title: Phenalenone Polyketide Cyclization Catalyzed by Fungal Polyketide Synthase and Flavin-Dependent Monooxygenase.
abstract: Phenalenones are polyketide natural products that display diverse structures and biological activities. The core of phenalenones is a peri-fused tricyclic ring system cyclized from a linear polyketide precursor via an unresolved mechanism. Toward understanding the unusual cyclization steps, the phn biosynthetic gene cluster responsible for herqueinone biosynthesis was identified from the genome of Penicillium herquei. A nonreducing polyketide synthase (NR-PKS) PhnA was shown to synthesize the heptaketide backbone and cyclize it into the angular, hemiketal-containing naphtho-γ-pyrone prephenalenone. The product template (PT) domain of PhnA catalyzes only the C4-C9 aldol condensation, which is unprecedented among known PT domains. The transformation of prephenalenone to phenalenone requires an FAD-dependent monooxygenase (FMO) PhnB, which catalyzes the C2 aromatic hydroxylation of prephenalenone and ring opening of the γ-pyrone ring simultaneously. Density functional theory calculations provide insights into why the hydroxylated intermediate undergoes an aldol-like phenoxide-ketone cyclization to yield the phenalenone core. This study therefore unveiled new routes and biocatalysts for polyketide cyclization.
authors.affiliation: Department of Chemical and Biomolecular Engineering and ‡Department of Chemistry and Biochemistry, University of California , Los Angeles, California 90095, United States.
authors.forename: Shu-Shan
authors.initials: SS
authors.lastname: Gao
authors.affiliation: Department of Chemical and Biomolecular Engineering and ‡Department of Chemistry and Biochemistry, University of California , Los Angeles, California 90095, United States.
authors.forename: Abing
authors.initials: A
authors.lastname: Duan
authors.affiliation: Department of Chemical and Biomolecular Engineering and ‡Department of Chemistry and Biochemistry, University of California , Los Angeles, California 90095, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Chemical and Biomolecular Engineering and ‡Department of Chemistry and Biochemistry, University of California , Los Angeles, California 90095, United States.
authors.forename: Peiyuan
authors.initials: P
authors.lastname: Yu
authors.affiliation: Department of Chemical and Biomolecular Engineering and ‡Department of Chemistry and Biochemistry, University of California , Los Angeles, California 90095, United States.
authors.forename: Leibniz
authors.initials: L
authors.lastname: Hang
authors.affiliation: Department of Chemical and Biomolecular Engineering and ‡Department of Chemistry and Biochemistry, University of California , Los Angeles, California 90095, United States.
authors.forename: K N
authors.initials: KN
authors.lastname: Houk
authors.affiliation: Department of Chemical and Biomolecular Engineering and ‡Department of Chemistry and Biochemistry, University of California , Los Angeles, California 90095, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tang
mesh_terms: D002384:Catalysis; D002853:Chromatography, Liquid; D003500:Cyclization; D005415:Flavins / Q000378:metabolism*; D005658:Fungi / Q000201:enzymology / Q000235:genetics; D015394:Molecular Structure; D005810:Multigene Family; D010105:Oxygenases / Q000378:metabolism*; D043803:Phenalenes / Q000737:chemistry*; D048630:Polyketide Synthases / Q000235:genetics / Q000378:metabolism*
chemical_list: D005415:Flavins; D043803:Phenalenes; C038036:phenalen-1-one; D048630:Polyketide Synthases; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)