Nanson Jeffrey D, Forwood Jade K
School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, 2678, Australia.
Graham Centre for Agricultural Innovation, Charles Sturt University, Wagga Wagga, NSW, 2678, Australia.
PLoS One. 2015 Nov 5;10(11):e0141543. doi: 10.1371/journal.pone.0141543. eCollection 2015.
Ketoacyl-acyl carrier protein reductases (FabG) are ubiquitously expressed enzymes that catalyse the reduction of acyl carrier protein (ACP) linked thioesters within the bacterial type II fatty acid synthesis (FASII) pathway. The products of these enzymes, saturated and unsaturated fatty acids, are essential components of the bacterial cell envelope. The FASII reductase enoyl-ACP reductase (FabI) has been the focus of numerous drug discovery efforts, some of which have led to clinical trials, yet few studies have focused on FabG. Like FabI, FabG appears to be essential for survival in many bacteria, similarly indicating the potential of this enzyme as a drug target. FabG enzymes are members of the short-chain alcohol dehydrogenase/reductase (SDR) family, and like other SDRs, exhibit highly conserved secondary and tertiary structures, and contain a number of conserved sequence motifs. Here we describe the crystal structures of FabG from Yersinia pestis (YpFabG), the causative agent of bubonic, pneumonic, and septicaemic plague, and three human pandemics. Y. pestis remains endemic in many parts of North America, South America, Southeast Asia, and Africa, and a threat to human health. YpFabG shares a high degree of structural similarity with bacterial homologues, and the ketoreductase domain of the mammalian fatty acid synthase from both Homo sapiens and Sus scrofa. Structural characterisation of YpFabG, and comparison with other bacterial FabGs and the mammalian fatty acid synthase, provides a strong platform for virtual screening of potential inhibitors, rational drug design, and the development of new antimicrobial agents to combat Y. pestis infections.
酮酰基 - 酰基载体蛋白还原酶（FabG）是广泛表达的酶，在细菌II型脂肪酸合成（FASII）途径中催化酰基载体蛋白（ACP）连接的硫酯的还原反应。这些酶的产物，饱和脂肪酸和不饱和脂肪酸，是细菌细胞膜的重要组成部分。FASII还原酶烯酰 - ACP还原酶（FabI）一直是众多药物研发工作的重点，其中一些已进入临床试验阶段，但针对FabG的研究却很少。与FabI一样，FabG在许多细菌中似乎对生存至关重要，同样表明该酶作为药物靶点的潜力。FabG酶是短链醇脱氢酶/还原酶（SDR）家族的成员，与其他SDR一样，具有高度保守的二级和三级结构，并包含许多保守的序列基序。在这里，我们描述了来自鼠疫耶尔森菌（YpFabG）的FabG的晶体结构，鼠疫耶尔森菌是腺鼠疫、肺鼠疫和败血性鼠疫以及三次人类大流行的病原体。鼠疫耶尔森菌在北美、南美、东南亚和非洲的许多地区仍然流行，对人类健康构成威胁。YpFabG与细菌同源物以及来自智人和野猪的哺乳动物脂肪酸合酶的酮还原酶结构域具有高度的结构相似性。YpFabG的结构表征以及与其他细菌FabG和哺乳动物脂肪酸合酶的比较，为虚拟筛选潜在抑制剂、合理药物设计以及开发对抗鼠疫耶尔森菌感染的新型抗菌药物提供了强大的平台。
