X-ray crystallographic and kinetic studies of human sorbitol dehydrogenase

Structure. 2003 Sep;11(9):1071-85. doi: 10.1016/s0969-2126(03)00167-9.

Thomas A Pauly ¹, 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

Affiliations

Affiliation

1 Exploratory Medicinal Sciences, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.

PMID: 12962626 DOI: 10.1016/s0969-2126(03)00167-9

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.

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