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Molecular Basis for Spirocycle Formation in the Paraherquamide Biosynthetic Pathway.


ABSTRACT: The paraherquamides are potent anthelmintic natural products with complex heptacyclic scaffolds. One key feature of these molecules is the spiro-oxindole moiety that lends a strained three-dimensional architecture to these structures. The flavin monooxygenase PhqK was found to catalyze spirocycle formation through two parallel pathways in the biosynthesis of paraherquamides A and G. Two new paraherquamides (K and L) were isolated from a ?phqK strain of Penicillium simplicissimum, and subsequent enzymatic reactions with these compounds generated two additional metabolites, paraherquamides M and N. Crystal structures of PhqK in complex with various substrates provided a foundation for mechanistic analyses and computational studies. While it is evident that PhqK can react with various substrates, reaction kinetics and molecular dynamics simulations indicated that the dioxepin-containing paraherquamide L is the favored substrate. Through this effort, we have elucidated a key step in the biosynthesis of the paraherquamides and provided a rationale for the selective spirocyclization of these powerful anthelmintic agents.

SUBMITTER: Fraley AE 

PROVIDER: S-EPMC7065246 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Molecular Basis for Spirocycle Formation in the Paraherquamide Biosynthetic Pathway.

Fraley Amy E AE   Caddell Haatveit Kersti K   Ye Ying Y   Kelly Samantha P SP   Newmister Sean A SA   Yu Fengan F   Williams Robert M RM   Smith Janet L JL   Houk K N KN   Sherman David H DH  

Journal of the American Chemical Society 20200116 5


The paraherquamides are potent anthelmintic natural products with complex heptacyclic scaffolds. One key feature of these molecules is the spiro-oxindole moiety that lends a strained three-dimensional architecture to these structures. The flavin monooxygenase PhqK was found to catalyze spirocycle formation through two parallel pathways in the biosynthesis of paraherquamides A and G. Two new paraherquamides (K and L) were isolated from a Δ<i>phqK</i> strain of <i>Penicillium simplicissimum</i>, a  ...[more]

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