School of Chemistry, Building F11. and The University of Sydney, Camperdown, NSW 2006, Australia.
Org Biomol Chem. 2013 Dec 14;11(46):8113-26. doi: 10.1039/c3ob41896k.
Peptidoglycan is an essential component of the cell wall of bacteria, including Mycobacterium tuberculosis, that provides structural strength and rigidity to enable internal osmotic pressure to be withstood. The first committed step in the biosynthesis of peptidoglycan involves the formation of uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) from uridine triphosphate (UTP) and GlcNAc-1-phosphate. This reaction is catalysed by N-acetylglucosamine-1-phosphate uridyltransferase (GlmU), a bifunctional enzyme with two independent active sites that possess acetyltransferase and uridyltransferase activities. Herein, we report the first inhibition study targeted against the uridyltransferase activity of M. tuberculosis GlmU. A number of potential inhibitors were initially prepared leading to the discovery of active aminoquinazoline-based compounds. The most potent inhibitor in this series exhibited an IC50 of 74 μM against GlmU uridyltransferase activity and serves as a promising starting point for the discovery of more potent inhibitors.
肽聚糖是包括结核分枝杆菌在内的细菌细胞壁的重要组成部分，它提供结构强度和刚性，以承受内部渗透压。肽聚糖生物合成的第一步涉及从三磷酸尿苷 (UTP) 和 GlcNAc-1-磷酸形成尿苷二磷酸-N-乙酰葡萄糖胺 (UDP-GlcNAc)。该反应由 N-乙酰葡萄糖胺-1-磷酸尿苷转移酶 (GlmU) 催化，GlmU 是一种具有两个独立活性位点的双功能酶，具有乙酰转移酶和尿苷转移酶活性。在此，我们报告了针对结核分枝杆菌 GlmU 的尿苷转移酶活性的首次抑制研究。最初制备了一些潜在的抑制剂，从而发现了基于氨基喹唑啉的活性化合物。该系列中最有效的抑制剂对 GlmU 尿苷转移酶活性的 IC50 为 74 μM，它为发现更有效的抑制剂提供了一个有希望的起点。
