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Catalytic Bases and Stereocontrol in Lamiaceae Class II Diterpene Cyclases

Schulte, Samuel and Potter, Kevin C. and Lemke, Cody and Peters, Reuben J. (2018) Catalytic Bases and Stereocontrol in Lamiaceae Class II Diterpene Cyclases. Biochemistry, 57 (25). pp. 3473-3479. ISSN 0006-2960. doi:10.1021/acs.biochem.8b00193.

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Plants from the widespread Lamiaceae family produce many labdane-related diterpenoids, a number of which serve medicinal roles, and whose biosynthesis is initiated by class II diterpene cyclases (DTCs). These enzymes utilize a general acid–base catalyzed cyclo-isomerization reaction to produce various stereoisomers of the eponymous labdaenyl carbocation intermediate, which can then undergo rearrangement and/or the addition of water prior to terminating deprotonation. Identification of the pair of residues that cooperatively serve as the catalytic base in the DTCs that produce ent-copalyl diphosphate (CPP) required for gibberellin phytohormone biosynthesis in all vascular plants has led to insight into the addition of water as well as rearrangement. Lamiaceae plants generally contain an additional DTC that produces the enantiomeric normal CPP, as well as others that yield hydroxylated products derived from the addition of water. Here the catalytic base in these DTCs was investigated. Notably, changing two adjacent residues that seem to serve as the catalytic base in the normal CPP synthase from Salvia miltiorrhiza (SmCPS) to the residues found in the closely related perigrinol diphosphate synthase from Marrubium vulgare (MvPPS), which produces a partially rearranged and hydroxylated product derived from the distinct syn stereoisomer of labdaenyl+, altered the product outcome in an unexpected fashion. Specifically, the relevant SmCPS:H315N/T316V double mutant produces terpentedienyl diphosphate, which is derived from complete substituent rearrangement of syn rather than normal labdaenyl+. Accordingly, alteration of the residues that normally serve as the catalytic base surprisingly can impact stereocontrol.

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Peters, Reuben J.0000-0003-4691-8477
Additional Information:© 2018 American Chemical Society. Received: February 16, 2018. Revised: May 21, 2018. Published: May 22, 2018. This article is part of the Current Topics in Mechanistic Enzymology special issue. S.S. and K.C.P. contributed equally to this study. This work was supported by a grant from the NIH (GM076324 to R.J.P.). The authors declare no competing financial interest.
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Issue or Number:25
Record Number:CaltechAUTHORS:20180718-143536056
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Official Citation:Catalytic Bases and Stereocontrol in Lamiaceae Class II Diterpene Cyclases Samuel Schulte, Kevin C. Potter, Cody Lemke, and Reuben J. Peters Biochemistry 2018 57 (25), 3473-3479 DOI: 10.1021/acs.biochem.8b00193
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:87965
Deposited By: George Porter
Deposited On:18 Jul 2018 22:04
Last Modified:16 Nov 2021 00:22

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