Terpenoids constitute the largest class of natural products with complex structures,essential functions,and versatile applications.Creation of new building blocks beyond the conventional five-carbon(C_(5))units,dimeth...Terpenoids constitute the largest class of natural products with complex structures,essential functions,and versatile applications.Creation of new building blocks beyond the conventional five-carbon(C_(5))units,dimethylallyl diphosphate(DMAPP)and isopentenyl diphosphate,expands significantly the chemical space of terpenoids.Structure-guided engineering of an S-adenosylmethionine-dependent geranyl diphosphate(GPP)C2-methyltransferase from Streptomyces coelicolor yielded variants converting DMAPP to a new C_(6) unit,2-methyl-DMAPP.Mutation of the Gly residue at the position 202 resulted in a smaller substrate-binding pocket to fit DMAPP instead of its native substrate GPP.Replacement of Phe residue at the position 222 with a Tyr residue contributed to DMAPP binding via hydrogen bond.Furthermore,using Escherichia coli as the chassis,we demonstrated that 2-methyl-DMAPP was accepted as a start unit to generate noncanonical trans-and cis-prenyl diphosphates(C_(5n+1))and terpenoids.This work provides insights into substrate recognition of prenyl diphosphate methyltransferases,and strategies to diversify terpenoids by expanding the building block portfolio.展开更多
基金supported in part by the National Key R&D Program of China (2021YFA0909600 and 2019YFA0909400).
文摘Terpenoids constitute the largest class of natural products with complex structures,essential functions,and versatile applications.Creation of new building blocks beyond the conventional five-carbon(C_(5))units,dimethylallyl diphosphate(DMAPP)and isopentenyl diphosphate,expands significantly the chemical space of terpenoids.Structure-guided engineering of an S-adenosylmethionine-dependent geranyl diphosphate(GPP)C2-methyltransferase from Streptomyces coelicolor yielded variants converting DMAPP to a new C_(6) unit,2-methyl-DMAPP.Mutation of the Gly residue at the position 202 resulted in a smaller substrate-binding pocket to fit DMAPP instead of its native substrate GPP.Replacement of Phe residue at the position 222 with a Tyr residue contributed to DMAPP binding via hydrogen bond.Furthermore,using Escherichia coli as the chassis,we demonstrated that 2-methyl-DMAPP was accepted as a start unit to generate noncanonical trans-and cis-prenyl diphosphates(C_(5n+1))and terpenoids.This work provides insights into substrate recognition of prenyl diphosphate methyltransferases,and strategies to diversify terpenoids by expanding the building block portfolio.
