Mechanism-based inactivator of isocitrate lyases 1 and 2 from Mycobacterium tuberculosis [Biochemistry]
![Mechanism-based inactivator of isocitrate lyases 1 and 2 from Mycobacterium tuberculosis [Biochemistry]](/image/eyJ1cmkiOiJodHRwOi8vc3RhY2thZGVtaWMuaGVyb2t1YXBwLmNvbS9pbWFnZT9pbWFnZV9pZD0xNDIwIiwiZm9ybWF0Ijoid2VicCIsInF1YWxpdHkiOjEwMCwibm9DYWNoZSI6dHJ1ZX0=.webp)
Isocitrate lyase (ICL, types 1 and 2) is the first enzyme of the glyoxylate shunt, an essential pathway for Mycobacterium tuberculosis (Mtb) during the persistent phase of human TB infection. Here, we report 2-vinyl-d-isocitrate (2-VIC) as a mechanism-based inactivator of Mtb 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 Cys191. 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 S-homopyruvoyl adduct of the active-site Cys191.
Publisher URL: http://feedproxy.google.com/~r/Pnas-RssFeedOfEarlyEditionArticles/~3/FhdfFwxTT94/1706134114.short
DOI: 10.1073/pnas.1706134114
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