SHORT-CHAIN DEHYDROGENASES REDUCTASES (SDR)

Short-chain dehydrogenases/reductases (SDR) constitute a large protein family. Presently, at least 57 characterized, highly different enzyme s belong to this family and typically exhibit residue identities only at the 15-30% level, indicating early duplicatory origins and extensiv e divergence. In addition, another family of 22 enzymes with extended protein chains exhibits part-chain SDR relationships and represents en zymes of no less than three EC classes. Furthermore, subform and speci es variants are known of both families. In the combined SDR superfamil y, only one residue is strictly conserved and ascribed a,crucial enzym atic function (Tyr 151 in the numbering system of human NAD(+)-linked prostaglandin dehydrogenase). Such a function for this Tyr residue in SDR enzymes in general is supported also by chemical modifications, si te-directed mutagenesis, and an active site position in those tertiary structures that have been characterized. A lysine residue four residu es downstream is also largely conserved. A model for catalysis is avai lable on the basis of these two residues. Binding of the coenzyme, NAD (H) or NADP(H), is in the N-terminal part of the molecules, where a co mmon GlyXXXGlyXGly pattern occurs. Two SDR enzymes established by X-ra y crystallography show a one-domain subunit with seven to eight beta-s trands. Conformational patterns are highly similar, except for variati ons in the C-terminal parts. Additional structures occur in the family with extended chains. Some of the SDR molecules are known under more than one name, and one of the enzymes has been shown to be susceptible to native, chemical modification, producing reduced Schiff base adduc ts with pyruvate and other metabolic keto derivatives, Most SDR enzyme s are dimers and tetramers. In those analyzed, the area of major subun it contacts involves two long alpha-helices (alpha E, alpha F) in simi lar and apparently strong subunit interactions. Future possibilities i nclude verification of the proposed reaction mechanism and tracing of additional relationships, perhaps also with other protein families. Sh ort-chain dehydrogenases illustrate the value of comparisons and diver sified research in generating unexpected discoveries.