Mechanism-based inactivator of isocitrate lyases 1 and 2 from <i>Mycobacterium tuberculosis</i>.
basic_science · Level V
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- Record sourced from PubMed, PMID 28679637.
- Also identified by DOI 10.1073/pnas.1706134114 and PMC identifier 5530696.
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Abstract
Isocitrate lyase (ICL, types 1 and 2) is the first enzyme of the glyoxylate shunt, an essential pathway for <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) during the persistent phase of human TB infection. Here, we report 2-vinyl-d-isocitrate (2-VIC) as a mechanism-based inactivator of <i>Mtb</i> ICL1 and ICL2. The enzyme-catalyzed retro-aldol cleavage of 2-VIC unmasks a Michael substrate, 2-vinylglyoxylate, which then forms a slowly reversible, covalent adduct with the thiolate form of active-site Cys<sub>191</sub> 2-VIC displayed kinetic properties consistent with covalent, mechanism-based inactivation of ICL1 and ICL2 with high efficiency (partition ratio, <1). Analysis of a complex of ICL1:2-VIC by electrospray ionization mass spectrometry and X-ray crystallography confirmed the formation of the predicted covalent <i>S</i>-homopyruvoyl adduct of the active-site Cys<sub>191</sub>.
Medical subject headings
- Bacterial Proteins
- Isocitrate Lyase
- Isocitrates
- Mycobacterium tuberculosis
- Tuberculosis