Functional analysis of modular enzymes and its application to the synthesis of antitumor agents

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Non-ribosomal peptide synthetase (NRPS) promotes condensations of amino acids forming amide linkages, with some modifications. We found that a single NRPS SfmC of the potent antitumor agents saframycin catalyzes a seven-step transformation from readily synthesized dipeptidyl substrates with long acyl chains into a pentacyclic tetrahydroisoquinoline scaffold. Based on deletion mutant analyses, we proposed the detailed mechanism involving the reductions of various peptidyl thioesters by an identical R-domain followed by the C-domain-mediated Pictet-Spengler reactions in an iterative manner.