title: Core assembly mechanism of quinocarcin/SF-1739: bimodular complex nonribosomal peptide synthetases for sequential mannich-type reactions.
abstract: Quinocarcin and SF-1739, potent antitumor antibiotics, share a common tetracyclic tetrahydroisoquinoline (THIQ)-pyrrolidine core scaffold. Herein, we describe the identification of their biosynthetic gene clusters and biochemical analysis of Qcn18/Cya18 generating the previously unidentified extender unit dehydroarginine, which is a component of the pyrrolidine ring. ATP-inorganic pyrophosphate exchange experiments with five nonribosomal peptide synthetases (NRPSs) enabled us to identify their substrates. On the basis of these data, we propose that a biosynthetic pathway comprising a three-component NRPS/MbtH family protein complex, Qcn16/17/19, plays a key role in the construction of tetracyclic THIQ-pyrrolidine core scaffold involving sequential Pictet-Spengler and intramolecular Mannich reactions. Furthermore, data derived from gene inactivation experiments led us to propose late-modification steps of quinocarcin.
authors.affiliation: Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan.
authors.forename: Tomoshige
authors.initials: T
authors.lastname: Hiratsuka
authors.affiliation: Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan.
authors.forename: Kento
authors.initials: K
authors.lastname: Koketsu
authors.affiliation: Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Minami
authors.affiliation: Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kaneko
authors.affiliation: Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Yamazaki
authors.affiliation: Division of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Oguri
authors.affiliation: Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan. Electronic address: hoik@sci.hokudai.ac.jp.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Oikawa
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000378:metabolism*; D053898:Biosynthetic Pathways; D005798:Genes, Bacterial; D007546:Isoquinolines / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D005810:Multigene Family; D010453:Peptide Synthases / Q000235:genetics / Q000378:metabolism*; D011809:Quinones / Q000737:chemistry / Q000378:metabolism; D013302:Streptomyces / Q000737:chemistry / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D007546:Isoquinolines; D011809:Quinones; D044005:Tetrahydroisoquinolines; C035433:SF 1739 HP; C038710:quinocarcin; D010453:Peptide Synthases