Itaconate is a covalent inhibitor of the Mycobacterium tuberculosis isocitrate lyase

Brooke X.C. Kwai; Annabelle J. Collins; Martin J. Middleditch; Jonathan Sperry; Ghader Bashiri; Ivanhoe K.H. Leung

doi:10.1039/d0md00301h

Itaconate is a covalent inhibitor of the Mycobacterium tuberculosis isocitrate lyase

Brooke X.C. Kwai
, Annabelle J. Collins
, Martin J. Middleditch
, Jonathan Sperry
, Ghader Bashiri
, Ivanhoe K.H. Leung

Medicinal Chemistry

Research output: Contribution to journal › Article › Research › peer-review

53 Citations (Scopus)

Abstract

Itaconate is a mammalian antimicrobial metabolite that inhibits the isocitrate lyases (ICLs) ofMycobacterium tuberculosis. Herein, we report that ICLs form a covalent adduct with itaconate through their catalytic cysteine residue. These results reveal atomic details of itaconate inhibition and provide insights into the catalytic mechanism of ICLs.

Original language	English
Pages (from-to)	57-61
Number of pages	5
Journal	RSC Medicinal Chemistry
Volume	12
Issue number	1
DOIs	https://doi.org/10.1039/d0md00301h
Publication status	Published - 1 Jan 2021

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10.1039/d0md00301h

Cite this

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title = "Itaconate is a covalent inhibitor of the Mycobacterium tuberculosis isocitrate lyase",

abstract = "Itaconate is a mammalian antimicrobial metabolite that inhibits the isocitrate lyases (ICLs) ofMycobacterium tuberculosis. Herein, we report that ICLs form a covalent adduct with itaconate through their catalytic cysteine residue. These results reveal atomic details of itaconate inhibition and provide insights into the catalytic mechanism of ICLs.",

author = "Kwai, \{Brooke X.C.\} and Collins, \{Annabelle J.\} and Middleditch, \{Martin J.\} and Jonathan Sperry and Ghader Bashiri and Leung, \{Ivanhoe K.H.\}",

note = "Funding Information: We thank the University of Auckland for funding. A. J. C. was supported by a University of Auckland Doctoral Scholarship. G. B. is supported by a Sir Charles Hercus Fellowship (Health Research Council of New Zealand). We thank Dr Michael Schmitz (The University of Auckland) for maintenance of the NMR spectroscopy facility. This research was undertaken in part using the MX2 beamline at the Australian Synchrotron, part of ANSTO, and made use of the Australian Cancer Research Foundation (ACRF) detector. The coordinates and structure factors have been deposited in the Protein Data Bank under accession code 6XPP. Publisher Copyright: {\textcopyright} The Royal Society of Chemistry 2020.",

year = "2021",

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doi = "10.1039/d0md00301h",

language = "English",

volume = "12",

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journal = "RSC Medicinal Chemistry",

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T1 - Itaconate is a covalent inhibitor of the Mycobacterium tuberculosis isocitrate lyase

AU - Kwai, Brooke X.C.

AU - Collins, Annabelle J.

AU - Middleditch, Martin J.

AU - Sperry, Jonathan

AU - Bashiri, Ghader

AU - Leung, Ivanhoe K.H.

N1 - Funding Information: We thank the University of Auckland for funding. A. J. C. was supported by a University of Auckland Doctoral Scholarship. G. B. is supported by a Sir Charles Hercus Fellowship (Health Research Council of New Zealand). We thank Dr Michael Schmitz (The University of Auckland) for maintenance of the NMR spectroscopy facility. This research was undertaken in part using the MX2 beamline at the Australian Synchrotron, part of ANSTO, and made use of the Australian Cancer Research Foundation (ACRF) detector. The coordinates and structure factors have been deposited in the Protein Data Bank under accession code 6XPP. Publisher Copyright: © The Royal Society of Chemistry 2020.

PY - 2021/1/1

Y1 - 2021/1/1

N2 - Itaconate is a mammalian antimicrobial metabolite that inhibits the isocitrate lyases (ICLs) ofMycobacterium tuberculosis. Herein, we report that ICLs form a covalent adduct with itaconate through their catalytic cysteine residue. These results reveal atomic details of itaconate inhibition and provide insights into the catalytic mechanism of ICLs.

AB - Itaconate is a mammalian antimicrobial metabolite that inhibits the isocitrate lyases (ICLs) ofMycobacterium tuberculosis. Herein, we report that ICLs form a covalent adduct with itaconate through their catalytic cysteine residue. These results reveal atomic details of itaconate inhibition and provide insights into the catalytic mechanism of ICLs.

UR - https://www.scopus.com/pages/publications/85100476260

U2 - 10.1039/d0md00301h

DO - 10.1039/d0md00301h

M3 - Article

AN - SCOPUS:85100476260

SN - 2632-8682

VL - 12

SP - 57

EP - 61

JO - RSC Medicinal Chemistry

JF - RSC Medicinal Chemistry

IS - 1

ER -

Itaconate is a covalent inhibitor of the Mycobacterium tuberculosis isocitrate lyase

Abstract

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Australian Synchrotron

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