DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: The terpene synthase gene family in Tripterygium wilfordii harbors a labdane-type diterpene synthase among the monoterpene synthase TPS-b subfamily

Abstract

We present Tripterygium wilfordii (Celastraceae) is a medicinal plant with anti-inflammatory and immunosuppressive properties. Identification of a vast array of unusual sesquiterpenoids, diterpenoids and triterpenoids in T. wilfordii has spurred investigations of their pharmacological properties. The tri-epoxide lactone triptolide was the first of many diterpenoids identified, attracting interest due to the spectrum of bioactivities. To probe the genetic underpinning of diterpenoid diversity, an expansion of the class II diterpene synthase (diTPS) family was recently identified in a leaf transcriptome. Following detection of triptolide and simple diterpene scaffolds in the root, we sequenced and mined the root transcriptome. This allowed identification of the root-specific complement of TPSs and an expansion in the class I diTPS family. Functional characterization of the class II diTPSs established their activities in the formation of four C-20 diphosphate intermediates, precursors of both generalized and specialized metabolism and a novel scaffold for Celastraceae. Functional pairs of the class I and II enzymes resulted in formation of three scaffolds, accounting for some of the terpenoid diversity found in T. wilfordii. The absence of activity-forming abietane-type diterpenes encouraged further testing of TPSs outside the canonical class I diTPS family. TwTPS27, close relative of mono-TPSs, was found to couple withmore » TwTPS9, converting normal-copalyl diphosphate to miltiradiene. The phylogenetic distance to established diTPSs indicates neo-functionalization of TwTPS27 into a diTPS, a function not previously observed in the TPS-b subfamily. Finally, this example of evolutionary convergence expands the functionality of TPSs in the TPS-b family and may contribute miltiradiene to the diterpenoids of T. wilfordii.« less

Authors:
 [1];  [1];  [1];  [2];  [3];  [1]; ORCiD logo [1]
  1. Univ. of Copenhagen (Denmark). Plant Biochemistry Laboratory, Department of Plant and Environmental Sciences; Center for Synthetic Biology 'bioSYNergy' and Copenhagen Plant Sciences Centre, Copenhagen (Denmark)
  2. Univ. of Copenhagen (Denmark). Plant Biochemistry Laboratory, Department of Plant and Environmental Sciences
  3. Royal Institute of Technology, Stockholm (Sweden). Science for Life Laboratory, Kungliga Tekniska Högskolan
Publication Date:
Research Org.:
Univ. of Wisconsin, Madison, WI (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER)
OSTI Identifier:
1427678
Grant/Contract Number:  
FC02-07ER64494
Resource Type:
Accepted Manuscript
Journal Name:
The Plant Journal
Additional Journal Information:
Journal Volume: 89; Journal Issue: 3; Journal ID: ISSN 0960-7412
Publisher:
Society for Experimental Biology
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Tripterygium wilfordii; terpene synthase; specialized metabolism; convergent evolution; bioactive diterpenoids

