title: Synthesis of unnatural alkaloid scaffolds by exploiting plant polyketide synthase.
abstract: HsPKS1 from Huperzia serrata is a type III polyketide synthase (PKS) with remarkable substrate tolerance and catalytic potential. Here we present the synthesis of unnatural unique polyketide-alkaloid hybrid molecules by exploiting the enzyme reaction using precursor-directed and structure-based approaches. HsPKS1 produced novel pyridoisoindole (or benzopyridoisoindole) with the 6.5.6-fused (or 6.6.5.6-fused) ring system by the condensation of 2-carbamoylbenzoyl-CoA (or 3-carbamoyl-2-naphthoyl-CoA), a synthetic nitrogen-containing nonphysiological starter substrate, with two molecules of malonyl-CoA. The structure-based S348G mutant not only extended the product chain length but also altered the cyclization mechanism to produce a biologically active, ring-expanded 6.7.6-fused dibenzoazepine, by the condensation of 2-carbamoylbenzoyl-CoA with three malonyl-CoAs. Thus, the basic nitrogen atom and the structure-based mutagenesis enabled additional C─C and C─N bond formation to generate the novel polyketide-alkaloid scaffold.
authors.affiliation: Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Morita
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamashita
authors.forename: She-Po
authors.initials: SP
authors.lastname: Shi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Wakimoto
authors.forename: Shin
authors.initials: S
authors.lastname: Kondo
authors.forename: Ryohei
authors.initials: R
authors.lastname: Kato
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Sugio
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kohno
authors.forename: Ikuro
authors.initials: I
authors.lastname: Abe
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis*; D002384:Catalysis; D020134:Catalytic Domain; D003500:Cyclization; D016297:Mutagenesis, Site-Directed; D010940:Plant Proteins; D048630:Polyketide Synthases / Q000378:metabolism*
chemical_list: D000470:Alkaloids; D010940:Plant Proteins; D048630:Polyketide Synthases