Retinaldehyde synthesis

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)]. 

Some reports have suggested that RA synthesis during embryonic development may also occur independently of RALDHs, possibly through the action of members of the cytochrome P450 family of monooxygenases (Collins and Mao 1999). Functional studies point to CYPIBI as a potential candidate (Chambers et al. 2007), because this enzyme can efficiently oxidize retinol to retinaldehyde and subsequently to RA and exhibits an expression pattern consistent with RA synthesis patterns in the developing embryo (Chambers et al. 2007). 

In this introduction, we do not provide a more detailed review of the classical discoveries in the field of vitamin A research. As already discussed in part, these classical discoveries included the original description of fat-soluble A and the introduction of the term ""vitamin A the recognition of retinol as a substance distinct from its carotenoid precursors the development of quantitative chemical methods for the analysis and assay of retinol and related substances the elucidation of the chemical structure and then the total synthesis of retinol, retinyl esters, and retinoic acid the description of the unique pathology of both hypovitaminosis A and h q)ervitaminosis A in experimental animals and man the elucidation of the fundamental role of retinaldehyde in vision the determination of human and animal needs for retinol or its precursors for adequate nutrition and the development of practical syntheses for the commercial production of retinyl esters to meet those nutritional needs. This historical story has been... 

The successful synthesis of (all- )-retinoic acid (3) was reported by Arens and van Dorp (van Dorp and Arens, 1946) in 1946, but almost 10 years passed before Robeson et aL (1955a) were able to prepare 13-cw-retinoic acid (17). Between 1946 and 1956, a large number of papers were published on successful syntheses of the natural C20 retinoids retinol (1), retinaldehyde (2), and retinoic acid (3), and nine industrial processes for the synthesis of vitamin A were developed during this period (Isler, 1979). 

Finally, in the past few years a large number of derivatives of natural retinaldehyde have been synthesized for use in the study of mechanistic details of the formation and function of rhodopsin (Vision Symposium, 1979 Sen et al., 1982 Liu and Asato, 1982) and bacteriorhodopsin (Ebrey and Yoshizawa, 1981). The efforts in the field of synthesis have been accompanied by the rapid development of analytical methods, especially NMR spectroscopy and high-performance liquid chromatography (HPLC), which permit rapid and reliable structure assignment. 

Protonated (91) was reduced in a one-electron process in acetonitrile, the radicals formed undergoing rapid dimerization. The reductive electrodimerization of retinaldehyde (2) in the presence of carbon acids such as diethyl malo-nate, led, in a one-electron process, to the 40 pinacol (94), which is of course of interest as an intermediate for the synthesis of p-carotene (Sioda et al., 1976 Powell and Wightman, 1979). With phosphorus triiodide, (94) gave p-carotene. 

The direct photolysis of (all- )-retinaldehyde (2) has been developed into an important preparative isomerization method that has been successfully used for the synthesis of (llZ)-retinaldehyde (377), the solvent employed being ethanol (Inoue et aL, 1979) or, more advantageously, acetonitrile (Denny et aL, 1981). Using this method, it has also been possible to prepare relatively small amounts of (9Z, 1 lZ)-retinaldehyde (371), (9Z,13Z)-retinaldehyde (389), (7Z,l3Z)-reti-naldehyde (353), and (7Z,9Z)-retinaldehyde (356). These aldehydes were separated from one another by preparative HPLC. 

For the synthesis of retinaldehyde (2), a large number of oxidation processes have been worked out that permit (2) to be prepared in a very simple manner from commercially available retinyl acetate (9). Thus, when manganese(lV) oxide precipitated in alkaline medium was used and the reaction was carried out in petroleum ether, retinol (1) was converted to retinaldehyde (2), without unde-... 

The synthesis of retinaldehyde (2) that employed the C,5 aldehyde (4) and dimethylacrolein (5) and was originally tested by Kuhn and Morris (1937) was modified by replacing the starting materials with the C,5 alcohol (164) and 3-methyI-2-buten-l-ol (165) these compounds were oxidized in situ to the aldehydes (4) and (5), which were then condensed with one another (Matsui et al., 1958). 

