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Publication Abstract from PubMed

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 horizontal line C and C horizontal line N bond formation to generate the novel polyketide-alkaloid scaffold.

Synthesis of unnatural alkaloid scaffolds by exploiting plant polyketide synthase.,Morita H, Yamashita M, Shi SP, Wakimoto T, Kondo S, Kato R, Sugio S, Kohno T, Abe I Proc Natl Acad Sci U S A. 2011 Aug 16;108(33):13504-9. Epub 2011 Aug 8. PMID:21825160^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.