School of Chemistry and Molecular Biosciences, Australian Infectious Disease Research Centre, The University of Queensland, St. Lucia, QLD, 4072, Australia.
School of Biomedical Sciences, The University of Queensland, St. Lucia, QLD, 4072, Australia.
Arch Biochem Biophys. 2020 Oct 15;692:108516. doi: 10.1016/j.abb.2020.108516. Epub 2020 Aug 1.
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 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 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 of ~26 nM for MtKARI, but binds rather slowly (k ~900 Ms). In contrast, IpOHA binds more rapidly (k ~7000 Ms) to CjKARI and irreversibly.
酮酸还原异构酶（KARI）是支链氨基酸（BCAA）生物合成途径中的第二个酶，是发现杀生物剂的新兴目标。在这里，我们证明环丙烷-1,1-二羧酸酯（CPD）可分别以 3.03 μM 和 0.59 μM 的 K 值可逆地抑制分枝杆菌（Mt）和空肠弯曲菌（Cj）的 KARIs。另一种可逆抑制剂 Hoe 704 对 MtKARI 和 CjKARI 的 K 值分别为 300 nM 和 110 nM，比 CPD 更有效。这里测试的最有效的抑制剂是 N-羟基-N-异丙基氧代乙酰胺（IpOHA）。它对 MtKARI 的 K 值约为 26 nM，但结合速度较慢（k ~900 Ms）。相比之下，IpOHA 与 CjKARI 结合更快（k ~7000 Ms）且不可逆。
