TY - JOUR
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.
N1 - Publisher Copyright:
© 2020 Elsevier Inc.
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 - http://www.scopus.com/inward/record.url?scp=85089463246&partnerID=8YFLogxK
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 -