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Structure ; 11(9): 1071-85, 2003 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-12962626

RESUMEN

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.


Asunto(s)
Cristalografía por Rayos X , L-Iditol 2-Deshidrogenasa/química , Sitios de Unión , Humanos , Cinética , L-Iditol 2-Deshidrogenasa/metabolismo , Funciones de Verosimilitud , Unión Proteica , Conformación Proteica
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