Variation on a Theme of SDR: dTDP-6-Deoxy-L- lyxo-4-Hexulose Reductase (RmlD) Shows a New Mg 2+-Dependent Dimerization Mode

• Published in: Structure (London) Vol. 10; no. 6; pp. 773 - 786
• Main Authors: Blankenfeldt, Wulf, Kerr, Iain D, Giraud, Marie-France, McMiken, Helen J, Leonard, Gordon, Whitfield, Chris, Messner, Paul, Graninger, Michael, Naismith, James H
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 2002
• Subjects: drug design; NAD(P)H; reductase; rhamnose; Salmonella enterica serovar Typhimurium; SDR; tuberculosis; SDR; reductase; rhamnose; drug design; tuberculosis; Salmonella enterica serovar Typhimurium; NAD(P)H
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/S0969-2126(02)00770-0

dTDP-6-deoxy-L- lyxo-4-hexulose reductase (RmlD) catalyzes the final step in the conversion of dTDP-D-glucose to dTDP-L-rhamnose in an NAD(P)H- and Mg 2+-dependent reaction. L-rhamnose biosynthesis is an antibacterial target. The structure of RmlD from Salmonella enterica serovar Typhimurium has been determined, and complexes with NADH, NADPH, and dTDP-L-rhamnose are reported. RmlD differs from other short chain dehydrogenases in that it has a novel dimer interface that contains Mg 2+. Enzyme catalysis involves hydride transfer from the nicotinamide ring of the cofactor to the C4′-carbonyl group of the substrate. The substrate is activated through protonation by a conserved tyrosine. NAD(P)H is bound in a solvent-exposed cleft, allowing facile replacement. We suggest a novel role for the conserved serine/threonine residue of the catalytic triad of SDR enzymes.