X-ray crystallographic and kinetic studies of human sorbitol dehydrogenase.
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.
Pauly
Thomas A
TA
Exploratory Medicinal Sciences, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.
Ekstrom
Jennifer L
JL
Beebe
David A
DA
Chrunyk
Boris
B
Cunningham
David
D
Griffor
Matthew
M
Kamath
Ajith
A
Lee
S Edward
SE
Madura
Rebecca
R
Mcguire
Dewitt
D
Subashi
Timothy
T
Wasilko
David
D
Watts
Paul
P
Mylari
Banavara L
BL
Oates
Peter J
PJ
Adams
Paul D
PD
Rath
Virginia L
VL
D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D007700:Kinetics; D007064:L-Iditol 2-Dehydrogenase / Q000737:chemistry* / Q000378:metabolism; D016013:Likelihood Functions; D011485:Protein Binding; D011487:Protein Conformation
D007064:L-Iditol 2-Dehydrogenase