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.


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.

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray*
  • Humans
  • Kinetics
  • L-Iditol 2-Dehydrogenase / chemistry*
  • L-Iditol 2-Dehydrogenase / metabolism
  • Likelihood Functions
  • Protein Binding
  • Protein Conformation


  • L-Iditol 2-Dehydrogenase

Associated data

  • PDB/1PL6
  • PDB/1PL7
  • PDB/1PL8