Review
Key enzymes of the retinoid (visual) cycle in vertebrate retina

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Abstract

A major goal in vision research over the past few decades has been to understand the molecular details of retinoid processing within the retinoid (visual) cycle. This includes the consequences of side reactions that result from delayed all-trans-retinal clearance and condensation with phospholipids that characterize a variety of serious retinal diseases. Knowledge of the basic retinoid biochemistry involved in these diseases is essential for development of effective therapeutics. Photoisomerization of the 11-cis-retinal chromophore of rhodopsin triggers a complex set of metabolic transformations collectively termed phototransduction that ultimately lead to light perception. Continuity of vision depends on continuous conversion of all-trans-retinal back to the 11-cis-retinal isomer. This process takes place in a series of reactions known as the retinoid cycle, which occur in photoreceptor and RPE cells. All-trans-retinal, the initial substrate of this cycle, is a chemically reactive aldehyde that can form toxic conjugates with proteins and lipids. Therefore, much experimental effort has been devoted to elucidate molecular mechanisms of the retinoid cycle and all-trans-retinal-mediated retinal degeneration, resulting in delineation of many key steps involved in regenerating 11-cis-retinal. Three particularly important reactions are catalyzed by enzymes broadly classified as acyltransferases, short-chain dehydrogenases/reductases and carotenoid/retinoid isomerases/oxygenases. This article is part of a Special Issue entitled: Retinoid and Lipid Metabolism.

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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      Citation Excerpt :

      The chromophore of rhodopsin, 11-cis retinal, is isomerized into all-trans retinal (ATRal) upon light absorption. The visual cycle allows the regeneration of 11-cis retinal from ATRal through a process which takes place both in ROS and the retinal pigment epithelium [3,5–7]. The first step involves the reduction of ATRal into all-trans retinol (ATRol) by retinol dehydrogenase 8 (RDH8) [8–10].

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    This article is part of a Special Issue entitled: Retinoid and Lipid Metabolism.

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