Identification of a metabolic disposal route for the oncometabolite S-(2-succino)cysteine in Bacillus subtilis

Thomas D. Niehaus, Jacob Folz, Donald R. McCarty, Arthur J.L. Cooper, David Moraga Amador, Oliver Fiehn, Andrew D. Hanson

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Cellular thiols such as cysteine spontaneously and readily react with the respiratory intermediate fumarate, resulting in the formation of stable S-(2-succino)-adducts. Fumarate-mediated succination of thiols increases in certain tumors and in response to glucotoxicity associated with diabetes. Therefore, S-(2-succino)-adducts such as S-(2-succino)cysteine (2SC) are considered oncometabolites and biomarkers for human disease. No disposal routes for S-(2-succino)-compounds have been reported prior to this study. Here, we show that Bacillus subtilis metabolizes 2SC to cysteine using a pathway encoded by the yxe operon. The first step is N-acetylation of 2SC followed by an oxygenation that we propose results in the release of oxaloacetate and N-acetylcysteine, which is deacetylated to give cysteine. Knockouts of the genes predicted to mediate each step in the pathway lose the ability to grow on 2SC as the sulfur source and accumulate the expected upstream metabolite(s). We further show that N-acetylation of 2SC relieves toxicity. This is the first demonstration of a metabolic disposal route for any S-(2-suc-cino)-compound, paving the way toward the identification of corresponding pathways in other species.

Original languageEnglish (US)
Pages (from-to)8255-8263
Number of pages9
JournalJournal of Biological Chemistry
Volume293
Issue number21
DOIs
StatePublished - May 25 2018
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by National Science Foundation Grant MCB-1153413 and by an endowment from the C. V. Griffin Sr. Foundation. The authors declare that they have no conflicts of interest with the contents of this article. We thank Christopher M. Johnson for providing the B. subtilis transposon library and for advice related to Tn-seq. We thank Antoine Danchin, Daniel Ziegler and the Bacillus Genetic Stock Center for providing B. subtilis strains and for advice. We thank Valérie de Crécy-Lagard and Leticia Pollo de Oliveira for advice.

Funding Information:
This work was supported by National Science Foundation Grant MCB-1153413 and by an endowment from the C. V. Griffin Sr. Foundation. The authors declare that they have no conflicts of interest with the contents of this article.

Publisher Copyright:
© 2018 Niehaus et al.

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