahedral, without the citing sentence’s trigonal-bipyramidal alternative. (LLM, conf=0.85)

  cites [452] Kiser P. D., 2009, Proc. Natl. Acad. Sci. U.S.A. sourceExperimental — accuracy not yet measured

In the paper

“The best characterized example is the acyltransferase activity of LRAT, which catalyzes the formation of retinyl esters by transferring an acyl group directly from the sn-1 position of phosphatidylcholine (PC) onto all-trans-retinol.145,146,414”

What the sources say

• Supported

  The Abstract (page not provided) says LRAT transfers an acyl group from lecithin to retinol to generate all-trans-retinyl esters. The Discussion (page not provided) specifies that LRAT uses acyl groups at the sn-1 position. The paper describes an acylated-enzyme intermediate, so ‘directly’ is supported as identifying lecithin as the acyl donor, not as a single-step mechanism. (LLM, conf=0.91)

  cites [145] Ruiz A., 1999, J. Biol. Chem. source
• ?Not checked — no full text of the sourcecites [146] MacDonald P. N., 1988, Biochem. Biophys. Res. Commun. source
• Partly supported

  The Abstract states that LRAT esterifies all-trans-retinol to form all-trans-retinyl ester, and its mechanism description says an acyl group passes from lecithin to vitamin A. The Results report ester formation using dipalmitoyl phosphatidylcholine. Our copy does not specify that the transferred acyl group comes from the sn-1 position, so that part of the claim is not supported. (LLM, conf=0.85)

  cites [414] Bok D., 2003, Biochemistry sourceExperimental — accuracy not yet measured

In the paper

“Mutations in the iron-coordinating His residues,447 the second sphere Glu residues,472−474 and even a third sphere of residues that form hydrogen bonding interactions with the second-sphere Glu residues468,475 either abolish or greatly reduce RPE65 activity.”

What the sources say

• Supported

  This citation is attached to the iron-coordinating His residues, not the later clauses about second- or third-sphere residues. The Results report that mutations of all four conserved histidines severely reduced or abolished isomerization activity; Table 1 lists each at less than 2% of wild-type activity. (LLM, conf=0.94)

  cites [447] Redmond T. M., 2005, Proc. Natl. Acad. Sci. U.S.A. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [472] Hanein S., 2004, Hum. Mutat. source
• Supported

  The citation to this paper is attached to the second-sphere Glu residues, not the separate claims about iron-coordinating His or third-sphere residues. The Results report that changing E417 to Q abolished detectable RPE65 activity, while changing it to D reduced activity approximately fivefold; the Discussion places E417 near an iron-coordinating His residue. These findings support this paper’s contribution to the cited claim. (LLM, conf=0.91)

  cites [473] Nikolaeva O., 2010, Biochem. Biophys. Res. Commun. sourceExperimental — accuracy not yet measured
• Supported

  This source is cited for the iron-coordinating His residues, not the second- or third-sphere residues assigned to other citations. Section 3.1 describes mutations of the four conserved His residues, and the Discussion reports that each abolished RPE65 activity; it identifies their role in iron binding from a structural model. (LLM, conf=0.91)

  cites [474] Takahashi Y., 2005, FEBS Lett. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [468] Redmond T. M., 2010, J. Biol. Chem. source

In the paper

“RPE65 is evolutionarily related to carotenoid cleavage oxygenases (CCOs), a group of enzymes that catalyze the oxidative cleavage of various carotenoids and apocarotenoids as well as certain other olefin-containing compounds, such as lignostilbenes.443,447”

What the sources say

• Partly supported

  The sequence-comparison passage links human RPE65 to VP14 and lignostilbene dioxygenase; the section “Evidence that VP14 Is the Cleavage Dioxygenase” reports oxidative cleavage of 9-cis-epoxy carotenoids. The paper also reports lignostilbene cleavage, but it does not establish apocarotenoids as substrates: it describes them as products or physiologically active compounds. (LLM, conf=0.86)

  cites [443] Tan B. C., 1997, Proc. Natl. Acad. Sci. U.S.A. sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract says RPE65 is closely related to carotenoid oxygenases, and the Discussion identifies an apocarotenal oxygenase as a related enzyme. Our copy does not describe the claimed range of compounds these enzymes oxidatively cleave, particularly lignostilbenes (searched for lignostilbenes, olefin-containing compounds, and oxidative cleavage). (LLM, conf=0.88)

  cites [447] Redmond T. M., 2005, Proc. Natl. Acad. Sci. U.S.A. sourceExperimental — accuracy not yet measured

In the paper

“On the basis of enzymatic studies, retinas isolated from cone-dominant species such as ground-squirrel and chicken revealed retinoid isomerase activity that, in contrast to RPE65, converts all-trans-retinol directly into 11-cis-retinol.302,430”

What the sources say

• ?Not checked — no full text of the sourcecites [302] Mata N. L., 2002, Neuron source
• Partly supported

  The Abstract reports an isomerase in cone-dominant chicken and ground-squirrel retinas, and the Discussion says chicken retinas directly convert all-trans-retinol to 11-cis-retinol, unlike the retinyl-ester-dependent activity in RPE. Our copy does not establish direct conversion specifically in ground-squirrel retinas or identify RPE65 as the enzyme tested in that comparison; it compares the chicken activity with RPE activity. (LLM, conf=0.84)

  cites [430] Mata N. L., 2005, Biochemistry sourceExperimental — accuracy not yet measured

In the paper

“In fact only RDH5, RDH8, RDH10, RDH11, RDH12, RDH13, RDH14, and retSDR1 were proven to be expressed in the retina or RPE, and their roles have been studied in the context of the visual (retinoid) cycle.68,287”

What the sources say

• Partly supported

  Sections 2–5 locate the listed RDHs and retSDR1 in the retina or RPE and discuss their possible or studied roles in the visual cycle. Section 5 explicitly says RDH13 and RDH14 are expressed in the retina. The review does not establish the claim’s exclusive “only” or “proven” wording; it also says RDH13 has no known role in the classical visual cycle. (LLM, conf=0.84)

  cites [68] Parker R. O., 2010, Exp. Eye Res. sourceExperimental — accuracy not yet measured
• Supported

  Section 3 (page not available in our copy) explicitly lists RDH5, RDH8, RDH10, RDH11, RDH12, RDH13, RDH14, and retSDR1 as identified by their expression in the retina and RPE. Its subsections describe expression evidence for the individual enzymes. (LLM, conf=0.91)

  cites [287] Kiser P. D., 2012, Biochim. Biophys. Acta source

In the paper

“Studies involving primary cultures of chicken Müller cells indicate that inner retinal ARAT enzymatic activity is associated with this cell type.85,302,431”

What the sources say

• Supported

  Section 4 reports that primary cultures of chicken Müller cells showed retinyl ester synthase activity and that this activity was subsequently confirmed to be ARAT. This supports the association attributed to the source; page numbers are not provided in our copy. (LLM, conf=0.93)

  cites [85] Wang J. S., 2011, Prog. Retinal Eye Res. source
• ?Not checked — no full text of the sourcecites [302] Mata N. L., 2002, Neuron source
• ?Could not verify

