Crystal structure of imidazole glycerol-phosphate dehydratase: duplication of an unusual fold

J Biol Chem. 2004 Apr 9;279(15):15491-8. doi: 10.1074/jbc.M312733200. Epub 2004 Jan 14.

Abstract

Imidazole glycerol-phosphate dehydratase (IGPD) catalyzes the sixth step of histidine biosynthesis. The enzyme is of fundamental biochemical interest, because it catalyzes removal of a non-acidic hydrogen atom in the dehydration reaction. It is also a potential target for development of herbicides. IGPD is a metalloenzyme in which transition metals induce aggregation and are required for catalysis. Addition of 1 equivalent of Mn(2+)/subunit is shown by analytical ultracentrifugation to induce the formation of 24-mers from trimeric IGPD. Two histidine-rich motifs may participate in metal binding and aggregation. The 2.3-A crystal structure of metal-free trimeric IGPD from the fungus Filobasidiella neoformans reveals a novel fold containing an internal repeat, apparently the result of gene duplication. The 95-residue alpha/beta half-domain occurs in a few other proteins, including the GHMP kinase superfamily (galacto-homoserine-mevalonate-phosphomevalonate), but duplication to form a compact domain has not been seen elsewhere. Conserved residues cluster at two types of sites in the trimer, each site containing a conserved histidine-rich motif. A model is proposed for the intact, active 24-mer in which all highly conserved residues, including the histidine-rich motifs in both the N- and C-terminal halves of the polypeptide, cluster at a common site between trimers. This site is a candidate for the active site and also for metal binding leading to aggregation of trimers. The structure provides a basis for further studies of enzyme function and mechanism and for development of more potent and specific herbicides.

Publication types

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

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Basidiomycota / metabolism
  • Binding Sites
  • Catalysis
  • Crystallography, X-Ray
  • Dimerization
  • Histidine / chemistry
  • Hydro-Lyases / chemistry*
  • Hydrogen / chemistry
  • Magnesium / chemistry
  • Models, Molecular
  • Molecular Sequence Data
  • Multigene Family
  • Peptides / chemistry
  • Protein Conformation
  • Protein Folding
  • Protein Structure, Quaternary
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid
  • Ultracentrifugation

Substances

  • Peptides
  • Histidine
  • Hydrogen
  • Hydro-Lyases
  • imidazoleglycerolphosphate dehydratase
  • Magnesium

Associated data

  • PDB/1RHY