title: Reconstruction of the saframycin core scaffold defines dual Pictet-Spengler mechanisms.
abstract: 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.
authors.affiliation: Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo, Japan.
authors.forename: Kento
authors.initials: K
authors.lastname: Koketsu
authors.forename: Kenji
authors.initials: K
authors.lastname: Watanabe
authors.forename: Haruna
authors.initials: H
authors.lastname: Suda
authors.forename: Hiroki
authors.initials: H
authors.lastname: Oguri
authors.forename: Hideaki
authors.initials: H
authors.lastname: Oikawa
mesh_terms: 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
chemical_list: D000903:Antibiotics, Antineoplastic; D005227:Fatty Acids; D007546:Isoquinolines; D009249:NADP; D003903:Deuterium; C026925:saframycin A; D003065:Coenzyme A
references.citation: Chem Biol. 2004 Feb;11(2):261-71
references.pmid: 15123287
references.citation: J Bacteriol. 2008 Jan;190(1):251-63
references.pmid: 17981978
references.citation: J Am Chem Soc. 2007 May 23;129(20):6366-7
references.pmid: 17472382
references.citation: Nat Prod Rep. 2009 Mar;26(3):322-37
references.pmid: 19240944
references.citation: J Microbiol Biotechnol. 2009 May;19(5):439-46
references.pmid: 19494690
references.citation: Nat Prod Rep. 2005 Dec;22(6):717-41
references.pmid: 16311632
references.citation: J Antibiot (Tokyo). 1977 Nov;30(11):1015-8
references.pmid: 591455
references.citation: J Biol Chem. 1985 Jan 10;260(1):344-8
references.pmid: 3880741
references.citation: Mol Microbiol. 2005 Apr;56(1):144-54
references.pmid: 15773985
references.citation: Chem Rev. 2006 Aug;106(8):3468-96
references.pmid: 16895337
references.citation: J Am Chem Soc. 2009 Jul 8;131(26):9347-53
references.pmid: 19514719
references.citation: Nat Chem Biol. 2009 Aug;5(8):593-9
references.pmid: 19561621
references.citation: Mol Microbiol. 2002 Sep;45(6):1673-85
references.pmid: 12354233
references.citation: Microbiology (Reading). 1996 Apr;142 ( Pt 4):741-746
references.pmid: 8936303
references.citation: Trends Microbiol. 2007 Jan;15(1):22-30
references.pmid: 17118662
references.citation: Org Lett. 2000 Aug 10;2(16):2545-8
references.pmid: 10956543
references.citation: Chem Biol. 2000 Aug;7(8):623-42
references.pmid: 11048953
references.citation: Chem Rev. 2002 May;102(5):1669-730
references.pmid: 11996547
references.citation: Chembiochem. 2009 Aug 17;10(12):1965-8
references.pmid: 19588480
references.citation: Nature. 2000 Feb 3;403(6769):571-5
references.pmid: 10676969
references.citation: Nat Chem Biol. 2006 Aug;2(8):423-8
references.pmid: 16799553