Structure of isocitrate lyase, a persistence factor of Mycobacterium tuberculosis

Vivek Sharma, Sujata Sharma, Kerstin Hoener Zu Bentrup, John D. McKinney, David G. Russell, William R. Jacobs, James C. Sacchettini

Research output: Contribution to journalArticle

193 Scopus citations

Abstract

Isocitrate lyase (ICL) plays a pivotal role in the persistence of Mycobacterium tuberculosis in mice by sustaining intracellular infection in inflammatory macrophages. The enzyme allows net carbon gain by diverting acetyl-CoA from β-oxidation of fatty acids into the glyoxylate shunt pathway. Given its potential as a drug target against persistent infections, we solved its structure without ligand and in complex with two inhibitors. Covalent modification of an active site residue, Cys 191, by the inhibitor 3-bromopyruvate traps the enzyme in a catalytic conformation with the active site completely inaccessible to solvent. The structure of a C191S mutant of the enzyme with the inhibitor 3-nitropropionate provides further insight into the reaction mechanism.

Original languageEnglish (US)
Pages (from-to)663-668
Number of pages6
JournalNature structural biology
Volume7
Issue number8
DOIs
StatePublished - Aug 1 2000

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Genetics

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    Sharma, V., Sharma, S., Hoener Zu Bentrup, K., McKinney, J. D., Russell, D. G., Jacobs, W. R., & Sacchettini, J. C. (2000). Structure of isocitrate lyase, a persistence factor of Mycobacterium tuberculosis. Nature structural biology, 7(8), 663-668. https://doi.org/10.1038/77964