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Complementary Deoxyribonucleic Acid Cloning and Enzymatic Characterization of a Novel 17ß/3-Hydroxysteroid/Retinoid Short Chain Dehydrogenase/Reductase¹

Department of Biochemistry, State University of New York School of Medicine and Biomedical Sciences, Buffalo, New York 14214

Address all correspondence and requests for reprints to: Dr. Joseph L. Napoli, Department of Nutritional Sciences, 119 Morgan Hall, MC#3104, University of California, Berkeley, California 97420-3104. E-mail: jln{at}uclink4.berkeley.edu

17ß-Hydroxysteroid dehydrogenases (17ßHSDs) 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. 17ßHSD9. Although 17ßHSD9 shares 88% amino acid identity with rat 17ßHSD6, its closest homolog, the two differ in substrate specificity. In contrast to other 17ßHSD, 17ßHSD9 has nearly equivalent activities as a 17ßHSD (with estradiol adiol) and as a 3HSD (with adiol androsterone). It also recognizes retinol as substrate and represents in part the NAD⁺-dependent liver microsomal 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, 17ßHSD 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.

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