Structural insight on assembly-line catalysis in terpene biosynthesis

Faylo, Jacque L.; van Eeuwen, Trevor; Kim, Hee Jong; Gorbea Colón, Jose J.; Garcia, Benjamin A.; Murakami, Kenji; Christianson, David W.

doi:10.1038/s41467-021-23589-9

DOE OSTI · 1816540

Structural insight on assembly-line catalysis in terpene biosynthesis

Faylo, Jacque L.·van Eeuwen, Trevor·Kim, Hee Jong·Gorbea Colón, Jose J.·Garcia, Benjamin A.·Murakami, Kenji·Christianson, David W.

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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.

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY 59 BASIC BIOLOGICAL SCIENCES cryoelectron microscopy enzyme mechanisms multienzyme complexes

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Faylo, Jacque L., van Eeuwen, Trevor, Kim, Hee Jong, Gorbea Colón, Jose J., Garcia, Benjamin A., Murakami, Kenji, Christianson, David W.. 2021-06-09. Structural insight on assembly-line catalysis in terpene biosynthesis. https://doi.org/10.1038/s41467-021-23589-9

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