  The Results section, “Müller Cells are Part of the Retina Visual Cycle” (page unavailable), links Müller cells to cone pigment regeneration in isolated salamander retina. It does not report ARAT activity or experiments with primary cultures of chicken Müller cells; searches for ARAT and cultured chicken Müller cells found no such passage in our copy. (LLM, conf=0.76)

  cites [431] Wang J. S., 2009, Nat. Neurosci. sourceExperimental — accuracy not yet measured

In the paper

“Recently, the proposed mechanism was proved by trapping the catalytic intermediate in the absence of an acyl acceptor and directly detecting the covalent thioester protein modification by mass spectrometry.415”

What the sources say

• Supported

  The Discussion says the thioester intermediate can be stabilized in the absence of retinol, the acyl acceptor. The Identification of Acylated Amino Acid section reports mass-spectrometric detection of an acyl group on Cys 161 and says this directly demonstrated transient thioester bonds, providing proof for the proposed mechanism. (LLM, conf=0.93)

  cites [415] Golczak M., 2010, J. Biol. Chem. source

In the paper

“The basic fold is a seven bladed β-propeller capped on one face by a group of α-helices.”

What the sources say

• Supported

  The Results and Discussion describes the basic RPE65 motif as a seven-bladed β-propeller and says its top face is covered by a helical cap. This supports the cited description of the fold. (LLM, conf=0.95)

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

In the paper

“Unlike other binding proteins that contain a single retinoid-binding site, IRBP has at least three high affinity sites.”

What the sources say

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

  The Results section reports 3.19 ± 0.10 all-trans-retinol binding sites per full-length Xenopus IRBP molecule, with a dissociation constant of 0.30 ± 0.05 μM. A second binding analysis reports 3.53 ± 0.19 sites and similarly low dissociation constants, supporting the claim of at least three high-affinity retinoid-binding sites. (LLM, conf=0.93)

  cites [511] Gonzalez-Fernandez F., 2007, BMC Biochem. source

In the paper

“When required by the body, vitamin A liberated from its hepatic storage sites in Stellate cells by retinyl ester hydrolysis is complexed with a 21 kDa retinoid-binding protein belonging to the lipocalin family called retinol-binding protein 4 (RBP4) to form holo-RBP4.24”

What the sources say

• Partly supported

  The Discussion (page not provided) identifies holo-RBP as retinol bound to RBP, and reports an RBP molecular weight of approximately 21–22 kDa. The paper does not establish the claim’s hepatic stellate-cell storage and retinyl ester hydrolysis steps, or identify RBP as RBP4 or a lipocalin. (LLM, conf=0.88)

  cites [24] Kanai M., 1968, J. Clin. Invest. sourceExperimental — accuracy not yet measured

In the paper

“Two retinoid-binding proteins are specifically expressed in the eye.494”

What the sources say

• Supported

  The visual-cycle section says the eye contains two unique retinoid-binding proteins, CRALBP and IRBP. The ocular retinoid-binding proteins section also describes them as found specifically in retina and neural tissue. (LLM, conf=0.92)

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

In the paper

“The crystallographic structure of the CRALBP–11-cis-retinal complex has been determined, revealing a curved binding pocket with high shape complementarity to 9-cis and 11-cis retinoid isomers, consistent with its ligand-binding preferences.507”

What the sources say

• Partly supported

  The Results and Discussion report crystal structures of CRALBP bound to 11-cis-retinal and describe shape complementarity between that ligand and its binding pocket. They do not establish high shape complementarity for 9-cis retinoids; instead, they say the pocket favors 11-cis retinoids because the 9-cis isomer cannot adopt the same complementary shape. The cited passages have no page numbers in our copy. (LLM, conf=0.89)

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

In the paper

“Holo-RBP4 circulates in the plasma in complex with a second protein called transthyretin, which by increasing the molecular weight of the overall complex prevents holo-RBP4 from being excreted in the urine.24,496”

What the sources say

• Supported

  The Discussion says that plasma RBP circulates in a complex with a larger protein identified as thyroxine-binding prealbumin (transthyretin), and estimates the complex at 80,000–90,000 molecular weight. It explicitly says this interaction prevents glomerular filtration of the smaller RBP molecule and its loss in urine. Page numbers were not supplied for these passages. (LLM, conf=0.91)

  cites [24] Kanai M., 1968, J. Clin. Invest. source
• ?Not checked — no full text of the sourcecites [496] Naylor H. M., 1999, Biochemistry source

In the paper

“The structure of CRBP, similar to that of RBP4, features a β-barrel fold that houses the retinoid-binding site.495”

What the sources say

• Partly supported

  The Results and Discussion describe a β-barrel with retinol inside it for RBP, supporting the comparison protein’s structure. But the same section says the structure of cRBP had yet to be elucidated; it does not establish that cRBP has that fold or binding-site arrangement. Page numbers are unavailable in our copy. (LLM, conf=0.88)

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

In the paper

“Notably, domain B of the IRBP module shares structural similarity with the ligand-binding domain of CRALBP.83”

What the sources say

• Supported

  The “Retinal and retinol-binding proteins” section states that the B domain of the second IRBP module is structurally related to the C-terminal, retinoid-binding domain of CRALBP. No page number is provided in our copy. (LLM, conf=0.94)

  cites [83] von Lintig J., 2010, Trends Biochem. Sci. source

In the paper

“Bound 11-cis-retinal is found in a 6-s-trans, 11-cis, twisted 12-s-cis configuration.”

What the sources say

• Supported

  The Results and Discussion passage [6] states the bound 11-cis-retinal conformation in exactly these terms. It describes the ligand in the CRALBP structure, particularly the higher-resolution R234W complex. (LLM, conf=0.95)

  cites [507] He X. Q., 2009, Proc. Natl. Acad. Sci. U.S.A. source

In the paper

“The binding pocket completely shields the retinoid from solvent.”

What the sources say

• Supported

  The Results and Discussion state that 11-cis-retinal is completely sequestered from bulk solvent in the binding pockets of both wild-type and R234W CRALBP. This directly supports the claim for the retinoid studied. (LLM, conf=0.95)

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

In the paper

“Nevertheless, the activity of ABCA4 turns out to be essential for lowering all-trans-retinal concentrations below the threshold that could cause photoreceptor toxicity.401”

What the sources say

• Partly supported

  Scheme 1 (p. 1) describes ABCA4 transporting a fraction of all-trans-retinal out of disc lumens, supporting its role in clearance. But the Results (p. 3) report that Abca4-knockout mice cleared all-trans-retinal at rates comparable to wild-type mice, and the Discussion (p. 7) says they showed little retinal pathology. The paper therefore does not establish that ABCA4 activity is essential to keep concentrations below a phototoxic threshold. (LLM, conf=0.86)

  cites [401] Maeda A., 2008, J. Biol. Chem. sourceExperimental — accuracy not yet measured

In the paper

“In addition, all-trans-retinal can stimulate increased levels of reactive oxygen species in a NADPH oxidase-dependent manner.531,532”

