Thomas A Pauly,
Jennifer L Ekstrom,
David A Beebe,
Boris Chrunyk,
David Cunningham,
Matthew Griffor,
Ajith Kamath,
S Edward Lee, Rebecca Madura,
Dewitt Mcguire,
Timothy Subashi,
David Wasilko,
Paul Watts,
Banavara L Mylari,
Peter J Oates,
Paul D Adams,
Virginia L Rath
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ABSTRACT: Sorbitol dehydrogenase (hSDH) and aldose reductase form the polyol pathway that interconverts glucose and fructose. Redox changes from overproduction of the coenzyme NADH by SDH may play a role in diabetes-induced dysfunction in sensitive tissues, making SDH a therapeutic target for diabetic complications. We have purified and determined the crystal structures of human SDH alone, SDH with NAD(+), and SDH with NADH and an inhibitor that is competitive with fructose. hSDH is a tetramer of identical, catalytically active subunits. In the apo and NAD(+) complex, the catalytic zinc is coordinated by His69, Cys44, Glu70, and a water molecule. The inhibitor coordinates the zinc through an oxygen and a nitrogen atom with the concomitant dissociation of Glu70. The inhibitor forms hydrophobic interactions to NADH and likely sterically occludes substrate binding. The structure of the inhibitor complex provides a framework for developing more potent inhibitors of hSDH.
Structure 10/2003; 11(9):1071-85. · 6.35 Impact Factor
