Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewKey enzymes of the retinoid (visual) cycle in vertebrate retina☆
Research highlights
► Great progress has been made in understanding enzymes of the retinoid cycle. ► Animal models are invaluable in elucidating functions of these enzymes. ► Genetic lesions have linked retinoid cycle enzymes with human retinal diseases. ► Structural data has provided mechanistic insights into retinoid cycle enzymology.
Section snippets
Introduction: regeneration of the chromophore: retinoid cycle
The pioneering studies of Boll and Kühne ca. 1877 demonstrated that exposure of frog retinas to light resulted in a series of color changes from purplish-red to yellow and then from yellow to white [1]. This process is known as photochemical bleaching and results from the sequential photoisomerization and hydrolysis of the rhodopsin chromophore [2]. A critical discovery made by Kühne was that the bleached retina could regain its purplish-red hue when repositioned in the back of the eye on top
Lecithin:retinol acyltransferase (LRAT) — structure, catalysis, and physiological significance
Retinyl esters are bioactive storage metabolites of vitamin A. Because of their chemical stability and hydrophobicity, these compounds serve as a transport and storage form of vitamin A in vertebrates and therefore play an essential role in maintenance of retinoid homeostasis. Vitamin A esters can be formed in vivo by enzymatic transfer of activated fatty acyl moieties from acyl-CoAs or directly from a phospholipid donor. However, phospholipid-dependent synthesis is quantitatively the most
Retinol dehydrogenases
Two reactions of the retinoid cycle are catalyzed by retinol dehydrogenases (RDHs). Based on biochemical approaches, several RDHs involved in the retinoid cycle have been identified. Reduction of all-trans-retinal to all-trans-retinol in photoreceptors is catalyzed by all-trans-RDHs, whereas oxidation of 11-cis-retinol to 11-cis-retinal in the RPE is catalyzed by 11-cis-RDHs. RDHs belong to the short-chain dehydrogenase/reductase (SDR) family, which catalyzes NAD(H)-/NADP(H)-dependent
Brief history of RPE65
RPE65, also known as p63, was identified in the early 1990's as a major protein of bovine RPE microsomal membranes [108], [109], [110], [111], [112]. The function of this protein remained obscure until 1997 when it was shown to bear sequence homology to a newly identified carotenoid cleavage oxygenase involved in abscisic acid biosynthesis known as viviparous 14 (VP14) [113], [114]. In this same year RPE65 mutations were found in patients with LCA, the childhood blinding disease, establishing a
Conclusions
Because the retinoid cycle lies at the heart of vertebrate vision, remarkable progress has been achieved by using genetic animal models and traditional biochemistry with conjunction with structural biology. Two reactions discussed in this review are common to other tissues including acyltransfer and redox reactions of retinol. Even eye specific isomerization reaction found relevance in the context of CCO enzymes. Combined with novel, cutting-edge biophysical techniques developed in vision
Acknowledgements
This research was supported in part by grant EY008061, and a core grant P30 EY11373 from the National Institutes of Health, and Foundation Fighting Blindness. We thank Drs. Leslie T. Webster Jr., Thomas Sundermeier and Brian Kevany for valuable comments and Michal Palczewski for advice on construction of phylogenetic trees.
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This article is part of a Special Issue entitled: Retinoid and Lipid Metabolism.
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Contributed equally.