Structural insight on assembly-line catalysis in terpene biosynthesis

Jacque L. Faylo, Trevor van Eeuwen, Hee Jong Kim, Jose J. Gorbea Colón, Benjamin A. Garcia, Kenji Murakami and David W. Christianson ()
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Jacque L. Faylo: Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania
Trevor van Eeuwen: University of Pennsylvania
Hee Jong Kim: University of Pennsylvania
Jose J. Gorbea Colón: University of Pennsylvania
Benjamin A. Garcia: University of Pennsylvania
Kenji Murakami: University of Pennsylvania
David W. Christianson: Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Fusicoccadiene synthase from Phomopsis amygdali (PaFS) is a unique bifunctional terpenoid synthase that catalyzes the first two steps in the biosynthesis of the diterpene glycoside Fusicoccin A, a mediator of 14-3-3 protein interactions. The prenyltransferase domain of PaFS generates geranylgeranyl diphosphate, which the cyclase domain then utilizes to generate fusicoccadiene, the tricyclic hydrocarbon skeleton of Fusicoccin A. Here, we use cryo-electron microscopy to show that the structure of full-length PaFS consists of a central octameric core of prenyltransferase domains, with the eight cyclase domains radiating outward via flexible linker segments in variable splayed-out positions. Cryo-electron microscopy and chemical crosslinking experiments additionally show that compact conformations can be achieved in which cyclase domains are more closely associated with the prenyltransferase core. This structural analysis provides a framework for understanding substrate channeling, since most of the geranylgeranyl diphosphate generated by the prenyltransferase domains remains on the enzyme for cyclization to form fusicoccadiene.

Date: 2021
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DOI: 10.1038/s41467-021-23589-9

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