Retinol isomerization

The dianions of the metallized acetylene compounds (7) and (300) were subjected to alkylation reactions with the C,4 aldehyde (6). The diols (8) and (412), which were obtained as intermediates, were acetylated and dehydrated to give the isomeric dehydroretinols (413) and (414). It proved possible to hydrogenate the latter compounds to give retinols. Isomeric 11,12-di-dehydroretinaldehydes were prepared in a very similar manner (01iv6 et al., 1969). 

Livrea MA, Tesoriere L, Bongiomo A (1991) AW-trans to ll-cis retinol isomerization in nuclear membrane fraction from bovine retinal pigment epithelium. Exp Eye Res 52 451-459... 

In the BASF synthesis, a Wittig reaction between two moles of phosphonium salt (vitamin A intermediate (24)) and C q dialdehyde (48) is the important synthetic step (9,28,29). Thermal isomerization affords all /ra/ j -P-carotene (Fig. 11). In an alternative preparation by Roche, vitamin A process streams can be used and in this scheme, retinol is carefully oxidized to retinal, and a second portion is converted to the C2Q phosphonium salt (49). These two halves are united using standard Wittig chemistry (8) (Fig. 12). 

A deficiency of vitamin A leads to vision defects, including a visual impairment at low light levels, termed night blindness. For the processes of vision, retinol needs to be converted first by oxidation into the aldehyde retinal, and then by enzymic isomerization to cw-retinal. c -Retinal is then bound to the protein opsin in the retina via an imine linkage (see Section 7.7.1) to give the red visual pigment rhodopsin. 

Biesalski, FI. K. (1990). Quantitative and qualitative microdetermination of different fatty acid esters of retinol including their isomeric configurations in small tissue samples. Methods Enzymol. 189, 83-91. 

Retinol can be oxidized to retinal (6.2) and further to retinoic acid (6.3). Cis-trans isomerization can also occur, e.g. the conversion of all trans-retinal to 11-cis-retinal (6.4), which is important for vision. 

The parent vitamin A compound, retinol, has the empirical formula C2oH3oO and a molecular weight (MW) of 286.44. The molecule comprises a cyclohexenyl (/3-ionone) ring attached at the carbon-6 (C-6) position to a polyene side chain whose four double bonds give rise to cis-trans (geometric) isomerism. The predominant isomer, all-trans-retinol (Fig. 1), possesses maximal (100%) vitamin A activity and is frequently accompanied in natural foodstuffs by smaller amounts of 13-ds-retinol, which exhibits 75% relative activity in the rat (6). Other cis isomers of retinol also occur in nature, but they are of low potency, and their contribution to the total vita-... 

GM Landers, JA Olson. Absence of isomerization of retinyl palmitate, retinol, and retinal in chlorinated and nonchlorinated solvents under gold light. J Assoc Off Anal Chem 69 50-55,1986. 

Retinoic acid (vitamin A acid), in which the alcohol group has been oxidized, shares some but not all of the actions of retinol. Retinoic acid is ineffective in restoring visual or reproductive function in certain species in which retinol is effective. Flowever, retinoic acid is very potent in promoting growth and controlling differentiation and maintenance of epithelial tissue in vitamin A-deficient animals. Indeed, all-trans-retinoic acid (tretinoin) appears to be the active form of vitamin A in all tissues except the retina, and is 10- to 100-fold more potent than retinol in various systems in vitro. Isomerization of this compound in the body yields 13-n.v-rctinoic acid (isotretinoin), which is nearly as potent as tretinoin in many of its actions on epithelial tissues but may be as much as fivefold less potent in producing the toxic symptoms of hypervitaminosis A. 

The lipase-catalysed hydrolysis of methyl 2-fluoro-2-arylpropionates was proposed to proceed via a mechanism whereby, after ester hydrolysis, the enzyme facilitates the elimination of fluoride ion with the formation of a carbocation stabilized by the adjacent C02 group.230 Determination of the crystal structure of human sialidase Neu2, an enzyme that catalyses the hydrolysis of sialic acids, reveals a tyrosine residue that is positioned in the active site to stabilize the carbocation proposed as an intermediate in the hydrolysis.231 ll-Fluoro-all-frans-retinol is found to undergo isomerization to its 11 -cis form in the presence of visual cycle enzymes, in contrast to a previous study where no isomerization was reported.232 The result of the prior study was taken as evidence for a carbonium ion pathway in the isomerization. Although the authors of the present study do not rule out such a mechanism, they suggest that the isomerization mechanism remains unknown. Data obtained in a study of the oxidation of... 

Since the time of Wald s demonstration that rhodopsin, the conceptual chromophore of vision relied upon retinol as a chromogen and Hubbard s contemporary proposal that photodetection involved an isomerism of the chromophore, the conventional wisdom has adopted that position. To support these proposals, Collins proposed that a Shiff-base was... 

Electronic Absorption Spectroscopy. The absorption spectra of some polyenes in the crystalline state have been studied. On adsorption of certain gases on the crystallite surfaces, a new band appears on the low-energy side of the long-wavelength band in the spectra of these polyenes, e.g. at 536, 537, and 375 nm for all- trans-ft-carotene, 15-cis-/3-carotene, and retinyl compounds, respectively.92 The surface pressure vs. area isotherms and absorption spectra of all-trans-, 9-cis-, and 13-cis-retinal, all-trans-retinol, and all- trans-retinyl acetate have been studied at air-water and air-solid interfaces, respectively. The spectra of monolayers of the isomeric retinals showed a red shift of 15 lnm compared with the solution spectra, whereas... 

With the exception of photodissociation to radical ions observed for retinol in polar solvents (144), cis-trans isomerization is the major photochemical transformation undergone by all forms of the free retinyl-polyene chromophore. [Unidentified photochemical damage has been reported to occur with very low quantum yields, e.g., 0.04 in the case of all-trans retinal (177).] We shall subsequently see that critical comparisons between the photochemical behavior of the biopigments and that of the opsin-free chromophore have led to the conclusion that the protein moiety plays a major role in governing the photochemical mechanism in rhodopsin (176). It is, therefore, natural that in parallel to spectroscopic and theoretical investigations, considerable attention has been devoted to the photoisomerization of model compounds, particularly to that of retinal isomers. 

Isomerization due to ionic photodissociation. The (all-trans) + (cis) photoisomerization of ROH, RAc, and RBA is markedly enhanced in polar solvents. Using pulsed laser photolysis it was also shown that ionic photodissociation is responsible for the polarity-induced shortening of the corresponding fluorescence lifetimes. An analysis of both effects led to the formulation of the following scheme (e.g., in the case of retinol)... 

Anhydroretinol may arise by nonenzymic isomerization of all-trans-retinol under acidic conditions and can act as a precursor for the synthesis of other biologically active retroretinoids (McBee et al., 2000). 

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. 

McBee JK, KuksaV, Alvarez R, de Fera AR, Prezhdo O, Haeseleer F, Sokal I, and Palczewski K (2000) Isomerization of all-fra s-retinol to as-retinols in bovine retinal pigment epithelial cells dependence on the specificity of retinoid-binding proteins. Biochemistry 39,11370-80. 

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