What the sources say

• Supported

  The Results report that all-trans-retinal promotes ROS production in photoreceptors after light exposure and that NADPH oxidase mediates the effect. They also report that inhibiting NADPH oxidase reduced all-trans-retinal-induced intracellular ROS in ARPE19 cells. These findings support the citing sentence's qualified claim that all-trans-retinal can increase ROS in an NADPH oxidase-dependent manner. (LLM, conf=0.94)

  cites [531] Chen Y., 2012, J. Biol. Chem. source
• ?Not checked — no full text of the sourcecites [532] Lochner J. E., 1986, Proc. Natl. Acad. Sci. U.S.A. source

In the paper

“Yet another consequence of elevated all-trans-retinal concentrations is the accelerated formation and accumulation of bis-retinoid lipofuscin chromophores within retina and RPE.314,401,520,534,535”

What the sources say

• Supported

  The section on photoreceptor origins reports that exposure of outer-segment membranes to exogenous all-trans-retinal readily produces A2PE and other bisretinoids. The discussion of bisretinoid formation says these compounds are subsequently deposited in RPE cells, where they accumulate as lipofuscin. No page numbers are available in our copy. (LLM, conf=0.86)

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

  The Results (p. 3) identify A2E and RALdi as condensation products of all-trans-retinal, and the Discussion (p. 7) reports substantially greater accumulation of both in mice with disrupted all-trans-retinal clearance. The Discussion (p. 8) also describes their precursors accumulating in photoreceptor discs and subsequently reaching the RPE. (LLM, conf=0.89)

  cites [401] Maeda A., 2008, J. Biol. Chem. source
• ?Not checked — no full text of the sourcecites [520] Weng J., 1999, Cell source
• Supported

  The introductory passage says the bisretinoid-forming pathway is more active at elevated all-trans-retinal concentrations. The Discussion reports substantially more ATR dimer at elevated concentrations and identifies the resulting pigment in neural retina and RPE, supporting the claimed formation and accumulation. (LLM, conf=0.88)

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

  The introduction describes progressive lipofuscin accumulation in RPE cells, and the paper explains that all-trans-retinal can form the bis-retinoid A2E. It does not show that elevated all-trans-retinal concentrations accelerate chromophore formation or accumulation in the retina or RPE. Page numbers are unavailable in our copy. (LLM, conf=0.85)

  cites [535] Parish C. A., 1998, Proc. Natl. Acad. Sci. U.S.A. sourceExperimental — accuracy not yet measured

In the paper

“Although formation of the Schiff base adduct of all-trans-retinal with PE is fully reversible, reaction of N-ret-PE with a second molecule of all-trans-retinal can initiate a cascade of irreversible nonenzymatic conversions that lead to the production of fluorescent”

What the sources say

• Supported

  The section on N-retinylidene-PE as a biosynthetic intermediate says that reaction with a second all-trans-retinal initiates a nonenzymatic pathway producing fluorescent di-retinal compounds, including all-trans-retinal dimer. The A2E precursors section identifies A2PE as the immediate precursor of A2E. The copy contrasts hydrolysis of the initial Schiff base with progression along this product-forming pathway. (LLM, conf=0.88)

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

  The Results (p. 3) describe A2E and RALdi as condensation products of all-trans-retinal formed through phosphatidyl bisretinoid precursors, and the introduction (p. 1) identifies them as major lipofuscin fluorophores. Our copy does not specify a reaction of N-ret-PE with a second retinal molecule or characterize the proposed conversions as irreversible and nonenzymatic. (LLM, conf=0.84)

  cites [401] Maeda A., 2008, J. Biol. Chem. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [520] Weng J., 1999, Cell source
• Supported

  The Discussion’s Fig. 10 describes a proposed pathway in which N-retinyl-PE reacts with a second all-trans-retinal molecule to form either A2-PE, the precursor of A2E, or an all-trans-retinal dimer. The paper characterizes the dimer’s PE conjugate as a fluorophore and describes A2-PE formation as nonenzymatic. The pathway is proposed rather than established as the exclusive route. (LLM, conf=0.85)

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

  The paper’s discussion of A2E formation (page not provided) proposes that an initial Schiff base involving all-trans-retinal and phosphatidylethanolamine could react with a second retinal molecule and ultimately yield fluorescent A2E. It explicitly calls this pathway speculative; our copy does not identify RALdi as a product or describe the conversions as irreversible. (LLM, conf=0.86)

  cites [535] Parish C. A., 1998, Proc. Natl. Acad. Sci. U.S.A. sourceExperimental — accuracy not yet measured

In the paper

“The subsequent reaction with a second molecule of all-trans-retinal can occur through amine condensation followed by 6π-electrocyclization to generate a reduced form of A2E, phosphatidyl-dihydropyridine bisretinoid (A2PE-H2) (Figure 34).”

What the sources say

• Partly supported

  The paper’s biosynthesis description (page unavailable) says a phosphatidylethanolamine-retinyl enamine reacts with a second all-trans-retinal molecule, followed by aza-6-electrocyclization and auto-oxidation to form A2-PE. It does not identify the product of electrocyclization as the reduced intermediate A2PE-H2 or specify amine condensation at that step. (LLM, conf=0.85)

  cites [536] Ben-Shabat S., 2002, J. Biol. Chem. sourceExperimental — accuracy not yet measured
• Supported

  The Discussion (page unavailable) describes a second retinaldehyde molecule reacting by amine condensation to yield a reduced form of A2E. It also identifies 2-azatriene electrocyclization in that pathway and describes the reduced intermediate as a dihydropyridine. The copy does not use the name A2PE-H2, but its account supports the cited mechanism. (LLM, conf=0.88)

  cites [537] Kaufman Y., 2011, J. Biol. Chem. source

In the paper

“In cultured ARPE-19 cells derived from human RPE cells, exposure to 10 μM all-trans-retinal caused profound cytotoxicity after less than 1 min of incubation by inducing a Ca2+-driven apoptotic cell death pathway.318”

What the sources say

• Partly supported

  The Results and Fig. 7 report dose-dependent ARPE19 cell death at 10 μM all-trans-retinal, but after 16 hours of incubation, not less than one minute. The Results and Fig. 8 report a rapid rise in intracellular calcium at 30 μM, while the apoptosis assays also used 30 μM; they do not establish that calcium drove cell death within a minute at 10 μM. (LLM, conf=0.91)

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

In the paper

“Upon a 45% bleach of rhodopsin in wild-type mice, about 24% of released all-trans-retinal was detected in the form of a conjugate with PE.529”

What the sources say

• Supported

  Table 1 (Materials and Methods, Analysis of Phospholipids, Lipofuscin, and Retinoids) reports that 24% of total all-trans-retinal was present as APE, a conjugate with phosphatidylethanolamine, in wild-type mouse outer segments immediately after a 45% photobleach. The Mouse Tissues methods identify this exposure as approximately 45% bleaching of rhodopsin. (LLM, conf=0.95)

  cites [529] Mata N. L., 2000, Proc. Natl. Acad. Sci. U.S.A. source

In the paper

“Such conformational changes have indeed been observed by electron microscopy and hydrogen–deuterium exchange.523”

What the sources say

• Supported

  The Introduction says electron microscopy revealed nucleotide-induced conformational transitions in ABCA4 and hydrogen/deuterium exchange detected ATP-induced local changes. The Results (Local environment of the ATP-binding sites) report that hydrogen/deuterium exchange confirmed structural alterations seen in the EM structures. (LLM, conf=0.94)

  cites [523] Tsybovsky Y., 2013, Structure source

In the paper

“Indeed, the primary fluorescent components of lipofuscin are all-trans-retinal conjugates such as A2E and RALdi.542”

