Vitamin A and the Visual Cycle

Figure 3 depicts a model of the functions of multiple proteins and forms of vitamin A that constitute the visual cycle. SRBP delivers atROH to the RPE, possibly through a plasma membrane SRBP receptor. No SRBP receptor has been isolated, however, and molecular characterization remains elusive. As in other tissues, CRBP(I) sequesters atROH and allows its esterification by the 25-kDa endoplasmic reticu-lum (ER) enzyme lecithin:retinol acyltransferase (LRAT). In fact, the amount of CRBP(I) may represent the controlling event in the rate of atROH uptake, and uptake may be coupled to retinyl ester (RE) formation. RPE65, an ^65-kDa RPE protein, binds the highly hydrophobic atRE with a Kd of ^20 pM. This accelerates mobilization of atRE and delivery to the next step, isomerization by an iso-merohydrolase (IMH). The RPE65 null mouse cannot produce 11-cis-retinoids, attesting to its importance in mobilizing atRE in the quantity and rate necessary to support the visual cycle. The IMH both hydrolyzes atRE and isomerizes the double bond at C11 to produce 11cROH. Unfortunately, little is known about the IMH: It has not been isolated or cloned. The cytosolic protein CRALBP sequesters 11cROH and also 11cRCHO produced by the ER enzyme 11-cis-retinol dehydrogenase (11cRDH), and it seems to enhance isomerization. The 11cRDH of the RPE belongs to the SDR (short-chain dehydrogenase/reductase) gene family: RDH4 and RDH5 encode the murine and human 11cRDH genes, respectively. 11cRDH also has been referred to as 9cRDH (9-cis-RDH) or cRDH, but the eye expresses 11cRDH mRNA far more intensely than other tissues, and more efficient potential 9cRDHs have been cloned and characterized, namely the SDR isozymes CRAD1 and -3 (cis-retinol/androgen dehydrogenase). Mutations in RDH5 cause the rare autosomal recessive disorder fundus albipunctatus, which is a form of night blindness characterized by delayed regeneration of photopigments in rods and cones. Enzymes in addition to RDH4/5 probably contribute to dehydrogenation of 11cROH in the RPE, which explains why the RDH5 mutation does not cause blindness.

Interphotoreceptor retinoid binding protein (IRBP) occupies the space between the RPE and the rod outer segment (ROS), the interphotoreceptor matrix, and binds both 11cROH and 11cRCHO.

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