The retinoid cycle metabolic pathway, also known as the visual cycle, represents the set of enzymatic reactions underlying the regeneration of vitamin A derived chromophore 11-cis retinal which assures the continued visual phototransduction response to light. The chromophore is covalently bound to the G-protein coupled (GPCR) photoreceptors; the linkage is supplied by a protonated Schiff base to a lysine residue. In the absence of light 11-cis retinal acts as an inverse agonist by constraining t
he receptor in an inactive conformation. Upon light stimulation, the 11-cis retinal is isomerized to all-trans retinal followed by a series of conformational changes in the photoreceptor and release of the isomerized choromophore. Membrane-bound enzymes in the photoreceptors outer segments (OS) and retinal pigment epithelium (RPE) catalyze the reduction, esterification, isomerization and final oxidation of substrates back to the 11-cis retinal. All-trans retinal is first reduced to all-trans retinol by retinol dehydrogenases (RDHs), specifically the all-trans RDHs. RDHs belong to the short-chain dehydrogenase/reductase (SDR) family involved in NAD(H)-/NADP(H)-dependent oxidation/reduction reactions. The RDH members involved in this reduction step are Rdh8 and 12 which generally require NADPH as a coenzyme. Transport of all trans-retinal from the site of its release from the photoreceptor to the cytoplasmic side of the membrane to serve as the substrate for the all-trans RDH-mediated reaction is carried out by the photoreceptor-specific ATP-binding cassette transporter Abca4. All-trans retinol is esterified to retinyl esters (RE), the storage form of retinol and substrate for the isomerization reaction, by Lrat using phosphatidylcholine (PC) as an acyl source. The reaction is important not only for capturing the released pigment but also the retinols present in the circulation. Retinols are bound by Rbp3, also known as the interphotoreceptor retinoid-binding protein (Irbp) in the extracellular space and by the cellular retinol-binding protein 1 Rbp1 in RPE, facilitating the transfer of retinol formed in OS to RPE for esterification (PDB entry for the NMR structure of Rbp1 from Rattus norvegicus). The isomerization of all-trans retinol/retinyl esters to 11-cis retinol is catalyzed by Rpe65 and is believed to represent the rate-limiting step in the cycle pathway. Rbp65 belongs to the family of carotenoid cleavage oxygenases (CCOs). Rbp65 catalyzes a coupled reaction involving an atypical ester hydrolysis coupled to a trans-to-cis double bond isomerization; the hydrolysis of the ester is thought to provide the energy necessary to drive the endergonic isomerization reaction. Conserved histidine and glutamate residues coordinate the catalytic ferrous iron cofactor. The iron in CCO enzymes activates molecular oxygen for the cleavage reaction; however, Rbp65 does not catalyze such as a reaction and the requirement for iron has been explained as acting as a Lewis acid that may facilitate the dissociation of the ester in the coupled reaction. Palmitoylation of three cysteine residues, of which one is conserved across species, was thought to contribute to the membrane localization of the enzyme and the reversible modification would underlie the cycling between a soluble and a membrane-bound state. Replacement of these cysteines with alanine in the human enzyme affected its activity but not the membrane association while the presence of labeled palmitic acid suggested that other cysteines residues are possible candidates for the modification reaction (the human protein has 11 cysteines). In addition, other mechanisms may be account for the membrane association of the enzyme. Rpe65 activity is essential for the regeneration of rhodopsin, the photoreceptor of rods cells while cone cells do not rely exclusively on Rpe65; an alternative 'cone visual cycle' has been proposed (PDB entry for the crystal structure of Rpe65 from B. taurus). The rod and cone cells in the retina mediate vision in dim and bright light, respectively. The final oxidation of 11-cis retinol to 11-cis retinal is carried out by 11-cis retinol dehydrogenases of the RDH family, Rdh5, 10 and 11 which generally require NAD+ as a coenzyme. The newly synthesized chromophore is protected via binding to Rlpb1, also known as Cralbp, which mediates its transport to the apical plasma membrane of RPE for insertion into the photoreceptors (PDB entry for the crystal structure of human RLBP1). Mutations in a number of components in the visual cycle and phototransduction pathways have been linked to several human autosomal recessive and retinal degeneration diseases. To see the ontology report for annotations, Gviewer and download, click here...(less)