What the sources say

• Partly supported

  The paper lists A2E and all-trans-retinal dimer-phosphatidylethanolamine (atRALdi-PE) among fluorophores in RPE lipofuscin and quantifies both in its bisretinoid analysis (p. 1401; Fig. 3). It does not establish that these are the primary fluorescent components, and the compound it identifies is atRALdi-PE rather than RALdi alone. (LLM, conf=0.82)

  cites [542] Ng K. P., 2008, Mol. Cell. Proteomics sourceExperimental — accuracy not yet measured

In the paper

“The strong kinetic isotope effect observed in RALdi synthesis as compared to that found for A2E supports this reaction mechanism537,538”

What the sources say

• Supported

  The Discussion reports a larger kinetic isotope effect for ATR-dimer formation than for A2E and says this difference suggests a particular enamine-formation mechanism. It presents the mechanistic inference as tentative, consistent with the citing sentence’s wording that the comparison supports it. (LLM, conf=0.92)

  cites [537] Kaufman Y., 2011, J. Biol. Chem. source
• Partly supported

  The ‘Ocular A2E and ATR-dimer’ results report 95% less ATR-dimer versus 80% less A2E in mice given C20-deuterated vitamin A, and the Discussion links slowed dimerization to cleavage of a C20–H bond. These findings support the proposed mechanism, but the paper reports product concentrations rather than a direct comparison of kinetic isotope effects in RALdi and A2E synthesis. (LLM, conf=0.82)

  cites [538] Ma L., 2011, J. Biol. Chem. sourceExperimental — accuracy not yet measured

In the paper

“The structure of native bovine ABCA4 has been determined by negative stain electron microscopy to a resolution of 18 Å, revealing the overall shape of the molecule.523”

What the sources say

• Supported

  The Results (Molecular architecture of ABCA4) state that negative-stain EM produced an 18.1 Å-resolution structure revealing the molecule’s overall shape. The Discussion says the ABCA4 was purified from bovine rod outer segments, its native source. The cited 18 Å resolution is a reasonable rounding. (LLM, conf=0.94)

  cites [523] Tsybovsky Y., 2013, Structure source

In the paper

“The topology of this protein in combination with the logic of the visual cycle suggest that ABCA4 acts as an importer, an assumption recently confirmed experimentally.525”

What the sources say

• Supported

  The Discussion reports direct biochemical evidence that ABCA4 functions as an importer, moving substrates from the lumen to the cytoplasmic side of photoreceptor disc membranes. It describes three experimental systems supporting that conclusion. (LLM, conf=0.95)

  cites [525] Quazi F., 2012, Nat. Commun. source

In the paper

“Because rhodopsin concentration in ROS reaches 4 mM,257 bleaching of just 0.5% of the total amount could potentially generate toxic levels of all-trans-retinal if this retinoid is not efficiently removed from the retina.”

What the sources say

• Supported

  The citation is attached to the rhodopsin-concentration figure, not the subsequent calculation about bleaching and toxicity. The Results (page not provided) calculate a concentration of 4.62 mM in murine ROS disc membranes, supporting the cited approximate value of 4 mM. (LLM, conf=0.90)

  cites [257] Nickell S., 2007, J. Cell Biol. source

In the paper

“As a result of incomplete lysosomal degradation, these byproducts of retinal metabolism accumulate in the RPE as residual bodies called lipofuscin.”

What the sources say

• Supported

  In the section on N-retinylidene-PE (page unavailable), the paper says RPE lipofuscin accumulates in lysosomal organelles called lipofuscin granules. It also says the bisretinoid compounds largely resist further hydrolytic degradation, explaining their accumulation. (LLM, conf=0.90)

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

In the paper

“As indicated by numerous biochemical studies and the phenotype of Abca4–/– mice, the main function of this transporter is to accelerate the clearance of all-trans-retinal from ROS/COS.401,518−520”

What the sources say

• Supported

  The introduction (p. 1) identifies ABCA4 as one of two proteins involved in removing light-generated all-trans-retinal from photoreceptors. Scheme 1 (p. 1) explains its role: ABCA4 transports the fraction released into disc lumens to the cytoplasm, where it can be reduced. This supports the claim about ABCA4’s clearance function in rod and cone outer segments. (LLM, conf=0.88)

  cites [401] Maeda A., 2008, J. Biol. Chem. source
• Partly supported

  The introductory passage labeled Abstract (page unavailable) says knockout-mouse and biochemical studies suggest ABCA4 facilitates removal of all-trans-retinal derivatives from photoreceptor disk membranes. This supports the clearance role, but the paper identifies N-retinylidene-PE as the preferred substrate and says transport itself was not measured; it does not establish clearance of free all-trans-retinal as ABCA4’s main function. (LLM, conf=0.85)

  cites [518] Beharry S., 2004, J. Biol. Chem. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [519] Sun H., 2000, Nat. Genet. source
• ?Not checked — no full text of the sourcecites [520] Weng J., 1999, Cell source

In the paper

“However, recent studies of Abca4–/–Rdh8–/– double knockout mice that closely recapitulate human retinal pathological conditions indicate that all-trans-retinal itself may play a decisive role in light-induced photoreceptor degeneration.318,320,531”

What the sources say

• Supported

  The Abstract says all-trans-retinal is most likely responsible for photoreceptor degeneration in Rdh8−/− Abca4−/− mice. The Results also identify it as the apparent trigger of light-induced acute retinal degeneration. The supplied passages do not give page numbers. (LLM, conf=0.94)

  cites [318] Maeda A., 2009, J. Biol. Chem. source
• Supported

  The section “Role of all-trans-RAL in mediating photodamage to the retina” reports light-dependent rod and cone degeneration in Rdh8−/−Abca4−/− mice, with features similar to human macular degeneration. It also says experiments with retinoid supplementation suggest that all-trans-retinal, rather than A2E, is a primary cause of degeneration in these mice. (LLM, conf=0.94)

  cites [320] Maeda T., 2012, Photochem. Photobiol. source
• Supported

  The Discussion (page not available in our copy) calls all-trans-retinal a critical player in retinal degeneration and reports that its effects were observed in Abca4−/−Rdh8−/− retinas after bright-light exposure. The Results also link all-trans-retinal to light-induced ROS production in these mice. This supports the citing sentence’s hedged claim that it may play a decisive role in photoreceptor degeneration. (LLM, conf=0.93)

  cites [531] Chen Y., 2012, J. Biol. Chem. source

In the paper

“The connection between delayed all-trans-retinal clearance, lipofuscin buildup, and retinal degeneration is exemplified by Stargardt disease, a human condition in which juvenile macular degeneration is caused by mutations in both alleles of the ABCA4 gene.487,545”

What the sources say

• Supported

  Section 7.1 describes Stargardt disease as an early-onset, autosomal recessive macular disorder and identifies ABCA4 mutations as its cause. The Conclusions also link loss of ABCA4 function to retinal degeneration through impaired retinal clearance and lipofuscin accumulation. (LLM, conf=0.92)

  cites [487] Molday R. S., 2009, Biochim. Biophys. Acta source
• ?Not checked — no full text of the sourcecites [545] Allikmets R., 1997, Nat. Genet. source

