Structural highlights
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.
References
- ↑ Morita H, Yamashita M, Shi SP, Wakimoto T, Kondo S, Kato R, Sugio S, Kohno T, Abe I. Synthesis of unnatural alkaloid scaffolds by exploiting plant polyketide synthase. Proc Natl Acad Sci U S A. 2011 Aug 16;108(33):13504-9. Epub 2011 Aug 8. PMID:21825160 doi:10.1073/pnas.1107782108
