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Mechanistic analysis for the origin of diverse diterpenes in Tripterygium wilfordii

Lichan Tu,  Xinbo Cai,  Yifeng Zhang,  Yuru Tong,  Jian Wang,  Ping Su,  Yun Lu,  Tianyuan Hu,  Yunfeng Luo,  Xiaoyi Wu,  Dan Li,  Luqi Huang,  Wei Gao

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Lichan Tu, Xinbo Cai, Yifeng Zhang, Yuru Tong, Jian Wang, Ping Su, Yun Lu, Tianyuan Hu, Yunfeng Luo, Xiaoyi Wu, Dan Li, Luqi Huang, Wei Gao. Mechanistic analysis for the origin of diverse diterpenes in Tripterygium wilfordii[J]. 机械工程学报. doi: 10.1016/j.apsb.2022.02.013
引用本文: Lichan Tu, Xinbo Cai, Yifeng Zhang, Yuru Tong, Jian Wang, Ping Su, Yun Lu, Tianyuan Hu, Yunfeng Luo, Xiaoyi Wu, Dan Li, Luqi Huang, Wei Gao. Mechanistic analysis for the origin of diverse diterpenes in Tripterygium wilfordii[J]. 机械工程学报. doi: 10.1016/j.apsb.2022.02.013
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Lichan Tu, Xinbo Cai, Yifeng Zhang, Yuru Tong, Jian Wang, Ping Su, Yun Lu, Tianyuan Hu, Yunfeng Luo, Xiaoyi Wu, Dan Li, Luqi Huang, Wei Gao. Mechanistic analysis for the origin of diverse diterpenes in Tripterygium wilfordii[J]. JOURNAL OF MECHANICAL ENGINEERING. doi: 10.1016/j.apsb.2022.02.013
Citation: Lichan Tu, Xinbo Cai, Yifeng Zhang, Yuru Tong, Jian Wang, Ping Su, Yun Lu, Tianyuan Hu, Yunfeng Luo, Xiaoyi Wu, Dan Li, Luqi Huang, Wei Gao. Mechanistic analysis for the origin of diverse diterpenes in Tripterygium wilfordii[J]. JOURNAL OF MECHANICAL ENGINEERING. doi: 10.1016/j.apsb.2022.02.013
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Mechanistic analysis for the origin of diverse diterpenes in Tripterygium wilfordii

doi: 10.1016/j.apsb.2022.02.013

  • a. Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China;

  • b. School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China;

  • c. School of Medicine, Zhejiang University City College, Hangzhou 310015, China;

  • d. School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China;

  • e. State Key Laboratory Breeding Base of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China;

  • f. Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA;

  • g. School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China

基金项目: 

We thank Yuhe Tu (Datian Taoyuan State Forest Farm in Fujian Province, Datian, China) and Sanbo Liu (China Resources Sanjiu (Huangshi) Pharmaceutical Co., Ltd. in Hubei province, Huangshi, China) for providing plant material of T. wilfordii. This work was supported by the National Key R&

D Program of China (No.2020YFA0908000), the Key Project at central government level: The ability establishment of sustainable use for valuable Chinese medicine resources (No.2060302-1806-03), and Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-D-202005).

详细信息
    通讯作者:

    Wei Gao,E-mail:weigao@ccmu.edu.cn

  • 中图分类号: https://www.sciencedirect.com/science/article/pii/S2211383522000697/pdf?md5=ebf4cf5167ad52bbd30f27d7e7ba4483&pid=1-s2.0-S2211383522000697-main.pdf

Mechanistic analysis for the origin of diverse diterpenes in Tripterygium wilfordii

  • a. Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China;

  • b. School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China;

  • c. School of Medicine, Zhejiang University City College, Hangzhou 310015, China;

  • d. School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China;

  • e. State Key Laboratory Breeding Base of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China;

  • f. Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA;

  • g. School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China

Funds: 

We thank Yuhe Tu (Datian Taoyuan State Forest Farm in Fujian Province, Datian, China) and Sanbo Liu (China Resources Sanjiu (Huangshi) Pharmaceutical Co., Ltd. in Hubei province, Huangshi, China) for providing plant material of T. wilfordii. This work was supported by the National Key R&

D Program of China (No.2020YFA0908000), the Key Project at central government level: The ability establishment of sustainable use for valuable Chinese medicine resources (No.2060302-1806-03), and Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-D-202005).