Citation Formats

Hansen, Nikolaj L., Heskes, Allison M., Hamberger, Britta, Olsen, Carl E., Hallstrom, Bjorn M., Andersen-Ranberg, Johan, and Hamberger, Bjorn. The terpene synthase gene family in Tripterygium wilfordii harbors a labdane-type diterpene synthase among the monoterpene synthase TPS-b subfamily. United States: N. p., 2016. Web. doi:10.1111/tpj.13410.
Hansen, Nikolaj L., Heskes, Allison M., Hamberger, Britta, Olsen, Carl E., Hallstrom, Bjorn M., Andersen-Ranberg, Johan, & Hamberger, Bjorn. The terpene synthase gene family in Tripterygium wilfordii harbors a labdane-type diterpene synthase among the monoterpene synthase TPS-b subfamily. United States. https://doi.org/10.1111/tpj.13410
Hansen, Nikolaj L., Heskes, Allison M., Hamberger, Britta, Olsen, Carl E., Hallstrom, Bjorn M., Andersen-Ranberg, Johan, and Hamberger, Bjorn. Tue . "The terpene synthase gene family in Tripterygium wilfordii harbors a labdane-type diterpene synthase among the monoterpene synthase TPS-b subfamily". United States. https://doi.org/10.1111/tpj.13410. https://www.osti.gov/servlets/purl/1427678.
@article{osti_1427678,
title = {The terpene synthase gene family in Tripterygium wilfordii harbors a labdane-type diterpene synthase among the monoterpene synthase TPS-b subfamily},
author = {Hansen, Nikolaj L. and Heskes, Allison M. and Hamberger, Britta and Olsen, Carl E. and Hallstrom, Bjorn M. and Andersen-Ranberg, Johan and Hamberger, Bjorn},
abstractNote = {We present Tripterygium wilfordii (Celastraceae) is a medicinal plant with anti-inflammatory and immunosuppressive properties. Identification of a vast array of unusual sesquiterpenoids, diterpenoids and triterpenoids in T. wilfordii has spurred investigations of their pharmacological properties. The tri-epoxide lactone triptolide was the first of many diterpenoids identified, attracting interest due to the spectrum of bioactivities. To probe the genetic underpinning of diterpenoid diversity, an expansion of the class II diterpene synthase (diTPS) family was recently identified in a leaf transcriptome. Following detection of triptolide and simple diterpene scaffolds in the root, we sequenced and mined the root transcriptome. This allowed identification of the root-specific complement of TPSs and an expansion in the class I diTPS family. Functional characterization of the class II diTPSs established their activities in the formation of four C-20 diphosphate intermediates, precursors of both generalized and specialized metabolism and a novel scaffold for Celastraceae. Functional pairs of the class I and II enzymes resulted in formation of three scaffolds, accounting for some of the terpenoid diversity found in T. wilfordii. The absence of activity-forming abietane-type diterpenes encouraged further testing of TPSs outside the canonical class I diTPS family. TwTPS27, close relative of mono-TPSs, was found to couple with TwTPS9, converting normal-copalyl diphosphate to miltiradiene. The phylogenetic distance to established diTPSs indicates neo-functionalization of TwTPS27 into a diTPS, a function not previously observed in the TPS-b subfamily. Finally, this example of evolutionary convergence expands the functionality of TPSs in the TPS-b family and may contribute miltiradiene to the diterpenoids of T. wilfordii.},
doi = {10.1111/tpj.13410},
journal = {The Plant Journal},
number = 3,
volume = 89,
place = {United States},
year = {Tue Nov 01 00:00:00 EDT 2016},
month = {Tue Nov 01 00:00:00 EDT 2016}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 53 works
Citation information provided by
Web of Science

Figures / Tables:

Figure 1 Figure 1: Six distinct diterpene scaffolds of Tripterygium wilfordii. Their shared decalin core appears in bold.

Save / Share:

Works referenced in this record:

A Preclinical Evaluation of Minnelide as a Therapeutic Agent Against Pancreatic Cancer
journal, October 2012


Codon-Substitution Models for Detecting Molecular Adaptation at Individual Sites Along Specific Lineages
journal, June 2002


Identification of a New Diterpene Biosynthetic Gene Cluster that Produces O -Methylkolavelool in Herpetosiphon aurantiacus
journal, February 2015


Plant diterpene synthases: exploring modularity and metabolic diversity for bioengineering
journal, July 2015


Immunosuppressive Diterpenoids from Tripterygium wilfordii
journal, November 1999

  • Duan, Hongquan; Takaishi, Yoshihisa; Momota, Hiroshi
  • Journal of Natural Products, Vol. 62, Issue 11
  • DOI: 10.1021/np9902183

Probing the Role of the DXDD Motif in Class II Diterpene Cyclases
journal, May 2007


Plant terpenoid synthases: Molecular biology and phylogenetic analysis
journal, April 1998

  • Bohlmann, J.; Meyer-Gauen, G.; Croteau, R.
  • Proceedings of the National Academy of Sciences, Vol. 95, Issue 8
  • DOI: 10.1073/pnas.95.8.4126

The Maize An2 Gene is Induced by Fusarium Attack and Encodes an ent-Copalyl Diphosphate Synthase
journal, December 2005


Identification and functional analysis of bifunctional ent -kaurene synthase from the moss Physcomitrella patens
journal, October 2006


Manoyl Oxide (13R), the Biosynthetic Precursor of Forskolin, Is Synthesized in Specialized Root Cork Cells in Coleus forskohlii
journal, January 2014

  • Pateraki, Irini; Andersen-Ranberg, Johan; Hamberger, Britta
  • Plant Physiology, Vol. 164, Issue 3
  • DOI: 10.1104/pp.113.228429

Additional diterpenes from Physcomitrella patens synthesized by copalyl diphosphate/kaurene synthase ( Pp CPS/KS)
journal, November 2015


Total Synthesis of Celastrol, Development of a Platform to Access Celastroid Natural Products
journal, September 2015

  • Camelio, Andrew M.; Johnson, Trevor C.; Siegel, Dionicio
  • Journal of the American Chemical Society, Vol. 137, Issue 37
  • DOI: 10.1021/jacs.5b06261

Structure and mechanism of the diterpene cyclase ent-copalyl diphosphate synthase
journal, May 2011

  • Köksal, Mustafa; Hu, Huayou; Coates, Robert M.
  • Nature Chemical Biology, Vol. 7, Issue 7
  • DOI: 10.1038/nchembio.578

Optimization of Biochemical Screening Methods for Volatile and Unstable Sesquiterpenoids Using HS-SPME-GC-MS
journal, June 2015


