title: Unconventional origin and hybrid system for construction of pyrrolopyrrole moiety in kosinostatin biosynthesis.
abstract: Kosinostatin (KST), an antitumor antibiotic, features a pyrrolopyrrole moiety spirally jointed to a five-membered ring of an anthraquinone framework glycosylated with a γ-branched octose. By a combination of in silico analysis, genetic characterization, biochemical assay, and precursor feeding experiments, a biosynthetic pathway for KST was proposed, which revealed (1) the pyrrolopyrrole moiety originates from nicotinic acid and ribose, (2) the bicyclic amidine is constructed by a process similar to the tryptophan biosynthetic pathway, and (3) a discrete adenylation enzyme and a peptidyl carrier protein (PCP) are responsible for producing a PCP-tethered building block parallel to type II polyketide synthase (PKS) rather than for the PKS priming step by providing the starter unit. These findings provide an opportunity to further explore the inexplicable enzymatic logic that governs the formation of pyrrolopyrrole moiety and the spirocyclic skeleton.
authors.affiliation: State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
authors.forename: Hong-Min
authors.initials: HM
authors.lastname: Ma
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhou
authors.forename: Yu-Min
authors.initials: YM
authors.lastname: Tang
authors.forename: Zhuan
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yong-Sheng
authors.initials: YS
authors.lastname: Chen
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: He
authors.forename: Hai-Xue
authors.initials: HX
authors.lastname: Pan
authors.forename: Man-Cheng
authors.initials: MC
authors.lastname: Tang
authors.forename: Ju-Fang
authors.initials: JF
authors.lastname: Gao
authors.forename: Sheng-Yin
authors.initials: SY
authors.lastname: Zhao
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Igarashi
authors.forename: Gong-Li
authors.initials: GL
authors.lastname: Tang
mesh_terms: D000617:Aminoglycosides / Q000096:biosynthesis* / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D001483:Base Sequence; D003001:Cloning, Molecular; D009682:Magnetic Resonance Spectroscopy; D008847:Micromonospora / Q000235:genetics / Q000378:metabolism; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D005810:Multigene Family; D010453:Peptide Synthases / Q000378:metabolism; D048630:Polyketide Synthases / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry*
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D011758:Pyrroles; C455260:kosinostatin; D048630:Polyketide Synthases; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase