Acetohydroxyacid synthase from Mycobacterium avium and its inhibition by sulfonylureas and imidazolinones

Yehudit Zohar, Monica Einav, David M. Chipman, Ze'ev Barak

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Tuberculosis (TB) remains one of the world's leading causes of death from infectious disease. It is caused by infection with Mycobacterium tuberculosis or sometimes, particularly in immune-compromised patients, Mycobacterium avium. The aim of this study was to create a tool that could be used in the search for new anti-TB drugs that inhibit branched-chain amino acid (BCAA) biosynthesis, as these are essential amino acids that are not available to a mycobacterium during growth in an infected organism. To this end, we cloned, overexpressed, purified and characterised for the first time an acetohydroxyacid synthase (AHAS), a key enzyme in the pathway to the biosynthesis of the BCAAs, from the genus Mycobacterium. Nine commercial herbicides of the sulfonylurea and imidazolinone classes were tested for their influence on this enzyme. Four of the sulfonylureas were potent inhibitors of the enzyme. The relative potency of the different inhibitors towards the M. avium enzyme was unlike their potency towards other AHASs whose inhibitor profile has been reported, emphasising the advantage of using a mycobacterial enzyme as a tool in the search for new anti-TB drugs.

Original languageEnglish
Pages (from-to)97-105
Number of pages9
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Volume1649
Issue number1
DOIs
StatePublished - 26 Jun 2003

Keywords

  • Acetohydroxyacid synthase
  • Acetolactate synthase
  • Imidazolinone
  • Mycobacterium
  • Sulfonylurea
  • Tuberculosis

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biophysics
  • Biochemistry
  • Molecular Biology

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