Staphylococcus aureus 3-hydroxy-3-methylglutaryl-CoA synthase: crystal structure and mechanism

J Biol Chem. 2004 Oct 22;279(43):44883-8. doi: 10.1074/jbc.M407882200. Epub 2004 Aug 2.

Abstract

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase, a member of the family of acyl-condensing enzymes, catalyzes the first committed step in the mevalonate pathway and is a potential target for novel antibiotics and cholesterol-lowering agents. The Staphylococcus aureus mvaS gene product (43.2 kDa) was overexpressed in Escherichia coli, purified to homogeneity, and shown biochemically to be an HMG-CoA synthase. The crystal structure of the full-length enzyme was determined at 2.0-A resolution, representing the first structure of an HMG-CoA synthase from any organism. HMG-CoA synthase forms a homodimer. The monomer, however, contains an important core structure of two similar alpha/beta motifs, a fold that is completely conserved among acyl-condensing enzymes. This common fold provides a scaffold for a catalytic triad made up of Cys, His, and Asn required by these enzymes. In addition, a crystal structure of HMG-CoA synthase with acetoacetyl-CoA was determined at 2.5-A resolution. Together, these structures provide the structural basis for an understanding of the mechanism of HMG-CoA synthase.

Publication types

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

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Asparagine / chemistry
  • Binding Sites
  • Catalysis
  • Cholesterol / metabolism
  • Cloning, Molecular
  • Crystallography, X-Ray
  • Cysteine / chemistry
  • Dimerization
  • Escherichia coli / metabolism
  • Histidine / chemistry
  • Hydroxymethylglutaryl-CoA Synthase / chemistry*
  • Hydroxymethylglutaryl-CoA Synthase / genetics
  • Kinetics
  • Models, Chemical
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Conformation
  • Sequence Homology, Amino Acid
  • Staphylococcus aureus / enzymology*

Substances

  • Histidine
  • Asparagine
  • Cholesterol
  • Hydroxymethylglutaryl-CoA Synthase
  • Cysteine

Associated data

  • PDB/1TVZ
  • PDB/1TXT