Structure of isocitrate lyase, a persistence factor of Mycobacterium tuberculosis. Academic Article

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.

authors

• Sacchettini, James

published proceedings

• Nat Struct Biol

altmetric score

• 3

author list (cited authors)

• Sharma, V., Sharma, S., Hoener zu Bentrup, K., McKinney, J. D., Russell, D. G., Jacobs, W. R., & Sacchettini, J. C.

citation count

• 206

complete list of authors

• Sharma, V||Sharma, S||Hoener zu Bentrup, K||McKinney, JD||Russell, DG||Jacobs, WR||Sacchettini, JC

publication date

• August 2000

publisher

• Springer Nature  Publisher

published in

• Nature Structural and Molecular Biology  Journal

keywords

• Amino Acid Substitution
• Animals
• Binding Sites
• Catalysis
• Crystallography, X-Ray
• Cysteine
• Glyoxylates
• Isocitrate Lyase
• Ligands
• Mice
• Models, Molecular
• Molecular Sequence Data
• Mutation
• Mycobacterium Tuberculosis
• Nitro Compounds
• Propionates
• Protein Binding
• Protein Structure, Secondary
• Protein Structure, Tertiary
• Pyruvates
• Solvents

PubMed Central ID

• 10932251

Digital Object Identifier (DOI)

• 10.1038/77964

start page

• 663

end page

• 668

volume

• 7

issue

• 8

URL

• http://dx.doi.org/10.1038/77964