Structural and mechanistic comparison of the Cyclopropane Mycolic Acid Synthases (CMAS) protein family of &ITMycobacterium tuberculosis&IT
Structural and mechanistic comparison of the Cyclopropane Mycolic Acid Synthases (CMAS) protein family of &ITMycobacterium tuberculosis&IT
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DOI：
10.1016/j.bbrc.2017.08.119
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发表时间：
2018-03-29
影响因子：
3.1
通讯作者：
Turjanski, Adrian G.
中科院分区：
文献类型：
--
作者：
Defelipe, Lucas A.;Osman, Federico;Turjanski, Adrian G.
结核病（TB）是由结核分枝杆菌（Mtb）引起的慢性疾病，并且仍然是全世界死亡的主要原因。细菌具有保护其免于被杀死的外壁，并且参与细胞壁组分的生物合成的酶已被提出作为未来药物开发工作的有希望的靶点。环丙烷分枝菌酸合成酶（CMAS）是分枝菌酸生物合成途径中的一组同源酶。这些酶具有S-腺苷-L-甲硫氨酸（SAM）依赖性甲基转移酶活性，具有特异性，它们中的每一种都具有强的底物选择性和反应特异性，能够从脂质烯烃基团产生环丙烷或甲醇基团等。CMAS是如何加工底物的，其特异性和选择性是如何被编码到蛋白质序列和结构中的，目前还不清楚.本文采用比较模拟、分子对接、Allatom分子动力学和QM/MM方法，详细研究了cmaA 2、mmaA 4和mmaAl CMAS的反应机理，并描述了导致不同产物的分子决定因素.我们模拟了蛋白质-底物复合物的结构，并确定了反应的自由能途径。不同复杂程度的建模工具的组合允许有一个完整的图片的CMAS结构-活性关系。(C)2017爱思唯尔公司All rights reserved.
Tuberculosis (TB) is a chronic disease caused by the bacillus Mycobacterium tuberculosis(Mtb) and remains a leading cause of mortality worldwide. The bacteria has an external wall which protects it from being killed, and the enzymes involved in the biosynthesis of the cell wall components have been proposed as promising targets for future drug development efforts. Cyclopropane Mycolic Acid Synthases (CMAS) constitute a group of ten homologous enzymes which belong to the mycolic acid biosynthesis pathway. These enzymes have S-adenosyl-L-methionine (SAM) dependent methyltransferase activity with a peculiarity, each one of them has strong substrate selectivity and reaction specificity, being able to produce among other things cyclopropanes or methyl-alcohol groups from the lipid olefin group. How each CMAS processes its substrate and how the specificity and selectivity are encoded in the protein sequence and structure, is still unclear.In this work, by using a combination of modeling tools, including comparative modeling, docking, allatom MD and QM/MM methodologies we studied in detail the reaction mechanism of cmaA2, mmaA4, and mmaAl CMAS and described the molecular determinants that lead to different products. We have modeled the protein-substrate complex structure and determined the free energy pathway for the reaction. The combination of modeling tools at different levels of complexity allows having a complete picture of the CMAS structure-activity relationship. (C) 2017 Elsevier Inc. All rights reserved.