Steroid dehydrogenase structures, mechanism of action, and disease.
Steroid dehydrogenase enzymes influence mammalian reproduction, hypertension, neoplasia, and digestion. The three-dimensional structures of steroid dehydrogenase enzymes reveal the position of the catalytic triad, a possible mechanism of keto-hydroxyl interconversion, a molecular mechanism of inhibition, and the basis for selectivity. Glycyrrhizic acid, the active ingredient in licorice, and its metabolite carbenoxolone are potent inhibitors of human 11 beta-hydroxysteroid dehydrogenase and bacterial 3 alpha, 20 beta-hydroxysteroid dehydrogenase (3 alpha, 20 beta-HSD). The three-dimensional structure of the 3 alpha, 20 beta-HSD carbenoxolone complex unequivocally verifies the postulated active site of the enzyme, shows that inhibition is a result of direct competition with the substrate for binding, and provides a plausible model for the mechanism of inhibition of 11 beta-hydroxysteroid dehydrogenase by carbenoxolone. The structure of the ternary complex of human 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD) with the cofactor NADP+ and the antiestrogen equilin reveals the details of binding of an inhibitor in the active site of the enzyme and the possible roles of various amino acids in the catalytic cleft. The short-chain dehydrogenase reductase (SDR) family includes these steroid dehydrogenase enzymes and more than 60 other proteins from human, mammalian, insect, and bacterial sources. Most members of the family contain the tyrosine and lysine of the catalytic triad in a YxxxK sequence. X-ray crystal structures of 13 members of the family have been completed. When the alpha-carbon backbone of the cofactor binding domains of the structures are superimposed, the conserved residues are at the core of the structure and in the cofactor binding domain, but not in the substrate binding pocket.
Duax
W L
WL
Hauptman-Woodward Medical Research Institute, Inc., Buffalo, New York 14203, USA.
Ghosh
D
D
Pletnev
V
V
D015067:17-Hydroxysteroid Dehydrogenases / Q000737:chemistry / Q000378:metabolism; D000450:Aldosterone; D000595:Amino Acid Sequence; D000818:Animals; D003349:Cortisone Reductase / Q000737:chemistry / Q000378:metabolism; D006035:Glycyrrhiza; D006801:Humans; D006854:Hydrocortisone; D006913:Hydroxysteroid Dehydrogenases / Q000737:chemistry* / Q000378:metabolism*; D006973:Hypertension / Q000201:enzymology*; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000201:enzymology*; D010946:Plants, Medicinal
D000450:Aldosterone; D015067:17-Hydroxysteroid Dehydrogenases; D006913:Hydroxysteroid Dehydrogenases; D003349:Cortisone Reductase; D006854:Hydrocortisone