Mechanism-Based Post-Translational Modification and Inactivation in Terpene Synthases
Abstract
Terpenes are ubiquitous natural chemicals with diverse biological functions spanning all three domains of life. In specialized metabolism, the active sites of terpene synthases (TPSs) evolve in shape and reactivity to direct the biosynthesis of a myriad of chemotypes for organismal fitness. As most terpene biosynthesis mechanistically involves highly reactive carbocationic intermediates, the protein surfaces catalyzing these cascade reactions possess reactive regions possibly prone to premature carbocation capture and potentially enzyme inactivation. Here, we show using proteomic and X-ray crystallographic analyses that cationic intermediates undergo capture by conserved active site residues leading to inhibitory self-alkylation. Furthermore, the level of cation-mediated inactivation increases with mutation of the active site, upon changes in the size and structure of isoprenoid diphosphate substrates, and alongside increases in reaction temperatures. TPSs that individually synthesize multiple products are less prone to self-alkylation then TPSs possessing relatively high product specificity. In total, the results presented suggest that mechanism-based alkylation represents an overlooked mechanistic pressure during the evolution of cation-derived terpene biosynthesis.
- Authors:
-
- Howard Hughes Medical Institute, Jack H. Skirball Center for Chemical Biology & Proteomics, The Salk Institute for Biological Studies, La Jolla, California 92037, United States
- Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, United States, Vincent J. Coates Mass Spectrometry Center, The Salk Institute of Biological Studies, La Jolla, California 92037, United States
- Publication Date:
- Research Org.:
- Salk Inst. for Biological Studies, La Jolla, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES)
- OSTI Identifier:
- 1221692
- Alternate Identifier(s):
- OSTI ID: 1345035
- Grant/Contract Number:
- AC02-693-05CH11231; AC02-05CH11231
- Resource Type:
- Published Article
- Journal Name:
- ACS Chemical Biology
- Additional Journal Information:
- Journal Name: ACS Chemical Biology Journal Volume: 10 Journal Issue: 11; Journal ID: ISSN 1554-8929
- Publisher:
- American Chemical Society
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Kersten, Roland D., Diedrich, Jolene K., Yates, III, John R., and Noel, Joseph P. Mechanism-Based Post-Translational Modification and Inactivation in Terpene Synthases. United States: N. p., 2015.
Web. doi:10.1021/acschembio.5b00539.
Kersten, Roland D., Diedrich, Jolene K., Yates, III, John R., & Noel, Joseph P. Mechanism-Based Post-Translational Modification and Inactivation in Terpene Synthases. United States. https://doi.org/10.1021/acschembio.5b00539
Kersten, Roland D., Diedrich, Jolene K., Yates, III, John R., and Noel, Joseph P. Thu .
"Mechanism-Based Post-Translational Modification and Inactivation in Terpene Synthases". United States. https://doi.org/10.1021/acschembio.5b00539.
@article{osti_1221692,
title = {Mechanism-Based Post-Translational Modification and Inactivation in Terpene Synthases},
author = {Kersten, Roland D. and Diedrich, Jolene K. and Yates, III, John R. and Noel, Joseph P.},
abstractNote = {Terpenes are ubiquitous natural chemicals with diverse biological functions spanning all three domains of life. In specialized metabolism, the active sites of terpene synthases (TPSs) evolve in shape and reactivity to direct the biosynthesis of a myriad of chemotypes for organismal fitness. As most terpene biosynthesis mechanistically involves highly reactive carbocationic intermediates, the protein surfaces catalyzing these cascade reactions possess reactive regions possibly prone to premature carbocation capture and potentially enzyme inactivation. Here, we show using proteomic and X-ray crystallographic analyses that cationic intermediates undergo capture by conserved active site residues leading to inhibitory self-alkylation. Furthermore, the level of cation-mediated inactivation increases with mutation of the active site, upon changes in the size and structure of isoprenoid diphosphate substrates, and alongside increases in reaction temperatures. TPSs that individually synthesize multiple products are less prone to self-alkylation then TPSs possessing relatively high product specificity. In total, the results presented suggest that mechanism-based alkylation represents an overlooked mechanistic pressure during the evolution of cation-derived terpene biosynthesis.},
doi = {10.1021/acschembio.5b00539},
journal = {ACS Chemical Biology},
number = 11,
volume = 10,
place = {United States},
year = {Thu Sep 17 00:00:00 EDT 2015},
month = {Thu Sep 17 00:00:00 EDT 2015}
}
https://doi.org/10.1021/acschembio.5b00539
Web of Science
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