ChemRxiv
These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
1/1
0/0

Molecular Basis for Spirocycle Formation in the Paraherquamide Biosynthetic Pathway

preprint
submitted on 20.08.2019 and posted on 21.08.2019 by Amy E. Fraley, Kersti Caddell Haatveit, Ying Ye, Samantha P. Kelly, Sean A. Newmister, Fengan Yu, Robert M. Williams, Janet L. Smith, K. N. Houk, David H. Sherman

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 ΔphqK 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 was 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.

Funding

NIH R01 CA070375 to R.M.W. and D.H.S.

NIH R35 GM118101 to D.H.S.

Hans Vahlteich Professorship to D.H.S.

R01 GM124480 to K.N.H.

Margaret J. Hunter Professorship to J.L.S.

Rackham Predoctoral Fellowship to A.E.F.

NIH Predoctoral Training Grant GM067555 to K.C.H.

History

Email Address of Submitting Author

davidhs@umich.edu

Institution

University of Michigan

Country

United States

ORCID For Submitting Author

0000-0001-8334-3647

Declaration of Conflict of Interest

The authors declare no competing financial interest.

Exports

Read the published paper

in Journal of the American Chemical Society

Logo branding

Exports