    摘要
  • 摘要: Tripterygium wilfordii is a valuable medicinal plant rich in biologically active diterpenoids, but there are few studies on the origins of these diterpenoids in its secondary metabolism. Here, we identified three regions containing tandemly duplicated diterpene synthase genes on chromosomes (Chr) 17 and 21 of T. wilfordii and obtained 11 diterpene synthases with different functions. We further revealed that these diterpene synthases underwent duplication and rearrangement at approximately 2.3–23.7 million years ago (MYA) by whole-genome triplication (WGT), transposon mediation, and tandem duplication, followed by functional divergence. We first demonstrated that four key amino acids in the sequences of TwCPS3, TwCPS5, and TwCPS6 were altered during evolution, leading to their functional divergence and the formation of diterpene secondary metabolites. Then, we demonstrated that the functional divergence of three TwKSLs was driven by mutations in two key amino acids. Finally, we discovered the mechanisms of evolution and pseudogenization of miltiradiene synthases in T. wilfordii and elucidated that the new function in TwMS1/2 from the terpene synthase (TPS)-b subfamily was caused by progressive changes in multiple amino acids after the WGT event. Our results provide key evidence for the formation of diverse diterpenoids during the evolution of secondary metabolites in T. wilfordii.

     

    Abstract: Tripterygium wilfordii is a valuable medicinal plant rich in biologically active diterpenoids, but there are few studies on the origins of these diterpenoids in its secondary metabolism. Here, we identified three regions containing tandemly duplicated diterpene synthase genes on chromosomes (Chr) 17 and 21 of T. wilfordii and obtained 11 diterpene synthases with different functions. We further revealed that these diterpene synthases underwent duplication and rearrangement at approximately 2.3–23.7 million years ago (MYA) by whole-genome triplication (WGT), transposon mediation, and tandem duplication, followed by functional divergence. We first demonstrated that four key amino acids in the sequences of TwCPS3, TwCPS5, and TwCPS6 were altered during evolution, leading to their functional divergence and the formation of diterpene secondary metabolites. Then, we demonstrated that the functional divergence of three TwKSLs was driven by mutations in two key amino acids. Finally, we discovered the mechanisms of evolution and pseudogenization of miltiradiene synthases in T. wilfordii and elucidated that the new function in TwMS1/2 from the terpene synthase (TPS)-b subfamily was caused by progressive changes in multiple amino acids after the WGT event. Our results provide key evidence for the formation of diverse diterpenoids during the evolution of secondary metabolites in T. wilfordii.

     

