Nanson Jeffrey D, Himiari Zainab, Swarbrick Crystall M D, Forwood Jade K
School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, 2678, Australia.
E.H. Graham Centre for Agricultural Innovation, Charles Sturt University, Wagga Wagga, NSW, 2678, Australia.
Sci Rep. 2015 Oct 15;5:14797. doi: 10.1038/srep14797.
Yersinia pestis, the causative agent of bubonic, pneumonic, and septicaemic plague, remains a major public health threat, with outbreaks of disease occurring in China, Madagascar, and Peru in the last five years. The existence of multidrug resistant Y. pestis and the potential of this bacterium as a bioterrorism agent illustrates the need for new antimicrobials. The β-ketoacyl-acyl carrier protein synthases, FabB, FabF, and FabH, catalyse the elongation of fatty acids as part of the type II fatty acid biosynthesis (FASII) system, to synthesise components of lipoproteins, phospholipids, and lipopolysaccharides essential for bacterial growth and survival. As such, these enzymes are promising targets for the development of novel therapeutic agents. We have determined the crystal structures of the Y. pestis β-ketoacyl-acyl carrier protein synthases FabF and FabH, and compared these with the unpublished, deposited structure of Y. pestis FabB. Comparison of FabB, FabF, and FabH provides insights into the substrate specificities of these enzymes, and investigation of possible interactions with known β-ketoacyl-acyl carrier protein synthase inhibitors suggests FabB, FabF and FabH may be targeted simultaneously to prevent synthesis of the fatty acids necessary for growth and survival.
鼠疫耶尔森菌是腺鼠疫、肺鼠疫和败血性鼠疫的病原体，仍然是一个重大的公共卫生威胁，在过去五年中，中国、马达加斯加和秘鲁都出现了疫情。多重耐药鼠疫耶尔森菌的存在以及这种细菌作为生物恐怖主义制剂的可能性表明需要新的抗菌药物。β-酮酰基-酰基载体蛋白合成酶FabB、FabF和FabH催化脂肪酸的延长，作为II型脂肪酸生物合成（FASII）系统的一部分，以合成细菌生长和存活所必需的脂蛋白、磷脂和脂多糖的成分。因此，这些酶是开发新型治疗剂的有希望的靶点。我们已经确定了鼠疫耶尔森菌β-酮酰基-酰基载体蛋白合成酶FabF和FabH的晶体结构，并将其与未发表的、已存入数据库的鼠疫耶尔森菌FabB结构进行了比较。对FabB、FabF和FabH的比较提供了对这些酶底物特异性的深入了解，对与已知β-酮酰基-酰基载体蛋白合成酶抑制剂可能相互作用的研究表明，FabB、FabF和FabH可能同时成为靶点，以防止合成生长和存活所需的脂肪酸。
