5dql | pdb_00005dql
Crystal Structure of 2-vinyl glyoxylate modified isocitrate lyase from Mycobacterium tuberculosis
Structural highlights
Function[ACEA1_MYCTE] Involved in the persistence and virulence of M.tuberculosis. Catalyzes the reversible formation of succinate and glyoxylate from isocitrate, a key step of the glyoxylate cycle, which operates as an anaplerotic route for replenishing the tricarboxylic acid cycle during growth on fatty acid substrates. It also catalyzes the formation of pyruvate and succinate from 2-methylisocitrate, a key step in the methylcitrate cycle (propionate degradation route).[1] Publication Abstract from PubMedIsocitrate 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. Mechanism-based inactivator of isocitrate lyases 1 and 2 from Mycobacterium tuberculosis.,Pham TV, Murkin AS, Moynihan MM, Harris L, Tyler PC, Shetty N, Sacchettini JC, Huang HL, Meek TD Proc Natl Acad Sci U S A. 2017 Jul 18;114(29):7617-7622. doi:, 10.1073/pnas.1706134114. Epub 2017 Jul 5. PMID:28679637[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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