Structure of isocitrate lyase, a persistence factor of Mycobacterium tuberculosis

Isocitrate lyase (ICL) plays a pivotal role in the persistence of Mycobacte rium tuberculosis in mice by sustaining intracellular infection in inflamma tory macrophages. The enzyme allows net carbon gain by diverting acetyl-CoA from beta-oxidation of fatty acids into the glyoxylate shunt pathway. Give n its potential as a drug target against persistent infections, we solved i ts structure without ligand and in complex with two inhibitors. Covalent mo dification of an active site residue, Cys 191, by the inhibitor 3-bromopyru vate traps the enzyme in a catalytic conformation with the active site comp letely inaccessible to solvent. The structure of a C191S mutant of the enzy me with the inhibitor 3-nitropropionate provides further insight into the r eaction mechanism.