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 beta-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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Substitution / genetics
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Animals
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Binding Sites
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Catalysis / drug effects
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Crystallography, X-Ray
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Cysteine / genetics
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Cysteine / metabolism
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Glyoxylates / chemistry
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Glyoxylates / metabolism
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Isocitrate Lyase / antagonists & inhibitors
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Isocitrate Lyase / chemistry*
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Isocitrate Lyase / genetics
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Isocitrate Lyase / metabolism*
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Ligands
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Mice
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Models, Molecular
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Molecular Sequence Data
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Mutation / genetics
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Mycobacterium tuberculosis / enzymology*
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Mycobacterium tuberculosis / pathogenicity*
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Nitro Compounds
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Propionates / chemistry
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Propionates / metabolism
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Propionates / pharmacology
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Protein Binding
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Protein Structure, Secondary / drug effects
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Protein Structure, Tertiary / drug effects
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Pyruvates / chemistry
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Pyruvates / metabolism
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Pyruvates / pharmacology
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Solvents
Substances
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Glyoxylates
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Ligands
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Nitro Compounds
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Propionates
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Pyruvates
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Solvents
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bromopyruvate
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Isocitrate Lyase
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glyoxylic acid
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Cysteine
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3-nitropropionic acid
Associated data
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PDB/1F61
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PDB/1F81
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PDB/1F8M