Crystal structure of human E1 enzyme and its complex with a substrate analog reveals the mechanism of its phosphatase/enolase activity

J Mol Biol. 2005 May 13;348(4):917-26. doi: 10.1016/j.jmb.2005.01.072.

Abstract

Enolase-phosphatase E1 (MASA) is a bifunctional enzyme in the ubiquitous methionine salvage pathway that catalyzes the continuous reactions of 2,3-diketo-5-methylthio-1-phosphopentane to yield the aci-reductone metabolite using Mg2+ as cofactor. In this study, we have determined the crystal structure of MASA and its complex with a substrate analog to 1.7A resolution by multi-wavelength anomalous diffraction and molecular replacement techniques, respectively. The structures support the proposed mechanism of phosphatase activity and further suggest the probable mechanism of enolization. We establish a model for substrate binding to describe in detail the enzymatic reaction and the formation of the transition state, which will provide insight into the reaction mechanisms of other enzymes in the same family.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Binding Sites
  • Conserved Sequence
  • Crystallography, X-Ray
  • Humans
  • Magnesium / pharmacology
  • Models, Biological
  • Models, Molecular
  • Molecular Sequence Data
  • Multienzyme Complexes / chemistry*
  • Multienzyme Complexes / metabolism*
  • Organophosphonates / chemistry*
  • Organophosphonates / metabolism*
  • Phosphoric Monoester Hydrolases / chemistry*
  • Phosphoric Monoester Hydrolases / metabolism*
  • Protein Structure, Tertiary
  • Sequence Alignment
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • (1-oxoheptyl)phosphonic acid
  • MASA enzyme, human
  • Multienzyme Complexes
  • Organophosphonates
  • Phosphoric Monoester Hydrolases
  • Magnesium