分枝杆菌 Eis 酶对卷曲霉素的非预期 N-乙酰化。
Unexpected N-acetylation of capreomycin by mycobacterial Eis enzymes.
机构信息
Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
出版信息
J Antimicrob Chemother. 2013 Apr;68(4):800-5. doi: 10.1093/jac/dks497. Epub 2012 Dec 11.
OBJECTIVES
The enhanced intracellular survival (Eis) protein from Mycobacterium tuberculosis (Eis_Mtb), a regio-versatile N-acetyltransferase active towards many aminoglycosides (AGs), confers resistance to kanamycin A in some cases of extensively drug-resistant tuberculosis (XDR-TB). We assessed the activity of Eis_Mtb and of its homologue from Mycobacterium smegmatis (Eis_Msm) against a panel of anti-tuberculosis (TB) drugs and lysine-containing compounds.
METHODS AND RESULTS
Both enzymes acetylated capreomycin and some lysine-containing compounds, but not other non-AG non-lysine-containing drugs tested. Modelling studies predicted the site of modification on capreomycin to be one of the two primary amines in its β-lysine side chain. Using Eis_Mtb, we established via nuclear magnetic resonance (NMR) spectroscopy that acetylation of capreomycin occurs on the ε-amine of the β-lysine side chain. Using Msm, we also demonstrated for the first time to our knowledge that acetylation of capreomycin results in deactivation of the drug.
CONCLUSIONS
Eis is a unique acetyltransferase capable of inactivating the anti-TB drug capreomycin, AGs and other lysine-containing compounds.
目的
结核分枝杆菌（Eis_Mtb）的增强型细胞内存活（Eis）蛋白是一种区域多功能 N-乙酰转移酶，可作用于许多氨基糖苷类（AGs），在某些情况下可赋予耐多药结核病（XDR-TB）对卡那霉素 A 的抗性。我们评估了 Eis_Mtb 及其分枝杆菌同源物（Eis_Msm）对一组抗结核（TB）药物和赖氨酸化合物的活性。
方法和结果
两种酶均可乙酰化卷曲霉素和一些赖氨酸化合物，但不能乙酰化其他非 AG 非赖氨酸化合物。建模研究预测卷曲霉素的修饰部位为其β-赖氨酸侧链中的两个伯胺之一。通过使用 Eis_Mtb，我们通过核磁共振（NMR）光谱学确定卷曲霉素的乙酰化发生在β-赖氨酸侧链的ε-胺上。使用 Msm，我们还首次证明，据我们所知，卷曲霉素的乙酰化导致药物失活。
结论
Eis 是一种独特的乙酰转移酶，能够使抗结核药物卷曲霉素、AGs 和其他赖氨酸化合物失活。
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