Structure and mechanism of action and inhibition of steroid dehydrogenase enzymes involved in hypertension

Members of the NADPH-dependent short chain dehydrogenase/reductase (SDR) fa mily control blood pressure, fertility, and natural and neoplastic growth. Despite the fact that only one amino acid residue is strictly conserved in the 100 known members of the family, all appear to have a dinucleotide-bind ing Rossmann fold and homologous catalytic residues including the conserved tyrosine. Variation in the binding pocket creates specificity for steroids , prostaglandins, sugars and alcohols. The critically important tyrosine ap pears to maintain a fixed position relative to the scaffolding of the Rossm ann fold and the cofactor position, while the substrate-binding pocket alte rs in such a way that the dehydrogenation/reduction reaction site is brough t into bonding distance of the tyrosine hydroxyl group. Licorice induces hi gh blood pressure by inhibiting an SDR in the kidney. The crystal structure of the complex of 3 alpha,20 beta-hydroxysteroid dehydrogenase and carbeno xolone reveals the mechanism of enzyme inhibition by licorice. The most pot ent dehydrogenase enzyme inhibitors are those that displace substrate and c ofactor and form strong hydrogen bonds to one or more amino acid residues i nvolved in catalysis.