Complementary deoxyribonucleic acid cloning and enzymatic characterization of a novel 17β/3α-hydroxysteroid/retinoid short chain dehydrogenase/reductase

17 beta-Hydroxysteroid dehydrogenases (17 beta HSDs) convert androgens and estrogens between their active and inactive forms, whereas retinol dehydrogenases catalyze the conversion between retinol and retinal. Retinol dehydrogenases function in the visual cycle, in the generation of the hormone retinoic acid, and some also act on androgens. Here we report cloning and expression of a complementary DNA that encodes a new mouse liver microsomal member of the short chain dehydrogenase/reductase (SDR) superfamily and its enzymatic characterization, i.e. 17 beta HSD9. Although 17 beta HSD9 shares 88% amino acid identity with rat 17 beta HSD6, its closest homolog, the two differ in substrate specificity. In contrast to other 17 beta HSD, 17 beta HSD9 has nearly equivalent activities as a 17 beta HSD (with estradiol similar or equal to adiol) and as a 3 alpha HSD (with adiol similar or equal to androsterone). It also recognizes retinol as substrate and represents in part the NAD(+)-dependent liver micrasomal dehydrogenase that uses unbound retinol, but not retinol complexed with cellular retinol-binding protein. Thus, this enzyme has catalytic properties that overlap with two subgroups of SDR, 17 beta HSD and retinol dehydrogenases. Inactivation of estrogen and a variety of androgens seems to be its most probable function. Because of its apparent inability to access retinol bound with cellular retinol-binding protein, a function in the pathway of retinoic acid biosynthesis seems less obvious. These data provide additional insight into the enzymology of estrogen, androgen, and retinoid metabolism and illustrate how closely related members of the SDR superfamily can have strikingly different substrate specificities.