In the paper

“Recent studies by von Lintig and co-workers suggest that ocular vitamin A uptake is favored over other peripheral tissues in vitamin A deficient states.492”

What the sources say

• Supported

  The paper states that ocular retinoid uptake was favored during vitamin A deficiency (p. 1). In “Role of LRAT in Cellular Retinol Uptake” (p. 11), it explains that retinol is mainly delivered to the eyes while lung and liver stores are depleted, supporting the comparison with peripheral tissues. (LLM, conf=0.94)

  cites [492] Amengual J., 2012, J. Biol. Chem. source

In the paper

“The toxicity of all-trans-retinal could be a major contributor to retinal degeneration in several human diseases, including Stargardt disease.318,401,570”

What the sources say

• Supported

  In the discussion section on A2E and retinal degeneration (page not provided), the authors identify all-trans-retinal as a cause of retinal degeneration in mice and propose reducing its production or removing excess retinal as possible therapies for Stargardt disease and age-related macular degeneration. This supports the citing sentence’s hedged suggestion of a substantial contribution to those human diseases, although the paper does not establish that contribution in patients. (LLM, conf=0.86)

  cites [318] Maeda A., 2009, J. Biol. Chem. source
• Supported

  The Discussion (pp. 7–8) describes all-trans-retinal and its reactive products as contributors to retinal degeneration in mice, while explicitly framing the role of free all-trans-retinal as speculation. The introduction (p. 1) links related retinal degeneration to human Stargardt disease and AMD, and the Discussion (p. 8) considers visual-cycle inhibition for both. Together, these support the citing sentence’s cautious 'could' claim, not a demonstrated causal finding in humans. (LLM, conf=0.84)

  cites [401] Maeda A., 2008, J. Biol. Chem. source
• Partly supported

  The Discussion (no page provided) says that a buildup of all-trans-retinal after light exposure has been suggested to lead to accumulation of potentially toxic A2E. It does not say that all-trans-retinal’s own toxicity is a major contributor to retinal degeneration in several human diseases, including Stargardt disease; Stargardt appears in the references, not in that proposed mechanism. (LLM, conf=0.82)

  cites [570] Maeda T., 2009, Invest. Ophthalmol. Vis. Sci. sourceExperimental — accuracy not yet measured

In the paper

“Significant amounts of 11-cis-retinyl esters and 11-cis-retinol in ground squirrel and chicken retinas not observed in rod-dominant mice, rat, or cow are associated with alternatives to RPE65 and LRAT enzymatic activities responsible for formation of these retinoids.302,305,430”

What the sources say

• ?Not checked — no full text of the sourcecites [302] Mata N. L., 2002, Neuron source
• ?Not checked — no full text of the sourcecites [305] Das S. R., 1992, Biochem. J. source
• Partly supported

  The Results and Discussion report production of 11-cis-retinyl esters and 11-cis-retinol in chicken retinas, with an isomerase distinct from the RPE pathway and an ARAT-like activity rather than detectable retinal LRAT. The paper mentions a previously reported isomerase in chicken and ground squirrel retinas, but does not establish significant amounts of both retinoids in ground squirrels or their absence from mouse, rat, and cow retinas. It also does not directly establish that the retinal activity is an alternative to RPE65. (LLM, conf=0.85)

  cites [430] Mata N. L., 2005, Biochemistry sourceExperimental — accuracy not yet measured

In the paper

“Mutations in other genes, such as those encoding RDH5 or IRBP, are associated with slowly progressive retinal degeneration.562−565”

What the sources say

• ?Not checked — no full text of the sourcecites [562] Driessen C. A., 2000, Mol. Cell. Biol. source
• ?Not checked — no full text of the sourcecites [563] Yamamoto H., 1999, Nat. Genet. source
• ?Not checked — no full text of the sourcecites [564] Dryja T. P., 2000, Am. J. Ophthalmol. source
• Supported

  The Results report retinal degeneration in a family with an RBP3 (IRBP) mutation and slower visual-field and cone ERG decline in one affected patient than the average for typical untreated retinitis pigmentosa. The Discussion notes that vitamin A treatment may have slowed that patient’s decline. This paper supports the IRBP example; it does not address RDH5. (LLM, conf=0.87)

  cites [565] den Hollander A. I., 2009, Invest. Ophthalmol. Vis. Sci. source

In the paper

“Most of the genes encoding retinoid cycle enzymes are associated with retinal disease (Figure 36).64,76,77,285,547−552”

What the sources say

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

  Section 3, “ABCA4 and Vision Diseases,” links mutations in ABCA4 to several retinal disorders, while Section 5.4 describes ABCA4 as a transporter involved in the visual cycle. Neither passage says that most genes encoding retinoid-cycle enzymes are associated with retinal disease; searches for that broader claim and for visual-cycle enzyme disease associations found no supporting passage. (LLM, conf=0.75)

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

  The Abbreviations section (p. 1) links ABCA4 mutations to visual disorders, and the retinoid-cycle overview (p. 3) places ABCA4 in that cycle. The paper does not establish that *most genes encoding retinoid-cycle enzymes* are associated with retinal disease; its disease discussion focuses on ABCA4. (LLM, conf=0.84)

  cites [77] Pollock N. L., 2011, FEBS J. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [285] Saari J. C., 2012, Annu. Rev. Nutr. source
• ?Not checked — no full text of the sourcecites [547] Rattner A., 1999, Annu. Rev. Genet. source
• ?Not checked — no full text of the sourcecites [548] Hartong D. T., 2006, Lancet source
• ?Not checked — no full text of the sourcecites [549] Rivolta C., 2002, Hum. Mol. Genet. source
• ?Not checked — no full text of the sourcecites [550] Dryja T. P., 1995, Invest. Ophthalmol. Vis. Sci.
• ?Not checked — no full text of the sourcecites [551] Dryja T. P., 1995, Hum. Mol. Genet. source
• ?Could not verify

  The sections on ABCR in retinal disease and its function in the visual cycle discuss one transporter and its association with retinal disease. Our copy does not address whether most genes encoding retinoid-cycle enzymes are associated with retinal disease (searched: retinoid cycle enzymes; visual cycle enzymes). (LLM, conf=0.76)

  cites [552] Allikmets R., 2000, Am. J. Hum. Genet. sourceExperimental — accuracy not yet measured

In the paper

“In contrast to other cell types, an overdose of all-trans-retinol does not result in excessive accumulation of retinyl esters in the RPE.567,575”

What the sources say

• Partly supported

  The Discussion (Leber Congenital Amaurosis and Potential Treatment; page unavailable) reports low, transient retinyl-ester levels in LRAT-deficient mice. That supports limited accumulation in this mouse model, but not the broader claim about an overdose of all-trans-retinol in the RPE or the comparison with other cell types. (LLM, conf=0.76)

  cites [567] Batten M. L., 2005, PLoS Med. sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (Fig. 6B; page unavailable) report only a mild increase in retinyl esters in wild-type mouse eyes after all-trans-retinyl acetate treatment. But the Discussion reports more than a threefold increase in treated Rpe65-deficient mice. The paper does not compare the RPE with other cell types, so it does not support the claim as a general statement about the RPE. (LLM, conf=0.84)

  cites [575] Maeda T., 2013, Invest. Ophthalmol. Vis. Sci. sourceExperimental — accuracy not yet measured

