title: X-ray crystallographic and kinetic studies of human sorbitol dehydrogenase.
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.
authors.affiliation: Exploratory Medicinal Sciences, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Pauly
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Ekstrom
authors.forename: David A
authors.initials: DA
authors.lastname: Beebe
authors.forename: Boris
authors.initials: B
authors.lastname: Chrunyk
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.forename: Matthew
authors.initials: M
authors.lastname: Griffor
authors.forename: Ajith
authors.initials: A
authors.lastname: Kamath
authors.forename: S Edward
authors.initials: SE
authors.lastname: Lee
authors.forename: Rebecca
authors.initials: R
authors.lastname: Madura
authors.forename: Dewitt
authors.initials: D
authors.lastname: Mcguire
authors.forename: Timothy
authors.initials: T
authors.lastname: Subashi
authors.forename: David
authors.initials: D
authors.lastname: Wasilko
authors.forename: Paul
authors.initials: P
authors.lastname: Watts
authors.forename: Banavara L
authors.initials: BL
authors.lastname: Mylari
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Oates
authors.forename: Paul D
authors.initials: PD
authors.lastname: Adams
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Rath
mesh_terms: 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
chemical_list: D007064:L-Iditol 2-Dehydrogenase