Mengrong Yan, Mengyuan Ma, Rong Chen, Yangzi Cao, Wei Zhang, Xiang Liu
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引用次数: 0
摘要
硫脂-1 (SL-1)是一种在结核分枝杆菌(Mtb)细胞壁中大量发现的脂质。MtbFadD23在SL-1合成途径中至关重要。先前,5 ' - o -[N-(11-苯氧十一烷酰)磺胺酰]腺苷(PhU-AMS)已被证明是结核分枝杆菌中脂肪酸腺苷化酶(fadd)的一般抑制剂。然而,fadd的脂肪酰基- amp连接酶(FAAL)类,包括MtbFadD23,在多种脂肪酸的产生中似乎在功能上没有冗余。本研究在体外条件下考察了PhU-AMS与MtbFadD23的结合能力。MtbFadD23-PhU-AMS配合物的晶体结构以2.64分辨率确定Å。通过结构分析和比较,发现了新的特征。PhU-AMS虽然能与MtbFadD23结合,但不抑制MtbFadD23的FAAL腺苷化活性。然而,PhU-AMS在差示扫描荧光分析中提高了主Tm值,并且MtbFadD23-PhU-AMS与FadD32和PA1221的结构比较表明,PhU-AMS阻断了酰基链加载到Pks2上。本研究揭示了基于结构的MtbFadD23特异性抑制剂和FAALs一般抑制剂的设计。
Structural basis for the development of potential inhibitors targeting FadD23 from Mycobacterium tuberculosis
Sulfolipid-1 (SL-1) is a lipid that is abundantly found in the cell wall of Mycobacterium tuberculosis (Mtb). MtbFadD23 is crucial in the SL-1 synthesis pathway. Previously, 5′-O-[N-(11-phenoxyundecanoyl)sulfamoyl]adenosine (PhU-AMS) has been shown to be a general inhibitor of fatty-acid-adenylating enzymes (FadDs) in Mtb. However, the fatty acyl-AMP ligase (FAAL) class of FadDs, which includes MtbFadD23, appears to be functionally nonredundant in the production of multiple fatty acids. In this study, the ability of PhU-AMS to bind to MtbFadD23 was examined under in vitro conditions. The crystal structure of the MtbFadD23–PhU-AMS complex was determined at a resolution of 2.64 Å. Novel features were identified by structural analysis and comparison. Although PhU-AMS could bind to MtbFadD23, it did not inhibit the FAAL adenylation activity of MtbFadD23. However, PhU-AMS improved the main Tm value in a differential scanning fluorimetry assay, and a structural comparison of MtbFadD23–PhU-AMS with FadD32 and PA1221 suggested that PhU-AMS blocks the loading of the acyl chain onto Pks2. This study sheds light on the structure-based design of specific inhibitors of MtbFadD23 and general inhibitors of FAALs.
期刊介绍:
Acta Crystallographica Section F is a rapid structural biology communications journal.
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