Reconstruction of the saframycin core scaffold defines dual Pictet-Spengler mechanisms.
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 propose a detailed mechanism involving the reduction of various peptidyl thioesters by a single R domain followed by iterative C domain-mediated Pictet-Spengler reactions.
Koketsu
Kento
K
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo, Japan.
Watanabe
Kenji
K
Suda
Haruna
H
Oguri
Hiroki
H
Oikawa
Hideaki
H
D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000302:isolation & purification; D003001:Cloning, Molecular; D003065:Coenzyme A / Q000378:metabolism; D003903:Deuterium; D004926:Escherichia coli / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D007546:Isoquinolines / Q000138:chemical synthesis / Q000302:isolation & purification; D007700:Kinetics; D008958:Models, Molecular; D009249:NADP / Q000378:metabolism; D013302:Streptomyces / Q000737:chemistry / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D005227:Fatty Acids; D007546:Isoquinolines; D009249:NADP; D003903:Deuterium; C026925:saframycin A; D003065:Coenzyme A
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