Expanding the Landscape of Diterpene Structural Diversity through Stereochemically Controlled Combinatorial Biosynthesis
journal, January 2016

  • Andersen-Ranberg, Johan; Kongstad, Kenneth Thermann; Nielsen, Morten Thrane
  • Angewandte Chemie International Edition, Vol. 55, Issue 6
  • DOI: 10.1002/anie.201510650

Efficient heterocyclisation by (di)terpene synthases
journal, January 2015

  • Mafu, S.; Potter, K. C.; Hillwig, M. L.
  • Chemical Communications, Vol. 51, Issue 70
  • DOI: 10.1039/C5CC05754J

Isoprene Synthase Genes form a Monophyletic Clade of Acyclic Terpene Synthases in the Tps-B Terpene Synthase Family: Isoprene Synthase Evolution
journal, December 2012

  • Sharkey, Thomas D.; Gray, Dennis W.; Pell, Heather K.
  • Evolution, Vol. 67, Issue 4
  • DOI: 10.1111/evo.12013

Terpenoid synthase structures: a so far incomplete view of complex catalysis
journal, January 2012

  • Gao, Yang; Honzatko, Richard B.; Peters, Reuben J.
  • Natural Product Reports, Vol. 29, Issue 10
  • DOI: 10.1039/c2np20059g

Terpenoids from Tripterygium wilfordii var. regelii
journal, July 1997


High-level semi-synthetic production of the potent antimalarial artemisinin
journal, April 2013

  • Paddon, C. J.; Westfall, P. J.; Pitera, D. J.
  • Nature, Vol. 496, Issue 7446
  • DOI: 10.1038/nature12051

Tumor inhibitors. LXXIV. Triptolide and tripdiolide, novel antileukemic diterpenoid triepoxides from Tripterygium wilfordii
journal, October 1972

  • Kupchan, S. Morris; Court, William A.; Dailey, Richard G.
  • Journal of the American Chemical Society, Vol. 94, Issue 20
  • DOI: 10.1021/ja00775a078

Functional analysis of (4 S )-limonene synthase mutants reveals determinants of catalytic outcome in a model monoterpene synthase
journal, March 2015

  • Srividya, Narayanan; Davis, Edward M.; Croteau, Rodney B.
  • Proceedings of the National Academy of Sciences, Vol. 112, Issue 11
  • DOI: 10.1073/pnas.1501203112

WebLogo: A Sequence Logo Generator
journal, May 2004

  • Crooks, Gavin E.; Hon, Gary; Chandonia, John-Marc
  • Genome Research, Vol. 14, Issue 6, p. 1188-1190
  • DOI: 10.1101/gr.849004

Cytotoxic diterpenes triptolide, tripdiolide, and cytotoxic triterpenes from tissue cultures of Tripterygium wilfordii
journal, September 1981

  • Kutney, James P.; Hewitt, Gary M.; Kurihara, Toshio
  • Canadian Journal of Chemistry, Vol. 59, Issue 17
  • DOI: 10.1139/v81-385

Efficacy and Safety of Tripterygium wilfordii Hook F Versus Acitretin in Moderate to Severe Psoriasis Vulgaris: A Randomized Clinical Trial
journal, January 2015


Cloning of casbene synthase cDNA: evidence for conserved structural features among terpenoid cyclases in plants.
journal, August 1994

  • Mau, C. J.; West, C. A.
  • Proceedings of the National Academy of Sciences, Vol. 91, Issue 18
  • DOI: 10.1073/pnas.91.18.8497

Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae)
journal, March 2007


Triptolide: Progress on research in pharmacodynamics and toxicology
journal, August 2014

  • Li, Xiao-Jiaoyang; Jiang, Zhen-Zhou; Zhang, Lu-yong
  • Journal of Ethnopharmacology, Vol. 155, Issue 1
  • DOI: 10.1016/j.jep.2014.06.006

Evaluation of an Improved Branch-Site Likelihood Method for Detecting Positive Selection at the Molecular Level
journal, August 2005


Two rings in them all: The labdane-related diterpenoids
journal, January 2010


Gene Discovery of Modular Diterpene Metabolism in Nonmodel Systems
journal, April 2013

  • Zerbe, Philipp; Hamberger, Björn; Yuen, Macaire M. S.
  • Plant Physiology, Vol. 162, Issue 2
  • DOI: 10.1104/pp.113.218347

Immunosuppressive terpenoids from extracts of Tripterygium wilfordii
journal, October 2001


Studies with plant-cell cultures of the Chinese herbal plant, Tripterygium wilfordii. Isolation and characterization of diterpenes
journal, January 1996

  • Kutney, James P.; Han, Kang
  • Recueil des Travaux Chimiques des Pays-Bas, Vol. 115, Issue 1
  • DOI: 10.1002/recl.19961150115

