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

doi:10.1038/77964

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

Microbiology & Immunology

Research output: Contribution to journal › Article › peer-review

223 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 language	English (US)
Pages (from-to)	663-668
Number of pages	6
Journal	Nature Structural Biology
Volume	7
Issue number	8
DOIs	https://doi.org/10.1038/77964
State	Published - Aug 2000

ASJC Scopus subject areas

Structural Biology
Biochemistry
Genetics

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10.1038/77964

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title = "Structure of isocitrate lyase, a persistence factor of Mycobacterium tuberculosis",

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.",

author = "Vivek Sharma and Sujata Sharma and {Hoener Zu Bentrup}, Kerstin and McKinney, {John D.} and Russell, {David G.} and Jacobs, {William R.} and Sacchettini, {James C.}",

note = "Funding Information: The authors thank F.J. Rotella at the SBC beam line 19-ID and W. Schildkamp and G. Navrotski at BioCARS beam line 14 for their help. Use of the Argonne National Laboratory Structural Biology Center beam lines at the Advanced Photon Source was supported by the US Department of Energy, Office of Energy Research. Use of the BioCARS Sector 14 was supported by the NIH, National Center for Research Resources. K.H. zu B. and colleagues were responsible for generating data shown in Fig. 1. This work was supported by the NIH, the Robert A. Welch Foundation and Glaxo Wellcome.",

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AU - Sharma, Vivek

AU - Sharma, Sujata

AU - Hoener Zu Bentrup, Kerstin

AU - McKinney, John D.

AU - Russell, David G.

AU - Jacobs, William R.

AU - Sacchettini, James C.

N1 - Funding Information: The authors thank F.J. Rotella at the SBC beam line 19-ID and W. Schildkamp and G. Navrotski at BioCARS beam line 14 for their help. Use of the Argonne National Laboratory Structural Biology Center beam lines at the Advanced Photon Source was supported by the US Department of Energy, Office of Energy Research. Use of the BioCARS Sector 14 was supported by the NIH, National Center for Research Resources. K.H. zu B. and colleagues were responsible for generating data shown in Fig. 1. This work was supported by the NIH, the Robert A. Welch Foundation and Glaxo Wellcome.

PY - 2000/8

Y1 - 2000/8

N2 - 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.

AB - 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.

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Structure of isocitrate lyase, a persistence factor of Mycobacterium tuberculosis

Abstract

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