Methionine biosynthesis and transport are functionally redundant for the growth and virulence of <i>Salmonella</i> Typhimurium



Ul Husna, Asma, Wang, Nancy, Cobbold, Simon A, Newton, Hayley J, Hocking, Dianna M, Wilksch, Jonathan J, Scott, Timothy A, Davies, Mark R, Hinton, Jay C ORCID: 0000-0003-2671-6026, Tree, Jai J
et al (show 3 more authors) (2018) Methionine biosynthesis and transport are functionally redundant for the growth and virulence of <i>Salmonella</i> Typhimurium. JOURNAL OF BIOLOGICAL CHEMISTRY, 293 (24). pp. 9506-9519.

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Husna et al 2018 Methionine biosynthesis & transport are functionally redundant for growth & virulence of S.Typhimurium - J. Biol. Chem..pdf - Published version

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Abstract

Methionine (Met) is an amino acid essential for many important cellular and biosynthetic functions, including the initiation of protein synthesis and <i>S</i>-adenosylmethionine-mediated methylation of proteins, RNA, and DNA. The <i>de novo</i> biosynthetic pathway of Met is well conserved across prokaryotes but absent from vertebrates, making it a plausible antimicrobial target. Using a systematic approach, we examined the essentiality of <i>de novo</i> methionine biosynthesis in <i>Salmonella enterica</i> serovar Typhimurium, a bacterial pathogen causing significant gastrointestinal and systemic diseases in humans and agricultural animals. Our data demonstrate that Met biosynthesis is essential for <i>S.</i> Typhimurium to grow in synthetic medium and within cultured epithelial cells where Met is depleted in the environment. During systemic infection of mice, the virulence of <i>S.</i> Typhimurium was not affected when either <i>de novo</i> Met biosynthesis or high-affinity Met transport was disrupted alone, but combined disruption in both led to severe <i>in vivo</i> growth attenuation, demonstrating a functional redundancy between <i>de novo</i> biosynthesis and acquisition as a mechanism of sourcing Met to support growth and virulence for <i>S.</i> Typhimurium during infection. In addition, our LC-MS analysis revealed global changes in the metabolome of <i>S.</i> Typhimurium mutants lacking Met biosynthesis and also uncovered unexpected interactions between Met and peptidoglycan biosynthesis. Together, this study highlights the complexity of the interactions between a single amino acid, Met, and other bacterial processes leading to virulence in the host and indicates that disrupting the <i>de novo</i> biosynthetic pathway alone is likely to be ineffective as an antimicrobial therapy against <i>S.</i> Typhimurium.

Item Type: Article
Uncontrolled Keywords: methionine, S-adenosylmethionine (SAM), biosynthesis, transporter, Salmonella enterica, peptidoglycan, in vivo infection, virulence
Depositing User: Symplectic Admin
Date Deposited: 14 Sep 2018 08:47
Last Modified: 16 Oct 2023 21:00
DOI: 10.1074/jbc.RA118.002592
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3026226