Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 136, Issue 49, Pages 17350-17354Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ja510489j
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Funding
- NSF CAREER Award [MCB-1149427]
- College of Pharmacy at the University of Kentucky
- FICYT (Government of Asturias) [PEST08-17]
- MICINN (Government of Spain) [AGL2010-20622]
- Direct For Biological Sciences [1408798] Funding Source: National Science Foundation
- Div Of Molecular and Cellular Bioscience [1408798] Funding Source: National Science Foundation
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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(T-4). The valuable insights gained into the pathway(s) followed for the production of S-Me-l-Cys-S-TioS(T-4) will serve as a guide for the development of novel engineered interrupted adenylation enzymes for combinatorial biosynthesis.
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