Understanding retinol metabolism: structure and function of retinol dehydrogenases.

Retinoids (vitamin A derivatives) have dual functions in physiology. 11-cisRetinal serves as the universal chromophore of the visual pigments in the eye, and the hormonal retinoids, mainly all-transand 9-cis-retinoic acid (RA),2 regulate the expression of target genes via activation of two classes of nuclear retinoid receptors, the retinoic acid receptors (RARs), and the retinoid X receptors (RXRs) (1). The dietary sources of retinoids are the proforms of the vitamin, mainly esterified retinol, or the ultimate precursors for retinoids, various carotenoids. Thus, the biosynthesis of active forms of retinoids is of crucial importance for many physiological processes, including embryonic development, reproduction, postnatal growth, differentiation and maintenance of various epithelia, immune responses, and vision (2–4). During fasting conditions the common precursor of the active retinoids, all-trans-retinol (vitamin A), is transported in plasma in a 1:1 complex with retinol-binding protein (RBP) (5). Retinol, in the form of retinyl esters, can also be transported to target cells using the common lipoproteins in plasma (6). Following uptake by target cells, retinol is converted, through several enzymatic steps, into its active derivatives (Fig. 1). Retinol is oxidized once to generate retinal and twice to generate RA. For the generation of the 9-cisor 11-cis-retinoids, an isomerization reaction takes place prior to the first oxidation (7). The enzymes for most of these activities have been identified. To date some 20 different enzymes displaying all-transor -cis-retinol dehydrogenase (RDH) activities have been isolated and partially characterized by standard biochemical methods (Table 1). However, whether all of these enzymes truly function as retinol dehydrogenases in vivo remains to be determined. To this end it will be of great importance to analyze the enzymatic characteristics of the identified RDHs in intact cells, isolated organs, and in animal models. Here we discuss current knowledge regarding the biological roles, and structurefunction relationships of RDHs, focusing on the microsomal members of the short chain dehydrogenase/reductase (SDR) family.