Retinaldehyde oxidation

The state of body reserves of the vitamin may affect the extent to which it is absorbed (by affecting the synthesis of binding and transport proteins) or the extent to which it is metabolized after uptake into the intestinal mucosa [e.g., the oxidative cleavage of carotene to retinaldehyde is regulated by vitamin A status (Section 2.2.1)]. 

Cytosolic alcohol dehydrogenases only act on free retinol, not retinol bound to CRBP, so they are unlikely to he involved in formation of retinaldehyde and retinoic acid. Furthermore, inhihition of cytosolic alcohol dehydrogenases does not inhibit the oxidation of retinol to retinoic acid (Boerman and Napoli, 1996). CRBP-bound retinol is a substrate for atleast three microsomal NADP+-dependent dehydrogenases hut, given the intracellular NADP+ NADPH ratio (0.01, compared with an NAD+ NADH ratio of the order of 10 ), it is likely that these microsomal enzymes wiU act mainly to reduce retinaldehyde to retinol and not to oxidize retinol. 

A microsomal retinol dehydrogenase catalyzes the oxidation of CRBP-hound all-trans-retinol to retinaldehyde it also acts as a 3a-hydroxysteroid dehydrogenase. A similar enzyme catalyzes the oxidation of 9-cis- and 11-ds-retinol, but not all-trans-retinol again, it has 3a-hydroxysteroid dehydrogenase activity. In the eye, the major product of this enzyme is 11-cts-retinaldehyde, whereas in other tissues it is 9-cts-retinaldehyde, which is then oxidized to 9-cis-retinoic acid (Section 2.3.2.1 Chen et al., 2000 Duester, 2000, 2001 Gamble et al., 2000 NapoU, 2001). Although there is known to be an isomerase in the eye for the formation of 11-cts-retinaldehyde as a... 

Figure 2.3. Oxidative cleavage of j6-carotene by carotene dioxygenase (EC 1.14.99.36), and onward metabolism of retinaldehyde catalyzed by retinol dehydrogenase (EC 1.1.1.105) and retinaldehyde oxidase (EC 1.2.3.11).

Carotene Dioxygenase As shown in Figure 2.3,/S-carotene and other provitamin A carotenoids undergo oxidative cleavage to retinaldehyde... 

Figure 2.4. Potential products arising from enzymic or nonenzymic symmetrical (a) or asymmetric (b to d) oxidative cleavage of, 6-carotene. Apocarotenals can undergo side chain oxidation to yield retinoic acid, but cannot form retinaldehyde or retinol.

The pigment epithelium of the retina receives all- fraws-retinol fromplasma RBP. It is then isomerized to ll-c(s-retinol, which may either be stored as ll-c(s-retinyl esters or oxidized to ll-c(s-retinaldehyde, which is transported to the photoreceptor cells bound to an interphotoreceptor retinoid binding protein. 

After the light-catalyzed reaction, all-mins-rctinal is released, which in turn is reduced to all-/ntm-retinol. To be used again by opsin, the all-/nins-retinol must be converted to I l-eis-rclinol. Isomerization occurs in the pigment epithelium of the retina. Oxidation of I l-cis-relinol to I -cis-relrnaldchyde occurs while retinol is bound to the protein cellular retinaldehyde-binding protein (CRALBP) by a microsomal enzyme in the pigment epithelium. ... 

A procedure for the preparation of 1-bromoacetylenes and conjugated enynes77 has been used to make the retinaldehyde derivative (126). Retro-aldol reaction of the retinylidenedimedone (127) with MeNHa gave all-Pms-retinaldehyde in 90% yield.78 Oxidation of (127) gave the 5,6- and 5,8-epoxides (128) and (130).79 The 4-acetoxy-, 4-hydroxy-, and 4-keto-derivatives (131) (X = H,OH, H,OAc, and O respectively) and the seco-compound (133) were also prepared. Compounds (128), (130 X = O), and (131) underwent retro-aldol reaction to give the aldehydes... 

Chemical structure of a -tmns retinol (vitamin Ai), the most active form of vitamin A. Oxidation of C15 to an aldehyde or an acid produces, respectively, retinaldehyde (retinal) and retinoic acid. The cis-trans isomerization of the double bond between Ci i and C12 occurs during functioning of retinaldehyde in vision. 

The second oxidation step is the conversion of retinaldehyde into RA, an irreversible reaction carried ont by retinaldehyde dehydrogenases (RALDHs) (Fignre 1.2). Three RALDHs of the ALDHl class (RALDHl, 2, and S also called ALDHIAI, ALDH1A2, and ALDHIAS, respectively) and one RALDH of the ALDH8 class... 

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