UDP-GlcNAc pathway: Potential target for inhibitor discovery against M-tuberculosis
UDP-GlcNAc pathway: Potential target for inhibitor discovery against M-tuberculosis
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DOI：
10.1016/j.ejps.2015.12.013
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发表时间：
2016-02-15
影响因子：
4.6
通讯作者：
Khan, Inshad Ali
中科院分区：
文献类型：
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作者：
Rani, Chitra;Khan, Inshad Ali
在过去五年中，据报告，耐多药结核病和广泛耐药结核病患者的数量惊人地增加，特别是在东欧、亚洲和南部非洲。目前结核病的控制和治疗面临挑战，迫切需要寻找具有不同化学结构和作用机制的新型抗结核药物。鉴定新型抗结核药物的一种非常富有成效的方法是开发靶向分枝杆菌细胞壁的生物合成和组装所必需的酶的化合物。尿苷二磷酸-N-乙酰葡糖胺（UDP-GlcNAc）的生物合成代表了这样的途径之一。参与UDP-GlcNAc生物合成的酶已被预测为结核分枝杆菌体外生长所必需。它是M的关键前体分子。结核细胞壁，位于两个基本生物合成途径的分支点，即肽聚糖和二糖接头D-N-GlcNAc-1-鼠李糖。本文就目前对M.结核病，特别强调N-乙酰葡糖胺-1-磷酸尿苷转移酶（GlmU），一种双功能酶，催化该途径的最后两个步骤。它还提供了一个深入了解目前的知识，对酶的抑制剂报告，这可以进一步用作化学支架的发现更有效的抗结核化合物。(C)2015 Elsevier B. V.版权所有。
In the past five years, an alarming increase in the number of patients with multidrug resistant tuberculosis (MDR TB) and extensively drug-resistant tuberculosis (XDR TB) has been reported, particularly in Eastern Europe, Asia and Southern Africa. Current situation has challenged the control and treatment of tuberculosis (TB) which sparked an emergent need to find new anti-tubercular agents with different chemical scaffolds andmechanisms of action. A very fruitful way to identify novel anti-tubercular agents is the development of compounds that target the enzymes essentially required for the biosynthesis and assembly of the mycobacterial cell wall. Biosynthesis of uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) represents one such pathway. Enzymes involved in UDP-GlcNAc biosynthesis have been predicted to be essential for Mycobacterium tuberculosis growth in vitro. It is a key precursor molecule of M. tuberculosis cell wall, being situated at the branched point of two essential biosynthetic pathways, namely peptidoglycan and a disaccharide linker, D-N-GlcNAc-1-rhamnose. This article provides a comprehensive overview of the present knowledge on the enzymes catalyzing the particular steps of the pathway in M. tuberculosis, with special emphasis put on N-acetylglucosamine-1-phosphate uridyltransferase (GlmU), a bifunctional enzyme, which catalyzes the last two steps of this pathway. It also gives an insight into the present knowledge about the inhibitors reported against the enzymes, which could be further used as chemical scaffold for the discovery of more potent anti-TB compounds. (C) 2015 Elsevier B.V. All rights reserved.