Visual cycle retinal

Takahashi, Y., G. Moiseyev et al. (2005). Identification of conserved histidines and glutamic acid as key residues for isomerohydrolase activity of RPE65, an enzyme of the visual cycle in the retinal pigment epithelium. FEBSLett. 579(24) 5414-5418. 

In lipid metabolism, ds-trans isomerism is particularly important. For example, double bonds in natural fatty acids (see p.48) usually have a as configuration. By contrast, unsaturated intermediates of p oxidation have a trans configuration. This makes the breakdown of unsaturated fatty acids more complicated (see p. 166). Light-induced cis-trans isomerization of retinal is of central importance in the visual cycle (see p.358). 

Since alcohol dehydrogenase is required for the conversion of retinol to retinal, excessive and prolonged ethanol ingestion can impair the physiological function of vitamin A. The decreased conversion of retinol to retinal results from competitive use of the enzyme by ethanol. Night blindness may result, since the visual cycle is a retinol-dependent physiological process. 

Reproduction Retinol and retinal are essential for normal repno duction, supporting spermatogenesis in the male and preventing fetal resorption in the female. Retinoic acid is inactive in maintain ing reproduction and in the visual cycle, but promotes growth and differentiation of epithelial cells thus, animals given vitamin A only as retinoic acid from birth are blind and sterile. 

Retinol A. can be enzymically formed from retinoic acid. B. is transported from the intestine to the liver in chylomicrons. C. is the light-absorbing portion of rhodopsin. D. is phosphorylated and dephosphorylated during the visual cycle. E. mediates most of the actions of the retinoids. Correct answer = B. Retinyf esters are incorporated into chylomicrons. Retinoic acid cannot be reduced to retinol. Retinal, the aldehyde form of retinol, is the chromophore for rhodopsin. Retinal is photoisomerized during the visual cycle. Retinoic acid, not retinol, is the most important retinoid. 

The retinal pigmented epithelium (RPE) is in intimate, anatomic, and functional contact with the retina. Separated from the retina by Bruch s membrane, the RPE serves to regulate nutrients to the retina, phagocytize retinal debris, remove metabolic end products, and control the visual cycle. From a mass transport perspective, the RPE represents the outer BRB. 

A number of geometric isomers of retinol exist because of the possible cis-trans configurations around the double bonds in the side chain. Fish liver oils contain mixtures of the stereoisomers synthetic retinol is the all-trans isomer. Interconversion between isomers readily takes place in the body. In the visual cycle, the reaction between retinal (vitamin A aldehyde) and opsin to form rhodopsin only occurs with the 11 -cis isomer. 

Trans-retinal eventually falls off of rhodopsin and must be reconverted to 11-cis-retinal and again bound by rhodopsin to get back to the starting point for another visual cycle. To accomplish this, trans-retinal is first chemically modified by an enzyme to trans-retinol—a form containing two more hydrogen atoms. A second enzyme then converts the molecule to 11-cis-retinol. Finally, a third enzyme removes the previously added hydrogen atoms to form 11-cis-rennal, a cycle is complete. ... 

Figure 29-5. The visual cycle of vitamin A is central to vision. In the retina, light stimulates the conversion of 1 l-c/.s-retinal, part of rhodopsin (Rho), to all-iraws-retinal and activates rhodopsin (Rho ).This initiates the first step of the signal transduction cascade that results in the transmission of the visual signal to the brain.The visual cycle involves biochemical and metabolic events in both the photoreceptors (rods) and the retinal pigment epithelium.

Describe the key enzymatic steps in the visual cycle converting bleached all- rrtws-re final back into light-sensitive ll-c(s-retinal. 

It is important to note that all-trans-retinal is incompletely converted to 11-cis-retinal hence a constant supply of vitamin A is needed in the diet. Describe other functions of vitamin A, besides visual cycle. 

Generally, vitamin A serves three classes of functions (1) support of the differentiation of epithelial cells, (2) support of the viability of the reproductive system (fetal growth and vitality of the testes), and (3) utilization in the visual cycle. Dietary retinoic acid can support only the first function. Animals raised on diets containing retinoic acid as the only source of vitamin lose their ability to see in dim light and become sterile. In males, sperm production ceases. In females, fetuses are resorbed. Retinoic acid cannot be stored in the liver, as it lacks the hydroxyl group needed for attachment of the fatty acid. Retinyl esters, retinol, and retinal are interconvertible. Retinal can be oxidized to form retinoic acid. All three functions of vitamin A can be supported by dietary retinyl esters, retinol, or retinal. Although these forms can be converted to retinoic acid, retinoic acid apparently cannot be reduced to form retinal. These relationships are summarized in Figure 9.44. 

Retinal is a functional component of the reactions of the visual cycle. 

The role of 11 -cis-retinal in the mammalian visual cycle is very well understood at the molecular level. This cycle is composed of three components (l)light detection, (2) initiation... 

About half of rhodopsln s mass forms seven a-hellces, which are embedded In the lipid bllayer of rod disks. The remaining polypeptide chains extend Into the aqueous environment of the cytoplasm or the disk Interior, linking the helices. Retinal Is bound as a protonated Schiff base to a lysine amino acid residue In the carboxyl terminal helix. The chromophore is held In a pocket that is nearly parallel to the membrane surface. When light strikes rhodopsln, the 11-cis double bond of the protein-bound retinal Isomerlzes to the trans form, which leads to the separation from the protein opsin. To complete the visual cycle, the all-transretlnal slowly Isomerlzes back to the 11-cis Isomer, which recombines with opsin to reform rhodopsln. However, little Is known about how the Isomerization of retinal In rhodopsln triggers the transduction process (72,73) ... 

Vitamin A is the isoprenoid alcohol retinol, which is required for a number of body processes including vision, growth, maintenance of mucous membranes, reproduction and proper growth of the cartilage matrix upon which bone is deposited. Of these, the molecular basis of its role in the visual cycle is best understood. In addition to the alcohol retinol, both retinal and retinoic acid (Fig. 2.4) also act to restore some of the deficiency symptoms. In rod vision, retinol is oxidised to retinal. 11-ds-Retinal combines with the protein opsin to form rhodopsin. After the absorption of a photon, rhodopsin undergoes a series of changes, eventually dissociating to opsin and all-fraMS-retinal. This last compound is converted back to 11-ds-retinal by retinal isomerase (EC.5.2.1.3) Retinoic acid is able to replace retinol in all functions except the visual cycle and reproduction. 

This is the intermediate metabolite between retinol and tRA and is used in the visual cycle where 11 -cis-retinal binds with the protein opsin to form rhodopsin, the visual pigment. It is undetectable in mammalian and chick embryos, but present at very high levels in amphibian (11,12) and zebrafish eggs (13). It is not active in inducing pattern duplication in the regenerating amphibian limb (8). 

In the recovery of the visual apparatus, the G(a)-GTP-PDE complex is inactivated by spontaneous cleavage of the GTP. Activated rhodopsin is the substrate for a kinase which may deactivate it. The kinase is inhibited by cGMP, so that the amount of activated rhodopsin may be subject to feedback regulation. The trans-retinal may be isomerized directly to 11-cis-retinal, which recombines with opsin to form rhodopsin or it may first be reduced to retinol by NADH-dependent alcohol dehydrogenase, followed by isomerization of the retinol and reoxidation to 11-ci s-retinal (Fig.). Some of the retinal is continually lost from the cells of the retina, so that the continuation of the visual cycle depends on continual replacement from the blood. 

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