Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States of America.
UCLA-DOE Institute of Genomics and Proteomics, University of California, Los Angeles, Los Angeles, United States of America.
PLoS Pathog. 2019 Apr 19;15(4):e1007723. doi: 10.1371/journal.ppat.1007723. eCollection 2019 Apr.
Staphylococcus aureus and other bacterial pathogens affix wall teichoic acids (WTAs) to their surface. These highly abundant anionic glycopolymers have critical functions in bacterial physiology and their susceptibility to β-lactam antibiotics. The membrane-associated TagA glycosyltransferase (GT) catalyzes the first-committed step in WTA biosynthesis and is a founding member of the WecB/TagA/CpsF GT family, more than 6,000 enzymes that synthesize a range of extracellular polysaccharides through a poorly understood mechanism. Crystal structures of TagA from T. italicus in its apo- and UDP-bound states reveal a novel GT fold, and coupled with biochemical and cellular data define the mechanism of catalysis. We propose that enzyme activity is regulated by interactions with the bilayer, which trigger a structural change that facilitates proper active site formation and recognition of the enzyme's lipid-linked substrate. These findings inform upon the molecular basis of WecB/TagA/CpsF activity and could guide the development of new anti-microbial drugs.
金黄色葡萄球菌和其他细菌病原体将壁磷壁酸（WTAs）固定在其表面。这些高度丰富的阴离子糖聚合物在细菌生理学及其对β-内酰胺类抗生素的敏感性方面具有关键功能。膜相关的TagA 糖基转移酶（GT）催化 WTA 生物合成的第一步，是 WecB/TagA/CpsF GT 家族的创始成员，该家族有超过 6000 种酶，通过一种了解甚少的机制合成一系列细胞外多糖。来自意大利栖热袍菌的 TagA 在其无配体和 UDP 结合状态下的晶体结构揭示了一种新的 GT 折叠，并结合生化和细胞数据定义了催化机制。我们提出，酶活性受与双层的相互作用调节，这种相互作用触发了结构变化，促进了适当的活性位点形成和酶的脂连接底物的识别。这些发现为 WecB/TagA/CpsF 的活性提供了分子基础，并为开发新的抗菌药物提供了指导。