Racemic 3-hydroxy-(9Z)-retinaldehyde (312) was obtained from the p-ionone (311) containing a functional group in position 3, the synthesis requiring several steps that had already been tested in other reactions (Surmatis et aL, 1980). 

In alcoholic solutions, retinaldehyde (2) was converted to the corresponding ketals (Takashima et al., 1974), which have also been isolated as end products in the synthesis of the C20 carbon skeleton of the natural retinoids (Pommer, 1960 Makin, 1976). 

The synthesis of 9-c/5-retinaldehyde-l 1- H, shown in Fig. 13, was carried out by a procedure similar to that used for frany-retinaldehyde-ll- H (Kaegi et aL,... 

The best way to prepare retinonitrile would probably be by direct synthesis. Methods for its preparation with tritium labels in position 11 and positions 11 and/or 10, as used as an intermediate in the preparation of labeled retinaldehyde, are described in Section II,B,1. 

Among humans, abnormal dark adaptation is reported in both vitamin A deficiency and zinc deficiency and is especially prevalent in alcoholic cirrhotics (Patek and Haig, 1939 Russell et aL, 1973 Morrison et aL, 1978 McClain et aL, 1979). In the former but not in the latter deficiency, treatment with vitamin A reverses the abnormality (Russell et aL, 1978) only after correcting the zinc deficiency does dark adaptation become normal in the latter case (Morrison et aL, 1978 McClain et aL, 1979). The molecular basis for these observations may be associated, at least in part, with the activity of retinaldehyde reductase in the retina which, as already mentioned, Huber and Gershoff (1975) showed to be especially sensitive to the level of zinc nutriture and Mezey and Holt (1971) showed was competitively inhibited by the presence of ethanol. In the alcoholic cirrhotic, however, the zinc-vitamin A interaction may be further complicated by a defective hepatic synthesis of transport proteins (Mobarhan et aL, 1981) or failure to sequester or retain zinc Nutrition Reviews, 1982) and/or vitamin A (Sato and Lieber, 1981 Leo and Lieber, 1982) in the appropriate tissues. The implications for human nutrition of the interaction of vitamin A and zinc were reviewed by Solomons and Russell (1980). 

In a study on adult mouse liver, AHD2 was identified as the principal enzyme for RA synthesis [7], and we confirmed this function for the embryonic retina [8]. Apart from AHD2, little information had been available on which other aldehyde dehydrogenases can oxidize reti-naldehyde to RA. Information was sparse because of the difficulty in dissolving the retinaldehyde substrate at a concentration sufficient for the standard aldehyde dehydrogenase... 

Lee M-0, Manthey CL, Sladek NE (1991) Identification of mouse liver aldehyde dehydrogenases that catalyze the oxidation of retinaldehyde to retinoic acid. Biochem Pharmacol 42 1279-1285 McCaffery P, Lee M-O, Wagner MA, Sladek NE, Drager UC (1992) Asymmetrical retinoic acid synthesis in the dorso-ventral axis of the retina. Development 115 371-382... 

The recent identification of 9-cw-retinol dehydrogenase in the mouse embryo reveals a pathway for 9-cw-RAs synthesis in this species [60]. This membrane-bound enzyme is able to oxidize 9-c/5-retinol into 9-c/5-retinaldehyde which can be subsequently oxidized to 9-cis-RA. The expression of this enzyme is temporally and spatially controlled during embryogenesis in parts of the nervous system, sensory organs, somites and myotomes, and several tissues of endoder-mal origin. Mertz et al. have also identified a stereospecific human enzyme that catalyzes 9-cis-retinol oxidation and is likewise a member of the short chain alcohol dehydrogenase protein family [61]. The mRNA for the protein is most abundant in human mammary tissues. 

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