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Quinolactacin Biosynthesis Involves Non‐Ribosomal‐Peptide‐Synthetase‐Catalyzed Dieckmann Condensation to Form the Quinolone‐γ‐lactam Hybrid
Author(s) -
Zhao Fanglong,
Liu Zhiwen,
Yang Shuyuan,
Ding Ning,
Gao Xue
Publication year - 2020
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202005770
Subject(s) - quinolone , pharmacophore , chemistry , polyketide synthase , stereochemistry , biosynthesis , lactam , decarboxylation , gene cluster , biochemistry , oxidative decarboxylation , polyketide , enzyme , catalysis , gene , antibiotics
Quinolactacins are novel fungal alkaloids that feature a quinolone‐γ‐lactam hybrid, which is a potential pharmacophore for the treatment of cancer and Alzheimer's disease. Herein, we report the identification of the quinolactacin A2 biosynthetic gene cluster and elucidate the enzymatic basis for the formation of the quinolone‐γ‐lactam structure. We reveal an unusual β‐keto acid ( N ‐methyl‐2‐aminobenzoylacetate) precursor that is derived from the primary metabolite l ‐kynurenine via methylation, oxidative decarboxylation, and amide hydrolysis reactions. In vitro assays reveal two single‐module non‐ribosomal peptide synthetases (NRPs) that incorporate the β‐keto acid and l ‐isoleucine, followed by Dieckmann condensation, to form the quinolone‐γ‐lactam. Notably, the bioconversion from l ‐kynurenine to the β‐keto acid is a unique strategy employed by nature to decouple R*‐domain‐containing NRPS from the polyketide synthase (PKS) machinery, expanding the paradigm for the biosynthesis of quinolone‐γ‐lactam natural products via Dieckmann condensation.