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
{"title":"Structural and functional characterization of FabG4 from Mycolicibacterium smegmatis","authors":"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","doi":"10.1107/S2053230X2400356X","DOIUrl":null,"url":null,"abstract":"<p>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 <i>Mycobacterium tuberculosis</i>, the causative agent of TB, harbor multiple homologs. FabG4 is a conserved, high-molecular-weight FabG (HMwFabG) that was first identified in <i>M. tuberculosis</i> and is distinct from the canonical low-molecular-weight FabG. Here, structural and functional analyses of <i>Mycolicibacterium smegmatis</i> FabG4, the third HMwFabG studied to date, are reported. Crystal structures of NAD<sup>+</sup> and apo <i>Ms</i>FabG4, along with kinetic analyses, show that <i>Ms</i>FabG4 preferentially binds and uses NADH when reducing CoA substrates. As <i>M. smegmatis</i> is often used as a model organism for <i>M. tuberculosis</i>, 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.</p>","PeriodicalId":7029,"journal":{"name":"Acta crystallographica. Section F, Structural biology communications","volume":null,"pages":null},"PeriodicalIF":1.1000,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta crystallographica. Section F, Structural biology communications","FirstCategoryId":"99","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1107/S2053230X2400356X","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"BIOCHEMICAL RESEARCH METHODS","Score":null,"Total":0}
引用次数: 0
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.
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.