In the paper

“For RPE65 the severity of disease has been associated with the degree of residual enzymatic activity.274,281,557”

What the sources say

• Partly supported

  Section 5.1 (page unavailable) reports that mice producing detectable 11-cis-retinal were thought to be more light-sensitive than RPE65 knockout mice, supporting an association in that model. But Section 3 says a quantitative relationship between human disease severity and genotype has not been definitively established, and notes that in vivo results appear to contradict in vitro predictions. The claim is therefore broader than the evidence in this review supports. (LLM, conf=0.86)

  cites [274] Cideciyan A. V., 2010, Prog. Retinal Eye Res. sourceExperimental — accuracy not yet measured
• Supported

  The “RPE65 associated diseases” section states that mutations with no detectable isomerohydrolase activity act as virtual null alleles, whereas mutations retaining more functional capacity cause a milder form of LCA. This supports the stated association between residual activity and disease severity. (LLM, conf=0.91)

  cites [281] Cai X., 2009, Ophthalmic Genet. source
• ?Not checked — no full text of the sourcecites [557] Caruso R. C., 2010, Invest. Ophthalmol. Vis. Sci. source

In the paper

“Thus, blockage in production of 11-cis-retinal was overcome with oral delivery of another photosensitive but chemically more stable retinoid, 9-cis-retinal (Figure 36)567−571”

What the sources say

• Supported

  The Results section reports that oral gavage with 9-cis-retinal restored visual pigment in Lrat-deficient mice by bypassing a blocked metabolic step. The Discussion says 9-cis-retinoids are more stable than 11-cis-retinoids and form sensitive visual pigments. The treatment bypassed the blockage; it did not restore production of 11-cis-retinal. (LLM, conf=0.90)

  cites [567] Batten M. L., 2005, PLoS Med. source
• ?Not checked — no full text of the sourcecites [568] Van Hooser J. P., 2002, J. Biol. Chem. source
• Supported

  In “Bypassing the Visual Cycle Defect of Rpe65−/− Mice” (page unavailable), the authors say they gave 9-cis-retinal by oral gavage to bypass the blocked retinoid cycle. They report that it produced the visual pigment isorhodopsin; the claim is supported as a bypass of the blockage, not a claim that normal 11-cis-retinal production was restored. (LLM, conf=0.91)

  cites [569] Van Hooser J. P., 2000, Proc. Natl. Acad. Sci. U.S.A. source
• Supported

  The Introduction states that the biochemical defects in Lrat−/− and Rpe65−/− mice, which may lack 11-cis-retinal, were bypassed by oral gavage with 9-cis-retinal. It reports recovery of normal rod function, supporting the claim in those mouse models. (LLM, conf=0.91)

  cites [570] Maeda T., 2009, Invest. Ophthalmol. Vis. Sci. source
• Partly supported

  The Introduction (page unavailable) says 9-cis-retinal can substitute for 11-cis-retinal in deficient photoreceptors, supporting the proposed way around the blockage. But the administration methods (page unavailable) describe intraperitoneal injections of 9-cis-retinyl acetate, a precursor, not oral delivery of 9-cis-retinal; the copy also does not establish the claimed greater chemical stability. (LLM, conf=0.88)

  cites [571] Maeda T., 2011, Mol. Pharmacol. sourceExperimental — accuracy not yet measured

In the paper

“Until recently, progress in this field has been marked only by NMR or crystal structures of soluble retinoid-binding proteins such as CRBPs, IRBP, and CRALBP.507,577,578”

What the sources say

• Partly supported

  The Abstract identifies CRALBP as a soluble retinoid carrier, and the Results and Discussion describe crystal structures of wild-type and mutant CRALBP. This supports CRALBP as one example, but the paper does not establish that structural progress had been limited to soluble retinoid-binding proteins or document structures of CRBPs and IRBP. (LLM, conf=0.86)

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

  The opening summary (p. 1) says this paper determined the solution structures of apo- and holo-CRBP using NMR spectroscopy. It therefore supports the CRBP example attributed to this citation; the sentence’s other protein examples have separate citations. (LLM, conf=0.92)

  cites [577] Franzoni L., 2002, J. Biol. Chem. source
• ?Not checked — no full text of the sourcecites [578] Lu J., 1999, J. Mol. Biol. source

In the paper

“A 22 Å structure was calculated from projections of negatively stained photoactivated rhodopsin–transducin complexes.”

In the paper

“Scanning transmission electron microscopy demonstrated about a 221 kDa molecular weight for this complex.”

In the paper

“An important role for CRBP in all-trans-retinol trafficking in the retina has been demonstrated in CRBP I–/– mice, which show defective transport of all-trans-retinol from photoreceptors to ER membranes of the RPE.”

What the sources say

• ?Not checked — no full text of the sourcecites [498] Saari J. C., 2002, Invest. Ophthalmol. Vis. Sci.

In the paper

“11-cis-Retinal and 11-cis-retinol are the main retinoids associated with CRALBP isolated from bovine retina.499,502”

What the sources say

• ?Not checked — no full text of the sourcecites [499] Futterman S., 1977, J. Biol. Chem. source
• ?Not checked — no full text of the sourcecites [502] Saari J. C., 1987, J. Biol. Chem. source

In the paper

“The mechanism of all-trans-retinal toxicity involves the generation of superoxide radical, singlet oxygen, and peroxides when irradiated with UVA or blue light.279”

What the sources say

• ?Not checked — no full text of the sourcecites [279] Rozanowska M., 2005, Photochem. Photobiol. source

In the paper

“Analysis of the isomeric composition of retinoids in rod- and cone-dominant retinas reveals striking differences.579”

What the sources say

• ?Not matched

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

  cites [579] Travis G. H., 2002, Invest. Ophthalmol. Vis. Sci.

In the paper

“Though supported by biochemical data, this pathway remains only a concept without molecular identification of its protein components.”

In the paper

“Despite several reports indicating interaction of particular proteins, the isomerization complex containing RPE65, RDH5, LRAT, or CRALBP has not been purified or reconstituted in vitro.”

In the paper

“In contrast to type I IDIs, type II enzymes rely on flavin mononucleotide (FMNred) and NADPH as well as divalent cations as cofactors to perform catalysis.105”

What the sources say

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

In the paper

“The thermodynamically unfavorable isomerization of the 11–12 double bond does not occur at the aldehyde level in vivo.142”

What the sources say

• ?Not checked — no full text of the sourcecites [142] Bernstein P. S., 1986, Biochemistry source

In the paper

“Two molecules of GGPP are then joined in a head to head fashion to form phytoene in a reaction catalyzed by the enzyme phytoene synthase, which is the first committed step in the synthesis of carotenoids.100”

What the sources say

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

In the paper

“But, it was Wald who discovered that retinol derivatives constitute the chemical basis of our vision,6 a contribution subsequently recognized by a Nobel Prize award in 1967.”

