The multifunctional enzyme S-adenosylhomocysteine/methylthioadenosine nucleosidase is a key metabolic enzyme in the virulence of Salmonella enterica var Typhimurium

Asma U. Husna, Nancy Wang, Jonathan J. Wilksch, Hayley J. Newton, Dianna M. Hocking, Iain D. Hay, Simon A. Cobbold, Mark R. Davies, Malcolm J. McConville, Trevor Lithgow, Richard A. Strugnell

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Abstract

Key physiological differences between bacterial and mammalian metabolism provide opportunities for the development of novel antimicrobials. We examined the role of the multifunctional enzyme S-adenosylhomocysteine/Methylthioadenosine (SAH/MTA) nucleosidase (Pfs) in the virulence of S. enterica var Typhimurium (S. Typhimurium) in mice, using a defined Pfs deletion mutant (i.e. Δpfs). Pfs was essential for growth of S. Typhimurium in M9 minimal medium, in tissue cultured cells, and in mice. Studies to resolve which of the three known functions of Pfs were key to murine virulence suggested that downstream production of autoinducer-2, spermidine and methylthioribose were non-essential for Salmonella virulence in a highly sensitive murine model. Mass spectrometry revealed the accumulation of SAH in S. Typhimurium Δpfs and complementation of the Pfs mutant with the specific SAH hydrolase from Legionella pneumophila reduced SAH levels, fully restored growth ex vivo and the virulence of S. Typhimurium Δpfs for mice. The data suggest that Pfs may be a legitimate target for antimicrobial development, and that the key role of Pfs in bacterial virulence may be in reducing the toxic accumulation of SAH which, in turn, suppresses an undefined methyltransferase.

Original languageEnglish
Pages (from-to)3435-3453
Number of pages19
JournalBiochemical Journal
Volume476
Issue number22
DOIs
Publication statusPublished - 29 Nov 2019

Keywords

  • activated methyl cycle
  • antimicrobial target
  • metabolism
  • pfs
  • salmonella

Cite this

Husna, A. U., Wang, N., Wilksch, J. J., Newton, H. J., Hocking, D. M., Hay, I. D., Cobbold, S. A., Davies, M. R., McConville, M. J., Lithgow, T., & Strugnell, R. A. (2019). The multifunctional enzyme S-adenosylhomocysteine/methylthioadenosine nucleosidase is a key metabolic enzyme in the virulence of Salmonella enterica var Typhimurium. Biochemical Journal, 476(22), 3435-3453. https://doi.org/10.1042/BCJ20190297