ArticleThe Journal of biological chemistry2012
Aromatic residues in the substrate cleft of RPE65 protein govern retinol isomerization and modulate its progression.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 18 citations in OpenAlex.
- Inactivity of human β,β-carotene-9',10'-dioxygenase (BCO2) underlies retinal accumulation of the human macular carotenoid pigment.Proceedings of the National Academy of Sciences of the United States of America · 2014Trial
- Genome-wide identification and characterization of the carotenoid cleavage dioxygenase gene family inFrontiers in plant science · 2026Article
- Retinal pigment epithelium 65 kDa protein (RPE65): An update.Progress in retinal and eye research · 2022Review
- GmCCD4 controls carotenoid content in soybeans.Plant biotechnology journal · 2021Article
- Evolutionary aspects and enzymology of metazoan carotenoid cleavage oxygenases.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2020Review
- Structural basis for carotenoid cleavage by an archaeal carotenoid dioxygenase.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Structural biology of 11-The Biochemical journal · 2018Review
- Key Residues for Catalytic Function and Metal Coordination in a Carotenoid Cleavage Dioxygenase.The Journal of biological chemistry · 2016Article
- Inhibition of RPE65 Retinol Isomerase Activity by Inhibitors of Lipid Metabolism.The Journal of biological chemistry · 2016Article
- Catalytic mechanism of a retinoid isomerase essential for vertebrate vision.Nature chemical biology · 2015Article
- Analysis of carotenoid isomerase activity in a prototypical carotenoid cleavage enzyme, apocarotenoid oxygenase (ACO).The Journal of biological chemistry · 2014Article
- Structural approaches to understanding retinal proteins needed for vision.Current opinion in cell biology · 2014Review
- Chemistry of the retinoid (visual) cycle.Chemical reviews · 2014Review
- Structural basis of carotenoid cleavage: from bacteria to mammals.Archives of biochemistry and biophysics · 2013Review
- Structure of RPE65 isomerase in a lipidic matrix reveals roles for phospholipids and iron in catalysis.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
- Pathways and disease-causing alterations in visual chromophore production for vertebrate vision.The Journal of biological chemistryReview
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Previously, we showed that mutating RPE65 residue Phe-103 preferentially produces 13-cis-retinol instead of 11-cis-retinol, supporting a carbocation/radical cation mechanism of retinol isomerization. We asked whether this modulation of specificity can occur with residues other than Phe-103 and what role it plays in substrate binding and isomerization. We modeled the substrate-binding cleft of RPE65 to identify residues lining its surface. Many are phenylalanines and tyrosines, including three Phe residues (Phe-61, Phe-312, and Phe-526) forming an arch-like arrangement astride the cleft and Tyr-338. Also, Phe-418 sits at the neck of the cleft, lending a bend to the volume enclosed by the cleft. All mutations of Phe-61, Phe-312, and Phe-418 result in severely impaired or inactive enzyme. However, mutation of Phe-526 and Tyr-338, like Phe-103, decreases 11-cis-retinol formation, whereas increasing the 13-cis isomer. Significantly, 2 of these 3 residues, Phe-103 and Tyr-338, are located on putatively mobile interstrand loops. We propose that residual densities located in the binding cleft of the RPE65 structure represents a post-cleavage snapshot consistent not only with a fatty acid product, as originally modeled, but also an 11-cis-retinol product. Substrate docking simulations permit 11-cis- or 13-cis-retinyl ester binding in this relatively closed cleft, with the latter favored in F103L, F526A, and Y338A mutant structures, but prohibit binding of all-trans-retinyl ester, suggesting that isomerization occurs early in the temporal sequence, with O-alkyl ester cleavage occurring later. These findings provide insight into the mechanism of isomerization central to the visual cycle.
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