Adenylation and S -methylation of cysteine by the bifunctional enzyme TioN in thiocoraline biosynthesis

Ahmad H. Al-Mestarihi, Germán Villamizar, Javier Fernández, Olga E. Zolova, Felipe Lombó, Sylvie Garneau-Tsodikova

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44 Scopus citations


The antitumor agent thiocoraline is a nonribosomally biosynthesized bisintercalator natural product, which contains in its peptidic backbone two S-methylated l-cysteine residues. S-Methylation occurs very rarely in nature, and is observed extremely rarely in nonribosomal peptide scaffolds. We have proposed that during thiocoraline biosynthesis, TioN, a stand-alone adenylation domain interrupted by the S-adenosyl-l-methionine binding region of a methyltransferase enzyme, is capable of performing two functions: the adenylation and S-methylation of l-cysteine. Herein, by preparation of knockouts of TioN and its MbtH-like protein partner TioT, we confirmed their role in thiocoraline biosynthesis. We also co-expressed recombinant TioN and TioT and biochemically investigated three potential pathways involving activation, methylation, and loading of l-cysteine onto the TioN partner thiolation domain, TioS(T4). The valuable insights gained into the pathway(s) followed for the production of S-Me-l-Cys-S-TioS(T4) will serve as a guide for the development of novel engineered interrupted adenylation enzymes for combinatorial biosynthesis.

Original languageEnglish
Pages (from-to)17350-17354
Number of pages5
JournalJournal of the American Chemical Society
Issue number49
StatePublished - Dec 10 2014

Bibliographical note

Publisher Copyright:
© 2014 American Chemical Society.

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry


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