Crystal Structure of Cucumene Synthase, a Terpenoid Cyclase That Generates a Linear Triquinane Sesquiterpene

Blank, Patrick N.; Pemberton, Travis A.; Chow, Jeng-Yeong; Poulter, C. Dale; Christianson, David W.

doi:10.1021/acs.biochem.8b00899

Crystal Structure of Cucumene Synthase, a Terpenoid Cyclase That Generates a Linear Triquinane Sesquiterpene

Journal Article · Mon Oct 22 00:00:00 EDT 2018 · Biochemistry

DOI:https://doi.org/10.1021/acs.biochem.8b00899· OSTI ID:1483892

Blank, Patrick N. ^[1]; Pemberton, Travis A. ^[1]; Chow, Jeng-Yeong ^[2]; ^[2]; ^[1]

Univ. of Pennsylvania, Philadelphia, PA (United States)
Univ. of Utah, Salt Lake City, UT (United States)

Linear triquinanes are sesquiterpene natural products with hydrocarbon skeletons consisting of three fused five-membered rings. Importantly, several of these compounds exhibit useful anticancer, anti-inflammatory, and antibiotic properties. However, linear triquinanes pose significant challenges to organic synthesis because of the structural and stereochemical complexity of their hydrocarbon skeletons. To illuminate nature’s solution to the generation of linear triquinanes, we now describe the crystal structure of Streptomyces clavuligerus cucumene synthase. This sesquiterpene cyclase catalyzes the stereospecific cyclization of farnesyl diphosphate to form a linear triquinane product, (5S,7S,10R,11S)-cucumene. Specifically, we report the structure of the wild-type enzyme at 3.05 Å resolution and the structure of the T181N variant at 1.96 Å resolution, both in the open active site conformations without any bound ligands. The high-resolution structure of T181N cucumene synthase enables inspection of the active site contour, which adopts a three-dimensional shape complementary to a linear triquinane. Several aromatic residues outline the active site contour and are believed to facilitate cation–π interactions that would stabilize carbocation intermediates in catalysis. Furthermore, aromatic residues in the active site not only define the template for catalysis but also play a role in reducing activation barriers in the multistep cyclization cascade.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); Northeastern Collaborative Access Team; National Inst. of Health

Grant/Contract Number:: AC02-06CH11357; SC0012704

OSTI ID:: 1483892

Alternate ID(s):: OSTI ID: 1688469

Journal Information:: Biochemistry, Journal Name: Biochemistry Journal Issue: 44 Vol. 57; ISSN 0006-2960

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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