If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
|Superclasses:||Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → Vitamins Biosynthesis → Vitamin A Biosynthesis → Visual Cycles|
Some taxa known to possess this pathway include : Homo sapiens
Expected Taxonomic Range: Metazoa
The source of the chromophore in the visual system is all-trans-retinol, derived from the blood circulation (see retinol biosynthesis for its synthesis). The compound is taken up from the choroid blood vessels into the retinal pigment epithelium (RPE) cells, a monolayer of epithelial cells adjacent to the outer segments of photoreceptors. In the RPE all-trans-retinol is converted in several steps to 11-cis-retinal, which is then introduced into the photoreceptors, where it combines with opsin to form the visual pigments.
Following photoactivation of the pigment, the chromophore is released as all-trans-retinal, which is reduced to all-trans-retinol and then removed from the bleached photoreceptors and transported back to the RPE, where it enters the cycle again. Since the supply of new all-trans-retinol from blood vessels is rather slow, the cycle is driven primarily by the recycled photolytic all-trans-retinol released from the bleached photoreceptors.
This process is known as the visual cycle, and it provides 11-cis-retinal for pigment regeneration in both rods and cones.
About This Pathway
When all-trans-retinol arrives in the blood, it is bound as an all-trans-retinol-(plasma-retinol-binding-protein) complex. Upon entering the RPE cells, retinol dissociates from the plasma retinol-binding protein (which remains outside the cells) and binds instead to the cellular retinol-binding protein 1 ( RBP1), which diffuses from the apical processes to the RPE cell body. Once there, it is esterified to all-trans retinyl ester by the enzyme lecithin retinol acyltransferase ( LRAT). The ester is then hydrolyzed and isomerized into 11-cis-retinol in a single reaction catalyzed by the enzyme retinoid isomerohydrolase ( RPE65).
Bound to another protein called cellular retinaldehyde binding protein ( RLBP1), 11-cis-retinol is oxidized into 11-cis-retinal by 11-cis retinol dehydrogenase ( RDH5). Still bound to RLBP, 11-cis-retinal diffuses to the apical processes of RPE cells, which are close to the photoreceptors outer segments. At the apical processes 11-cis-retinal exits the RPE to the extracellular interphotoreceptor matrix (IPM), possibly facilitated by RLBP and other proteins. Binding with another carrier protein, interphotoreceptor retinoid-binding protein (IRBP), 11-cis-retinal is transferred back to the photoreceptor outer segment, where it recombines with apo-opsin to regenerate the visual pigment.
Photon absorption by 11-cis-retinal converts it to the all-trans form, which is a strong agonist for opsin. The photoisomerization of the retinoid induces a series of rapid conformational changes of the pigment molecule that convert it to the physiologically active state ( Meta II) within ~1 milisecond. Meta II is the form of rhodopsin that activates the visual G-protein, transducin, triggering a second messenger cascade. Meta II decays to an inactive form, Meta III, and following the hydrolysis of the Schiff-base bond dissociates into free opsin and all-trans-retinal. This decay takes minutes in rods but only seconds in cones. The released all-trans-retinal is reduced to all-trans-retinol by several NADPH-dependent retinol dehydrogenases, and all-trans-retinol is transferred from the photoreceptors to the apical processes of the RPE cells in a process facilitated by the interphotoreceptor retinoid-binding protein (IRBP). In the RPE, all-trans-retinol binds to the Cellular Retinol Binding Protein and re-enters the cycle.
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