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Deciphering Nature’s Intricate Way of N,S-Dimethylating l‑Cysteine: Sequential Action of Two Bifunctional Adenylation Domains

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journal contribution
posted on 06.11.2017, 15:20 by Shogo Mori, Atefeh Garzan, Oleg V. Tsodikov, Sylvie Garneau-Tsodikova
Dimethylation of amino acids consists of an interesting and puzzling series of events that could be achieved, during nonribosomal peptide biosynthesis, either by a single adenylation (A) domain interrupted by a methyltransferase (M) domain or by the sequential action of two of such independent enzymes. Herein, to establish the method by which Nature N,S-dimethylates l-Cys, we studied its formation during thiochondrilline A biosynthesis by evaluating TioS­(A3aM3SA3bT3) and TioN­(AaMNAb). This study not only led to identification of the exact pathway followed in Nature by these two enzymes for N,S-dimethylation of l-Cys, but also revealed that a single interrupted A domain can N,N-dimethylate amino acids, a novel phenomenon in the nonribosomal peptide field. These findings offer important and useful insights for the development and engineering of novel interrupted A domain enzymes to serve, in the future, as tools for combinatorial biosynthesis.

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