Mechanism-based inactivator of isocitrate lyases 1 and 2 from Mycobacterium tuberculosis

Pham, Truc V.; Murkin, Andrew S.; Moynihan, Margaret M.; Harris, Lawrence; Tyler, Peter C.; Shetty, Nishant; Sacchettini, James C.; Huang, Hsiao-ling; Meek, Thomas D.

doi:10.1073/pnas.1706134114

Title: Mechanism-based inactivator of isocitrate lyases 1 and 2 from Mycobacterium tuberculosis

Journal Article · Wed Jul 05 00:00:00 EDT 2017 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1706134114· OSTI ID:1390888

Pham, Truc V. ^[1]; Murkin, Andrew S. ^[2]; Moynihan, Margaret M. ^[3]; Harris, Lawrence ^[4];

^[4];

^[5]; Sacchettini, James C. ^[1]; Huang, Hsiao-ling ^[6]; Meek, Thomas D. ^[1]

Texas A & M Univ., College Station, TX (United States)
Univ. at Buffalo, The State Univ. of New York, Buffalo, NY (United States)
Univ. at Buffalo, The State Univ. of New York, Buffalo, NY (United States); Janssen Research and Development, Malvern, PA (United States)
Victoria Univ. of Wellington (New Zealand)
Texas A & M Univ., College Station, TX (United States); Fujifilm Diosynth Biotechnologies Texas, College Station, TX (United States)
Texas A & M Univ., College Station, TX (United States); Albany Molecular Research, Inc., Albany, NY (United States)

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). As a result, 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.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Institutes of Health (NIH); Welch Foundation

Grant/Contract Number:: P011AI095208; A-0015

OSTI ID:: 1390888

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, Issue 29; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 26 works

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References (17)

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Cited By (3)

Erratum: Mechanistic enzymology in drug discovery: a fresh perspective Holdgate, Geoffrey A.; Meek, Thomas D.; Grimley, Rachel L. Nature Reviews Drug Discovery, Vol. 17, Issue 1 https://doi.org/10.1038/nrd.2017.257	journal	December 2017
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Mechanistic enzymology in drug discovery: a fresh perspective Holdgate, Geoffrey A.; Meek, Thomas D.; Grimley, Rachel L. Nature Reviews Drug Discovery, Vol. 17, Issue 2 https://doi.org/10.1038/nrd.2017.219	journal	December 2017

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59 BASIC BIOLOGICAL SCIENCES
mechanism-based inactivation
isocitrate lyase
tuberculosis
2-vinyl isocitrate
covalent adduct

Title: Mechanism-based inactivator of isocitrate lyases 1 and 2 from Mycobacterium tuberculosis

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