PAML 4: Phylogenetic Analysis by Maximum Likelihood
journal, April 2007


To Gibberellins and Beyond! Surveying the Evolution of (Di)Terpenoid Metabolism
journal, April 2014


Characterization of CYP76AH4 clarifies phenolic diterpenoid biosynthesis in the Lamiaceae
journal, January 2013

  • Zi, Jiachen; Peters, Reuben J.
  • Organic & Biomolecular Chemistry, Vol. 11, Issue 44
  • DOI: 10.1039/c3ob41885e

Tripterygium wilfordii bioactive compounds as anticancer and anti-inflammatory agents: Tripterygium bioactive compounds
journal, February 2012


Molecular cloning and characterization of monoterpene synthases from Litsea cubeba (Lour.) Persoon
journal, March 2011


MEGA6: Molecular Evolutionary Genetics Analysis Version 6.0
journal, October 2013

  • Tamura, Koichiro; Stecher, Glen; Peterson, Daniel
  • Molecular Biology and Evolution, Vol. 30, Issue 12
  • DOI: 10.1093/molbev/mst197

Crystal structure of p19 ? a universal suppressor of RNA silencing
journal, June 2004


Extracts of Tripterygium wilfordii Hook F in the Treatment of Rheumatoid Arthritis: A Systemic Review and Meta-Analysis of Randomised Controlled Trials
journal, January 2013

  • Liu, Yafei; Tu, Shenghao; Gao, Weina
  • Evidence-Based Complementary and Alternative Medicine, Vol. 2013
  • DOI: 10.1155/2013/410793

Expanding the Landscape of Diterpene Structural Diversity through Stereochemically Controlled Combinatorial Biosynthesis
journal, January 2016

  • Andersen-Ranberg, Johan; Kongstad, Kenneth Thermann; Nielsen, Morten Thrane
  • Angewandte Chemie, Vol. 128, Issue 6
  • DOI: 10.1002/ange.201510650

Medicinal Chemistry and Pharmacology of Genus Tripterygium (Celastraceae)
journal, July 2007


Works referencing / citing this record:

Trends in herbgenomics
journal, August 2018


Promiscuous terpene synthases from Prunella vulgaris highlight the importance of substrate and compartment switching in terpene synthase evolution
journal, April 2019

  • Johnson, Sean R.; Bhat, Wajid Waheed; Sadre, Radin
  • New Phytologist, Vol. 223, Issue 1
  • DOI: 10.1111/nph.15778

The expression of TwDXS in the MEP pathway specifically affects the accumulation of triptolide
journal, December 2019

  • Zhang, Yifeng; Zhao, Yujun; Wang, Jiadian
  • Physiologia Plantarum, Vol. 169, Issue 1
  • DOI: 10.1111/ppl.13051

Identification and functional characterization of diterpene synthases for triptolide biosynthesis from Tripterygium wilfordii
journal, December 2017

  • Su, Ping; Guan, Hongyu; Zhao, Yujun
  • The Plant Journal, Vol. 93, Issue 1
  • DOI: 10.1111/tpj.13756

Nerylneryl diphosphate is the precursor of serrulatane, viscidane and cembrane-type diterpenoids in Eremophila species
journal, February 2020

  • Gericke, Oliver; Hansen, Nikolaj Lervad; Pedersen, Gustav Blichfeldt
  • BMC Plant Biology, Vol. 20, Issue 1
  • DOI: 10.1186/s12870-020-2293-x

Integrating pathway elucidation with yeast engineering to produce polpunonic acid the precursor of the anti-obesity agent celastrol
journal, January 2020


Genome of Tripterygium wilfordii and identification of cytochrome P450 involved in triptolide biosynthesis
journal, February 2020


Promiscuous terpene synthases from Prunella vulgaris highlight the importance of substrate and compartment switching in terpene synthase evolution
journal, April 2019

  • Johnson, Sean R.; Bhat, Wajid Waheed; Sadre, Radin
  • New Phytologist, Vol. 223, Issue 1
  • DOI: 10.1111/nph.15778

Nerylneryl diphosphate is the precursor of serrulatane, viscidane and cembrane-type diterpenoids in Eremophila species
journal, February 2020

  • Gericke, Oliver; Hansen, Nikolaj Lervad; Pedersen, Gustav Blichfeldt
  • BMC Plant Biology, Vol. 20, Issue 1
  • DOI: 10.1186/s12870-020-2293-x

Integrating pathway elucidation with yeast engineering to produce polpunonic acid the precursor of the anti-obesity agent celastrol
journal, January 2020


Terpene Synthases as Metabolic Gatekeepers in the Evolution of Plant Terpenoid Chemical Diversity
journal, October 2019


Production of Putative Diterpene Carboxylic Acid Intermediates of Triptolide in Yeast
journal, June 2017