Slow-onset feedback inhibition: Inhibition of Mycobacterium tuberculosis α-isopropylmalate synthase by L-leucine

Luiz P.S. De Carvalho, Argyrides Argyrou, John S. Blanchard

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

This report describes the first demonstration of slow-onset feedback inhibition of an enzyme that catalyzes the first committed step in a biosynthetic pathway. α-Isopropylmalate synthase (IPMS) catalyzes the first committed step of the l-leucine biosynthetic pathway and is feedback-inhibited by l-leucine. Initial velocity experiments on the Mycobacterium tuberculosis IPMS indicate that inhibition by l-leucine is linearly noncompetitive versus α-ketoisovalerate. Time-courses displayed a burst of product formation followed by a linear steady-state rate when reactions were initiated by the addition of enzyme. The burst rate showed a hyperbolic dependence on the concentration of l-leucine indicating that inhibition proceeds in two steps, an initial rapid binding step followed by slow isomerization to a more tightly bound complex.

Original languageEnglish (US)
Pages (from-to)10004-10005
Number of pages2
JournalJournal of the American Chemical Society
Volume127
Issue number28
DOIs
StatePublished - Jul 20 2005

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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