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.
journal_name
Proc Natl Acad Sci U S Aauthors
Morita H,Yamashita M,Shi SP,Wakimoto T,Kondo S,Kato R,Sugio S,Kohno T,Abe Idoi
10.1073/pnas.1107782108subject
Has Abstractpub_date
2011-08-16 00:00:00pages
13504-9issue
33eissn
0027-8424issn
1091-6490pii
1107782108journal_volume
108pub_type
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