What the sources say

• ?Not checked — no full text of the sourcecites [6] Wald G., 1968, Nature source

In the paper

“An alternative metabolic pathway of all-trans-retinal leads to formation of 11-cis-retinal, a visual chromophore that couples to rod and cone opsins to form photosensitive pigments.139−141”

What the sources say

• ?Not checked — no full text of the sourcecites [139] Palczewski K., 2000, Science source
• ?Not checked — no full text of the sourcecites [140] Nathans J., 1990, Biochemistry source
• ?Not checked — no full text of the sourcecites [141] Nathans J., 1992, Annu. Rev. Genet. source

In the paper

“In animals, carotenoids and retinoids must be acquired through the diet, as they cannot be synthesized de novo.”

What the sources say

• ?Not checked — no full text of the sourcecites [86] Hill G. E., 2012, Am. Nat. source

In the paper

“The highest resolution method for separating retinyl esters, retinal, and retinol as well as their isomers present in the eye is normal phase HPLC (Figure 6B).161”

What the sources say

• ?Not checked — no full text of the sourcecites [161] Kane M. A., 2008, Anal. Chem. source

In the paper

“The influence of solvents on the efficiency and composition of isomers at photoequilibrium has been attributed to solvent-dependent shifting of the nπ* and ππ* excited states.190−192”

What the sources say

• ?Not checked — no full text of the sourcecites [190] Becker R. S., 1988, Photochem. Photobiol. source
• ?Not checked — no full text of the sourcecites [191] Das P. K., 1979, J. Am. Chem. Soc. source
• ?Not checked — no full text of the sourcecites [192] Deval P., 1988, J. Photochem. Photobiol., A: Chem. source

In the paper

“Because opsins are membrane proteins, they are densely packed into specific regions of the cell to prevent their random diffusion.”

What the sources say

• ?Not checked — no full text of the sourcecites [229] Muller D. J., 2008, Pharmacol. Rev. source

In the paper

“The radical-mediated, iodine-catalyzed isomerization of polyenes is a three-step process that involves binding of an iodine atom to a carbon, an internal rotation, and then detachment of the iodine.178,179”

What the sources say

• ?Not checked — no full text of the sourcecites [178] Hepperle S. S., 2005, J. Phys. Chem. A source
• ?Not checked — no full text of the sourcecites [179] Benson S. W., 1965, J. Chem. Phys. source

In the paper

“The most stable conformation for retinoids is all-trans.174,175”

What the sources say

• ?Not checked — no full text of the sourcecites [174] Warshel A., 1974, Chem. Phys. source
• ?Not checked — no full text of the sourcecites [175] Warshel A., 1974, J. Mol. Struct. source

In the paper

“Light activated ciliary opsins, on the other hand, do not undergo photoreversal but instead rely on biochemical regeneration of the visual chromophore via the retinoid (visual) cycle.”

In the paper

“The quantum yields for all-trans-retinal were considerably lower in polar (0.1–0.2) than in nonpolar (0.4–0.7) solvents.185−189”

What the sources say

• ?Not checked — no full text of the sourcecites [185] Fisher M. M., 1974, Photochem. Photobiol. source
• ?Not matched

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

  cites [186] Bensasson R., 1978, New J. Chem.
• ?Not checked — no full text of the sourcecites [187] Bensasson R., 1973, Photochem. Photobiol. source
• ?Not checked — no full text of the sourcecites [188] Rosenfel. T., 1974, J. Phys. Chem. source
• ?Not checked — no full text of the sourcecites [189] Land E. J., 1975, Photochem. Photobiol. source

In the paper

“The same results were obtained when all-trans-retinol or its palmitoyl ester was used as the starting material.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

“Alternative geometrical isomers introduce some steric hindrance that increases the conformational energy compared to the all-trans isomer.176”

What the sources say

• ?Not checked — no full text of the sourcecites [176] Rowan R., 1974, Biochemistry source

In the paper

“Nevertheless, these early studies on retinoid isomerization clearly showed that the mixture of isomers obtained by any of the available methods did not recapitulate the equilibrium observed in living tissue.”

In the paper

“Starting from all-trans-retinal, the composition of retinal isomers at equilibrium was consistent among multiple reports that included all-trans, 13-cis, 9-cis, 11-cis, and 9,13-di-cis isomers in ratios of about 0.62, 0.23, 0.11, 0.001, and 0.04, respectively.177,180,181”

What the sources say

• ?Not checked — no full text of the sourcecites [177] Hubbard R., 1966, J. Biol. Chem. source
• ?Not checked — no full text of the sourcecites [180] Futterman S., 1973, J. Biol. Chem. source
• ?Not checked — no full text of the sourcecites [181] Rando R. R., 1983, J. Am. Chem. Soc. source

In the paper

“each RPE cell phagocytoses hundreds of thousands of OS disks over a human lifetime.”

What the sources say

• ?Not checked — no full text of the sourcecites [269] Anderson D. H., 1978, Invest. Ophthalmol. Vis. Sci.

In the paper

“membranes of ROS and COS contain high levels of unsaturated lipids.265 These lipids are prone to oxidation in the presence of light, (photo)reactive retinal, and high oxygen tension”

What the sources say

• ?Not checked — no full text of the sourcecites [265] Bazan N. G., 2006, Trends Neurosci. source
• ?Not checked — no full text of the sourcecites [266] Lange C. A., 2012, Ophthalmologica source
• ?Not checked — no full text of the sourcecites [267] Caprara C., 2012, Prog. Retinal Eye Res. source

In the paper

“Forced twisting of the polyene backbone away from its normally planar configuration induced by the binding pocket as well as the electrostatic environment surrounding the chromophore are major factors that influence its absorbance maximum.”

What the sources say

• ?Not checked — no full text of the sourcecites [249] Sakmar T. P., 2012, Science source

In the paper

“another critical enzyme called RPE65 (retinoid isomerase) catalyzes the conversion of all-trans-retinyl esters into 11-cis-retinol.”

In the paper

“This cis-retinol is oxidized and sent back to ROS/COS to re-form photoactive visual pigments.”

In the paper

“the canonical visual cycle is too slow to provide enough visual chromophore to maintain cone light responsiveness under bright light conditions.”

What the sources say

• ?Not checked — no full text of the sourcecites [302] Mata N. L., 2002, Neuron source

In the paper

“Photoactivation of rhodopsin causes conformational changes that provide a binding site for the rod G protein called transducin.”

What the sources say

• ?Not checked — no full text of the sourcecites [343] Choe H. W., 2011, Nature source
• ?Not checked — no full text of the sourcecites [344] Salom D., 2006, Proc. Natl. Acad. Sci. U.S.A. source

In the paper

“In disk membranes, the density of rhodopsin translates into about 50% of the entire volume or surface area.”

In the paper

“The distribution of retinoids in cone-dominant retinas is substantially different from that of rod-dominant species, with an abundance of 11-cis-retinyl esters found in the retina as opposed to the stores of all-trans-retinyl esters in the RPE.”

