Department of Chemistry, Vassar College, 124 Raymond Avenue, Poughkeepsie, NY 12604, USA.
Seattle Structural Genomics Center for Infectious Disease (SSGCID), 307 Westlake Avenue North, Seattle, WA 98109, USA.
Acta Crystallogr F Struct Biol Commun. 2024 Apr 1;80(Pt 4):82-91. doi: 10.1107/S2053230X2400356X. Epub 2024 Apr 24.
The rise in antimicrobial resistance is a global health crisis and necessitates the development of novel strategies to treat infections. For example, in 2022 tuberculosis (TB) was the second leading infectious killer after COVID-19, with multi-drug-resistant strains of TB having an ∼40% fatality rate. Targeting essential biosynthetic pathways in pathogens has proven to be successful for the development of novel antimicrobial treatments. Fatty-acid synthesis (FAS) in bacteria proceeds via the type II pathway, which is substantially different from the type I pathway utilized in animals. This makes bacterial fatty-acid biosynthesis (Fab) enzymes appealing as drug targets. FabG is an essential FASII enzyme, and some bacteria, such as Mycobacterium tuberculosis, the causative agent of TB, harbor multiple homologs. FabG4 is a conserved, high-molecular-weight FabG (HMwFabG) that was first identified in M. tuberculosis and is distinct from the canonical low-molecular-weight FabG. Here, structural and functional analyses of Mycolicibacterium smegmatis FabG4, the third HMwFabG studied to date, are reported. Crystal structures of NAD and apo MsFabG4, along with kinetic analyses, show that MsFabG4 preferentially binds and uses NADH when reducing CoA substrates. As M. smegmatis is often used as a model organism for M. tuberculosis, these studies may aid the development of drugs to treat TB and add to the growing body of research that distinguish HMwFabGs from the archetypal low-molecular-weight FabG.
抗微生物药物耐药性的上升是一个全球性的健康危机，需要开发新的策略来治疗感染。例如，2022 年结核病（TB）是继 COVID-19 之后的第二大传染性致死疾病，耐多药结核菌株的死亡率约为 40%。针对病原体必需的生物合成途径已被证明是开发新型抗菌治疗方法的成功途径。细菌中的脂肪酸合成（FAS）通过 II 型途径进行，该途径与动物中使用的 I 型途径有很大的不同。这使得细菌脂肪酸生物合成（Fab）酶成为有吸引力的药物靶标。FabG 是一种必需的 FASII 酶，一些细菌，如结核分枝杆菌，即结核病的病原体，拥有多个同源物。FabG4 是一种保守的高分子量 FabG（HMwFabG），最初在结核分枝杆菌中被发现，与典型的低分子量 FabG 不同。本文报道了迄今研究的第三种 HMwFabG——耻垢分枝杆菌 FabG4 的结构和功能分析。NAD 和apo MsFabG4 的晶体结构以及动力学分析表明，MsFabG4 在还原 CoA 底物时优先结合并使用 NADH。由于耻垢分枝杆菌通常被用作结核分枝杆菌的模型生物，这些研究可能有助于开发治疗结核病的药物，并为区分 HMwFabG 与典型的低分子量 FabG 的不断增长的研究提供帮助。
