Pictet-Spenglerase involved in tetrahydroisoquinoline antibiotic biosynthesis

Nonribosomal peptide synthetase (NRPS) is a programmable modular machinery that produces a number of biologically active small-molecule peptides. Saframycin A is a potent antitumor antibiotic with a unique pentacyclic tetrahydroisoquinoline scaffold. We found that the nonribosomal peptide synthetase SfmC catalyzes a seven-step transformation of readily synthesized dipeptidyl substrates with long acyl chains into a complex saframycin scaffold. Based on a series of enzymatic reactions, we proposed a detailed mechanism involving the reduction of various peptidyl thioesters by a single R domain followed by iterative C domain-mediated Pictet-Spengler reactions. This shows that NRPSs possess a remarkable capability to acquire novel function for diversifying structures of peptide natural products.

► Remarkable multiple-catalysis of NRPS: construction of complex saframycin scaffold. ► Novel functions of nonribosomal peptide synthetase found in saframycin biosynthesis. ► Pictet-Spenglerase involved in tetrahydroisoquinoline antibiotic biosynthesis.