Inhibition studies of ketol-acid reductoisomerases from pathogenic microorganisms.

Inhibition studies of ketol-acid reductoisomerases from pathogenic microorganisms. Arch Biochem Biophys. 2020 Jul 31;:108516 Authors: Wun SJ, Johnson LA, You L, McGeary RP, Brueck T, Schenk G, Guddat LW 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 ∼26 nM for MtKARI, but binds rather slowly (kon ∼900 M-1s-1). In contrast, IpOHA binds more rapidly (kon ∼7,000 M-1s-1) to CjKARI and irreversibly. PMID: 32745463 [PubMed - as supplied by publisher]
Source: Archives of Biochemistry and Biophysics - Category: Biochemistry Authors: Tags: Arch Biochem Biophys Source Type: research