Citation

Ruetz M, Campanello GC, Purchal M, Shen H, McDevitt L, Gouda H, Wakabayashi S, Zhu J, Rubin EJ, Warncke K, Mootha VK, Koutmos M, Banerjee R. Science 2019; 366(6465): 589-593.

Copyright

(Copyright © 2019, American Association for the Advancement of Science)

DOI

10.1126/science.aay0934

PMID

31672889

PMCID

PMC7070230

Abstract

Itaconate is an immunometabolite with both anti-inflammatory and bactericidal effects. Its coenzyme A (CoA) derivative, itaconyl-CoA, inhibits B12-dependent methylmalonyl-CoA mutase (MCM) by an unknown mechanism. We demonstrate that itaconyl-CoA is a suicide inactivator of human and Mycobacterium tuberculosis MCM, which forms a markedly air-stable biradical adduct with the 5'-deoxyadenosyl moiety of the B12 coenzyme. Termination of the catalytic cycle in this way impairs communication between MCM and its auxiliary repair proteins. Crystallography and spectroscopy of the inhibited enzyme are consistent with a metal-centered cobalt radical ~6 angstroms away from the tertiary carbon-centered radical and suggest a means of controlling radical trajectories during MCM catalysis. Mycobacterial MCM thus joins enzymes in the glyoxylate shunt and the methylcitrate cycle as targets of itaconate in pathogen propionate metabolism.

Language: en

Keywords

Humans; Mycobacterium tuberculosis; Macrophages; Catalytic Domain; Models, Molecular; Vitamin B 12; Protein Conformation; Crystallography, X-Ray; Hydrogen Bonding; Succinates; Electron Spin Resonance Spectroscopy; Propionates; Protein Subunits; Biocatalysis; Deoxyadenosines; Coenzyme A; Methylmalonyl-CoA Mutase; Protein Multimerization