V-type allosteric inhibition is described by a shift in the rate-determining step for α-isopropylmalate synthase from Mycobacterium tuberculosis

Biochemistry. 2013 Oct 1;52(39):6737-9. doi: 10.1021/bi401186v. Epub 2013 Sep 18.

Abstract

The kinetic parameters affected by allosteric mechanisms contain collections of rate constants that vary based on differences in the relative rates of individual steps in the reaction. Thus, it may not be useful to compare enzymes with similar allosteric mechanisms unless the point of regulation has been identified. Rapid reaction kinetics and kinetic isotope effects provide a detailed description of V-type feedback allosteric inhibition in α-isopropylmalate synthase from Mycobacterium tuberculosis, an evolutionarily conserved model allosteric system. Results are consistent with a shift in the rate-determining step from product release to the hydrolytic step in catalysis in the presence of the effector.

Publication types

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

MeSH terms

  • 2-Isopropylmalate Synthase / antagonists & inhibitors*
  • 2-Isopropylmalate Synthase / metabolism
  • Allosteric Regulation / drug effects*
  • Amino Acids / chemistry
  • Amino Acids / pharmacology*
  • Biocatalysis
  • Kinetics
  • Leucine / biosynthesis
  • Leucine / chemistry
  • Molecular Structure
  • Mycobacterium tuberculosis / enzymology*
  • Structure-Activity Relationship

Substances

  • Amino Acids
  • 2-Isopropylmalate Synthase
  • Leucine