Inhibition studies of ketol-acid reductoisomerases from pathogenic microorganisms

Shun Jie Wun; Lambro A. Johnson; Lv You; Ross P. McGeary; Thomas Brueck; Gerhard Schenk; Luke W. Guddat

doi:10.1016/j.abb.2020.108516

Inhibition studies of ketol-acid reductoisomerases from pathogenic microorganisms

Shun Jie Wun
, Lambro A. Johnson
, Lv You
, Ross P. McGeary
, Thomas Brueck
, Gerhard Schenk
, Luke W. Guddat

Werner Siemens-Chair of Synthetic Biotechnology

University of Queensland

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

10 Scopus citations

Abstract

Ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid (BCAA) biosynthesis pathway, is an emerging target for the discovery of biocides. Here, we demonstrate that cyclopropane-1,1-dicarboxylate (CPD) inhibits KARIs from the pathogens Mycobacterium tuberculosis (Mt) and Campylobacter jejuni (Cj) reversibly with K_i values of 3.03 μM and 0.59 μM, respectively. Another reversible inhibitor of both KARIs, Hoe 704, is more potent than CPD with K_i values of 300 nM and 110 nM for MtKARI and CjKARI, respectively. The most potent inhibitor tested here is N-hydroxy-N-isopropyloxamate (IpOHA). It has a K_i of ~26 nM for MtKARI, but binds rather slowly (k_on ~900 M⁻¹s⁻¹). In contrast, IpOHA binds more rapidly (k_on ~7000 M⁻¹s⁻¹) to CjKARI and irreversibly.

Original language	English
Article number	108516
Journal	Archives of Biochemistry and Biophysics
Volume	692
DOIs	https://doi.org/10.1016/j.abb.2020.108516
State	Published - 15 Oct 2020

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Antimicrobial chemotherapeutics
Branched-chain amino acid biosynthesis
Campylobacter jejuni
Ketol-acid reductoisomerase
Mycobacterium tuberculosis

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10.1016/j.abb.2020.108516

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title = "Inhibition studies of ketol-acid reductoisomerases from pathogenic microorganisms",

abstract = "Ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid (BCAA) biosynthesis pathway, is an emerging target for the discovery of biocides. Here, we demonstrate that cyclopropane-1,1-dicarboxylate (CPD) inhibits KARIs from the pathogens Mycobacterium tuberculosis (Mt) and Campylobacter jejuni (Cj) reversibly with Ki values of 3.03 μM and 0.59 μM, respectively. Another reversible inhibitor of both KARIs, Hoe 704, is more potent than CPD with Ki values of 300 nM and 110 nM for MtKARI and CjKARI, respectively. The most potent inhibitor tested here is N-hydroxy-N-isopropyloxamate (IpOHA). It has a Ki of \textasciitilde{}26 nM for MtKARI, but binds rather slowly (kon \textasciitilde{}900 M−1s−1). In contrast, IpOHA binds more rapidly (kon \textasciitilde{}7000 M−1s−1) to CjKARI and irreversibly.",

keywords = "Antimicrobial chemotherapeutics, Branched-chain amino acid biosynthesis, Campylobacter jejuni, Ketol-acid reductoisomerase, Mycobacterium tuberculosis",

author = "Wun, \{Shun Jie\} and Johnson, \{Lambro A.\} and Lv You and McGeary, \{Ross P.\} and Thomas Brueck and Gerhard Schenk and Guddat, \{Luke W.\}",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = oct,

day = "15",

doi = "10.1016/j.abb.2020.108516",

language = "English",

volume = "692",

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T1 - Inhibition studies of ketol-acid reductoisomerases from pathogenic microorganisms

AU - Wun, Shun Jie

AU - Johnson, Lambro A.

AU - You, Lv

AU - McGeary, Ross P.

AU - Brueck, Thomas

AU - Schenk, Gerhard

AU - Guddat, Luke W.

PY - 2020/10/15

Y1 - 2020/10/15

N2 - Ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid (BCAA) biosynthesis pathway, is an emerging target for the discovery of biocides. Here, we demonstrate that cyclopropane-1,1-dicarboxylate (CPD) inhibits KARIs from the pathogens Mycobacterium tuberculosis (Mt) and Campylobacter jejuni (Cj) reversibly with Ki values of 3.03 μM and 0.59 μM, respectively. Another reversible inhibitor of both KARIs, Hoe 704, is more potent than CPD with Ki values of 300 nM and 110 nM for MtKARI and CjKARI, respectively. The most potent inhibitor tested here is N-hydroxy-N-isopropyloxamate (IpOHA). It has a Ki of ~26 nM for MtKARI, but binds rather slowly (kon ~900 M−1s−1). In contrast, IpOHA binds more rapidly (kon ~7000 M−1s−1) to CjKARI and irreversibly.

AB - Ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid (BCAA) biosynthesis pathway, is an emerging target for the discovery of biocides. Here, we demonstrate that cyclopropane-1,1-dicarboxylate (CPD) inhibits KARIs from the pathogens Mycobacterium tuberculosis (Mt) and Campylobacter jejuni (Cj) reversibly with Ki values of 3.03 μM and 0.59 μM, respectively. Another reversible inhibitor of both KARIs, Hoe 704, is more potent than CPD with Ki values of 300 nM and 110 nM for MtKARI and CjKARI, respectively. The most potent inhibitor tested here is N-hydroxy-N-isopropyloxamate (IpOHA). It has a Ki of ~26 nM for MtKARI, but binds rather slowly (kon ~900 M−1s−1). In contrast, IpOHA binds more rapidly (kon ~7000 M−1s−1) to CjKARI and irreversibly.

KW - Antimicrobial chemotherapeutics

KW - Branched-chain amino acid biosynthesis

KW - Campylobacter jejuni

KW - Ketol-acid reductoisomerase

KW - Mycobacterium tuberculosis

UR - https://www.scopus.com/pages/publications/85089463246

U2 - 10.1016/j.abb.2020.108516

DO - 10.1016/j.abb.2020.108516

M3 - Article

C2 - 32745463

AN - SCOPUS:85089463246

SN - 0003-9861

VL - 692

JO - Archives of Biochemistry and Biophysics

JF - Archives of Biochemistry and Biophysics

M1 - 108516

ER -

Inhibition studies of ketol-acid reductoisomerases from pathogenic microorganisms

Abstract

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Keywords

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