Crystal structures of the active and alloxanthine-inhibited forms of xanthine dehydrogenase from Rhodobacter capsulatus

Structure. 2002 Jan;10(1):115-25. doi: 10.1016/s0969-2126(01)00697-9.

Abstract

Xanthine dehydrogenase (XDH), a complex molybdo/iron-sulfur/flavoprotein, catalyzes the oxidation of hypoxanthine to xanthine followed by oxidation of xanthine to uric acid with concomitant reduction of NAD+. The 2.7 A resolution structure of Rhodobacter capsulatus XDH reveals that the bacterial and bovine XDH have highly similar folds despite differences in subunit composition. The NAD+ binding pocket of the bacterial XDH resembles that of the dehydrogenase form of the bovine enzyme rather than that of the oxidase form, which reduces O(2) instead of NAD+. The drug allopurinol is used to treat XDH-catalyzed uric acid build-up occurring in gout or during cancer chemotherapy. As a hypoxanthine analog, it is oxidized to alloxanthine, which cannot be further oxidized but acts as a tight binding inhibitor of XDH. The 3.0 A resolution structure of the XDH-alloxanthine complex shows direct coordination of alloxanthine to the molybdenum via a nitrogen atom. These results provide a starting point for the rational design of new XDH inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cattle
  • Crystallography, X-Ray
  • Enzyme Inhibitors / metabolism
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Oxypurinol / metabolism
  • Protein Structure, Quaternary*
  • Rhodobacter capsulatus / enzymology*
  • Sequence Alignment
  • Xanthine Dehydrogenase / antagonists & inhibitors
  • Xanthine Dehydrogenase / chemistry*
  • Xanthine Dehydrogenase / metabolism

Substances

  • Enzyme Inhibitors
  • Xanthine Dehydrogenase
  • Oxypurinol

Associated data

  • PDB/1JRO
  • PDB/1JRP