What the sources say

• ?Not checked — no full text of the sourcecites [303] Berman E. R., 1980, Biochim. Biophys. Acta source
• ?Not checked — no full text of the sourcecites [304] Rodriguez K. A., 1989, Am. J. Physiol. source

In the paper

“The fundamental photochemical reaction of our visual system is isomerization of 11-cis-retinylidene to all-trans-retinylidene”

In the paper

“Retinyl esters in retinosomes accumulate in Rpe65–/– mice lacking retinoid enzymatic isomerization.”

In the paper

“the expression level of rhodopsin dictates the size of the ROS.”

What the sources say

• ?Not checked — no full text of the sourcecites [259] Liang Y., 2004, J. Biol. Chem. source
• ?Not checked — no full text of the sourcecites [325] Liang X., 2001, J. Biol. Chem. source
• ?Not checked — no full text of the sourcecites [326] Olsson J. E., 1992, Neuron source
• ?Not checked — no full text of the sourcecites [327] Humphries M. M., 1997, Nat. Genet. source

In the paper

“There, this alcohol is esterified by fatty acid in a reaction catalyzed by LRAT.”

In the paper

“Three enzymatic activities, namely isomerase, 11-cis- and all-trans-retinyl ester synthase, and retinol dehydrogenase/reductase, are associated with membrane fractions from chicken neural retina.”

What the sources say

• ?Not checked — no full text of the sourcecites [302] Mata N. L., 2002, Neuron source

In the paper

“Regeneration and recombination of 11-cis-retinal with opsin restores the dark state condition needed for subsequent photon absorption.”

In the paper

“Upon illumination of rhodopsin (λmax = 500 nm), the chromophore undergoes geometrical isomerization.”

What the sources say

• ?Not checked — no full text of the sourcecites [356] Kandori H., 2001, Biochemistry source
• ?Not checked — no full text of the sourcecites [357] Surya A., 1998, Trends Pharmacol. Sci. source

In the paper

“rhodopsin also has two other retinoid-binding sites within opsin368,369 in addition to the retinylidene pocket (site 1).”

What the sources say

• ?Not checked — no full text of the sourcecites [368] Schadel S. A., 2003, J. Biol. Chem. source
• ?Not checked — no full text of the sourcecites [369] Heck M., 2003, Vision Res. source

In the paper

“From both Meta II and Meta III, a protonated carbinol ammonium ion is formed before all-trans-retinal is released from opsin.”

In the paper

“In addition to the interaction with the nicotinamide ring of the cofactor, the reaction intermediate is stabilized by the hydroxyl group of an adjacent serine residue (Figure 20).382”

What the sources say

• ?Not checked — no full text of the sourcecites [382] Oppermann U. C., 1997, Eur. J. Biochem. source

In the paper

“Enzymes that catalyze this process can be classified into three major protein families: cytosolic alcohol dehydrogenases (ADH’s) that belong to a medium-chain dehydrogenase/reductase family and selected members of the aldo–keto reductase family (AKR’s)373 and microsomal RDH’s that represent the short-chain dehydrogenase/reductase (SDR) group.”

What the sources say

• ?Not checked — no full text of the sourcecites [373] Porte S., 2013, Chem. Biol. Interact. source
• ?Not checked — no full text of the sourcecites [374] Duester G., 2000, Eur. J. Biochem. source

In the paper

“Based on biochemical studies, RDH1 is anchored in ER membranes with the catalytic domain facing the cytoplasm.385”

What the sources say

• ?Not checked — no full text of the sourcecites [385] Zhang M., 2004, J. Biol. Chem. source

In the paper

“Next, rapidly formed and decaying intermediates have been detected before Meta I is observed (λmax = 478 nm).”

In the paper

“Initially, a role for Cys161 and His60 in catalysis was derived from site-directed mutagenesis studies where replacement of either of these two amino acids abolished retinyl ester formation.417,418”

What the sources say

• ?Not checked — no full text of the sourcecites [417] Jahng W. J., 2002, Biochemistry source
• ?Not checked — no full text of the sourcecites [418] Xue L., 2004, Biochemistry source

In the paper

“Furthermore, human RPE65 mutations were shown to cause Leber Congenital Amaurosis (LCA), a recessive, severe childhood blinding disease.440,441”

What the sources say

• ?Not checked — no full text of the sourcecites [440] Marlhens F., 1997, Nat. Genet. source
• ?Not checked — no full text of the sourcecites [441] Gu S. M., 1997, Nat. Genet. source

In the paper

“The reaction catalyzed by RPE65 consists of two steps: a trans/cis alkene bond isomerization and an ester bond cleavage.”

In the paper

“Because 11-cis-retinol is thermodynamically less stable than all-trans-retinol by ∼4 kcal/mol,181 it has been argued that ester cleavage, which typically releases ∼5 kcal/mol of free energy, could be used to drive the isomerization reaction.479”

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

“Once thought to function solely as a retinoid-binding protein, RPE65 has now been conclusively identified as the retinoid isomerase of the canonical retinoid cycle.”

In the paper

“The ester cleavage reaction catalyzed by RPE65 is not an ordinary ester bond hydrolysis whereby attack of water on the acyl carbon generates a tetrahedral intermediate that collapses to form a carboxylic acid and an alcohol (Figure 28). Instead, the ester dissociates by cleavage of the O-alkyl bond.”

In the paper

“A patch of basic amino acid residues on the protein’s surface probably mediates the interaction of the protein with acidic phospholipids, which induce dissociation of the bound retinoid.508”

What the sources say

• ?Not checked — no full text of the sourcecites [508] Saari J. C., 2009, Mol. Vis.

In the paper

“The near perfect cis configuration of the 11–12 double bond imposed by the retinoid-binding pocket is likely important to prevent unwanted photoisomerization and thermal isomerization.”

In the paper

“Because retinoids quickly equilibrate between membranes by passage through the aqueous phase,483,484”

What the sources say

• ?Not checked — no full text of the sourcecites [483] Noy N., 1990, Biochemistry source
• ?Not checked — no full text of the sourcecites [484] Noy N., 1990, Biochemistry source

In the paper

“The first of these is an intracellular-binding protein CRALBP that displays a binding preference for 11-cis-retinoids.499”

What the sources say

• ?Not checked — no full text of the sourcecites [499] Futterman S., 1977, J. Biol. Chem. source

In the paper

“The retinoid-binding preferences and localization of IRBP indicate that it participates in the retinoid cycle by transporting retinoids between photoreceptors, RPE, and Müller cells.”

In the paper

“Inside cells, retinol is transported between membranes in complex with a second binding protein called cellular retinol-binding protein (CRBP).”

What the sources say

• ?Not checked — no full text of the sourcecites [497] Cowan S. W., 1993, J. Mol. Biol. source

In the paper

“Retinoid-binding proteins overcome this barrier by reversibly binding and sequestering retinoids away from water in internal cavities, greatly facilitating their diffusion.”

In the paper

“part of their transport likely takes place by passive diffusion.”

In the paper

“The relatively high hydrophobicity of all-trans-retinal allows its rapid partition between the inner and outer leaflets of disk membranes, ensuring its accessibility to RDHs.526,527”

What the sources say

• ?Not checked — no full text of the sourcecites [526] Ho M. T., 1989, J. Biol. Chem. source
• ?Not checked — no full text of the sourcecites [527] Rando R. R., 1982, Biochem. Biophys. Res. Commun. source