Structural and functional characterization of FabG4 from Mycolicibacterium smegmatis

IF 1.1 4区 生物学 Q4 BIOCHEMICAL RESEARCH METHODS
Xinping Ran, Prashit Parikh, Jan Abendroth, Tracy L. Arakaki, Matthew C. Clifton, Thomas E. Edwards, Donald D. Lorimer, Stephen Mayclin, Bart L. Staker, Peter Myler, Krystle J. McLaughlin
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Abstract

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.

Abstract Image

烟曲霉分枝杆菌 FabG4 的结构和功能表征
抗菌药耐药性的增加是一个全球性的健康危机,因此有必要开发治疗感染的新策略。例如,在 2022 年,结核病(TB)是仅次于 COVID-19 的第二大传染病杀手,耐多药结核菌株的致死率高达 40%。事实证明,针对病原体的重要生物合成途径开发新型抗菌治疗方法是成功的。细菌中的脂肪酸合成(FAS)是通过 II 型途径进行的,与动物体内的 I 型途径有很大不同。这使得细菌脂肪酸生物合成(Fab)酶成为有吸引力的药物靶点。FabG 是一种重要的 FASII 酶,某些细菌(如结核病的致病菌结核分枝杆菌)含有多种同源物。FabG4 是一种保守的高分子量 FabG(HMwFabG),最早在结核分枝杆菌中被发现,它与典型的低分子量 FabG 不同。 本文报告了迄今为止研究的第三种 HMwFabG--烟草分枝杆菌 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M. smegmatis经常被用作结核杆菌的模式生物,这些研究可能有助于开发治疗结核病的药物,并为越来越多的研究增添了新的内容,这些研究将HMwFabGs与典型的低分子量FabG区分开来。
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来源期刊
Acta crystallographica. Section F, Structural biology communications
Acta crystallographica. Section F, Structural biology communications BIOCHEMICAL RESEARCH METHODSBIOCHEMISTRY &-BIOCHEMISTRY & MOLECULAR BIOLOGY
CiteScore
1.90
自引率
0.00%
发文量
95
期刊介绍: Acta Crystallographica Section F is a rapid structural biology communications journal. Articles on any aspect of structural biology, including structures determined using high-throughput methods or from iterative studies such as those used in the pharmaceutical industry, are welcomed by the journal. The journal offers the option of open access, and all communications benefit from unlimited free use of colour illustrations and no page charges. Authors are encouraged to submit multimedia content for publication with their articles. Acta Cryst. F has a dedicated online tool called publBio that is designed to make the preparation and submission of articles easier for authors.
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