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    • 参考文献(54)
  • [1] Upadhyay A. Natural compounds in the regulation of proteostatic pathways:an invincible artillery against stress, ageing, and diseases. Acta Pharm Sin B 2021; 11:2995-3014
    [2] Corson TW, Crews CM. Molecular understanding and modern application of traditional medicines:triumphs and trials. Cell 2007; 130:769-774
    [3] Tang G, Li S, Zhang C, Chen H, Wang N, Feng Y. Clinical efficacies, underlying mechanisms and molecular targets of Chinese medicines for diabetic nephropathy treatment and management. Acta Pharm Sin B 2021; 11:2749-2767
    [4] Zhou ZL, Yang YX, Ding J, Li YC, Miao ZH. Triptolide:structural modifications, structure-activity relationships, bioactivities, clinical development and mechanisms. Nat Prod Rep 2012; 29:457-475
    [5] Gao J, Zhang Y, Liu X, Wu X, Huang L, Gao W. Triptolide:pharmacological spectrum, biosynthesis, chemical synthesis and derivatives. Theranostics 2021; 11:7199-7221
    [6] Titov DV, Gilman B, He QL, Bhat S, Low WK, Dang Y, et al. XPB, a subunit of TFIIH, is a target of the natural product triptolide. Nat Chem Biol 2011; 7:182-188
    [7] Chen R, Huang L, Hu K. Natural products remodel cancer-associated fibroblasts in desmoplastic tumors. Acta Pharm Sin B 2020; 10:2140-2155
    [8] Chang Z, Qin W, Zheng H, Schegg K, Han L, Liu X, et al. Triptonide is a reversible non-hormonal male contraceptive agent in mice and non-human primates. Nat Commun 2021; 12:1253
    [9] Chen K, Shi QA, Fujioka T, Zhang DC, Hu CQ, Jin JQ, et al. Anti-AIDS agents, 4. Tripterifordin, a novel anti-HIV principle from Tripterygium wilfordii:isolation and structural elucidation. J Nat Prod 1992; 55:88-92
    [10] Park NH, Kang YG, Kim SH, Bae IH, Lee SH, Kim DY, et al. Dehydroabietic acid induces regeneration of collagen fibers in ultraviolet B-irradiated human dermal fibroblasts and skin equivalents. Skin Pharmacol Physiol 2019; 32:109-116
    [11] Kim E, Kang YG, Kim YJ, Lee TR, Yoo BC, Jo M, et al. Dehydroabietic acid suppresses inflammatory response via suppression of Src-, Syk-, and TAK1-mediated pathways. Int J Mol Sci 2019; 20:1953
    [12] Hansen NL, Heskes AM, Hamberger B, Olsen CE, Hallstrom BM, Andersen-Ranberg J, et al. The terpene synthase gene family in Tripterygium wilfordii harbors a labdane-type diterpene synthase among the monoterpene synthase TPS-b subfamily. Plant J 2017; 89:429-441
    [13] Su P, Guan H, Zhao Y, Tong Y, Xu M, Zhang Y, et al. Identification and functional characterization of diterpene synthases for triptolide biosynthesis from Tripterygium wilfordii. Plant J 2018; 93:50-65
    [14] Jin B, Guo J, Tang J, Tong Y, Ma Y, Chen T, et al. An alternative splicing alters the product outcome of a class I terpene synthase in Isodon rubescens. Biochem Biophys Res Commun 2019; 512:310-313
    [15] Pateraki I, Andersen-Ranberg J, Hamberger B, Heskes AM, Martens HJ, Zerbe P, et al. Manoyl oxide (13R), the biosynthetic precursor of forskolin, is synthesized in specialized root cork cells in Coleus forskohlii. Plant Physiol 2014; 164:1222-1236
    [16] Cui G, Duan L, Jin B, Qian J, Xue Z, Shen G, et al. Functional divergence of diterpene syntheses in the medicinal plant Salvia miltiorrhiza. Plant Physiol 2015; 169:1607-1618
    [17] Jin B, Cui G, Guo J, Tang J, Duan L, Lin H, et al. Functional diversification of kaurene synthase-like genes in Isodon rubescens. Plant Physiol 2017; 174:943-955
    [18] Chen R, Bu Y, Ren J, Pelot KA, Hu X, Diao Y, et al. Discovery and modulation of diterpenoid metabolism improves glandular trichome formation, artemisinin production and stress resilience in Artemisia annua. New Phytol 2021; 230:2387-2403
    [19] Zerbe P, Chiang A, Dullat H, O'Neil-Johnson M, Starks C, Hamberger B, et al. Diterpene synthases of the biosynthetic system of medicinally active diterpenoids in Marrubium vulgare. Plant J 2014; 79:914-927
    [20] Inabuy FS, Fischedick JT, Lange I, Hartmann M, Srividya N, Parrish AN, et al. Biosynthesis of diterpenoids in Tripterygium adventitious root cultures. Plant Physiol 2017; 175:92-103
    [21] Andersen-Ranberg J, Kongstad KT, Nielsen MT, Jensen NB, Pateraki I, Bach SS, et al. Expanding the landscape of diterpene structural diversity through stereochemically controlled combinatorial biosynthesis. Angew Chem Int Ed Engl 2016; 55:2142c6
    [22] Carrington Y, Guo J, Le CH, Fillo A, Kwon J, Tran LT, et al. Evolution of a secondary metabolic pathway from primary metabolism:shikimate and quinate biosynthesis in plants. Plant J 2018; 95:823-833
    [23] Xu M, Wilderman PR, Peters RJ. Following evolution's lead to a single residue switch for diterpene synthase product outcome. Proc Natl Acad Sci U S A 2007; 104:7397-7401
    [24] Zerbe P, Chiang A, Bohlmann J. Mutational analysis of white spruce (Picea glauca) ent-kaurene synthase (PgKS) reveals common and distinct mechanisms of conifer diterpene synthases of general and specialized metabolism. Phytochemistry 2012; 74:30-39
    [25] Potter KC, Zi J, Hong YJ, Schulte S, Malchow B, Tantillo DJ, et al. Blocking deprotonation with retention of aromaticity in a plant ent-copalyl diphosphate synthase leads to product rearrangement. Angew Chem Int Ed Engl 2016; 55:634-638
    [26] Potter K, Criswell J, Zi J, Stubbs A, Peters RJ. Novel product chemistry from mechanistic analysis of ent-copalyl diphosphate synthases from plant hormone biosynthesis. Angew Chem Int Ed Engl 2014; 53:7198-7202
    [27] Jia M, Zhou K, Tufts S, Schulte S, Peters RJ. A pair of residues that interactively affect diterpene synthase product outcome. ACS Chem Biol 2017; 12:862-867
    [28] Christianson DW. Structural and chemical biology of terpenoid cyclases. Chem Rev 2017; 117:11570-11648
    [29] Tu L, Su P, Zhang Z, Gao L, Wang J, Hu T, et al. Genome of Tripterygium wilfordii and identification of cytochrome P450 involved in triptolide biosynthesis. Nat Commun 2020; 11:971
    [30] A HT. BioEdit:a user-friendly biological sequence alignment editor and analysis program for windows 95/98/NT. Nucleic Acids Symp Ser 1999; 41:95-98
    [31] Wei C, Yang H, Wang S, Zhao J, Liu C, Gao L, et al. Draft genome sequence of Camellia sinensis var. sinensis provides insights into the evolution of the tea genome and tea quality. Proc Natl Acad Sci U S A 2018; 115:E4151-E4158
    [32] Kumar S, Stecher G, Li M, Knyaz C, Tamura K. Mega X:molecular evolutionary genetics analysis across computing platforms. Mol Biol Evol 2018; 35:1547-1549
    [33] Chen C, Chen H, Zhang Y, Thomas HR, Frank MH, He Y, et al. TBtools:an integrative toolkit developed for interactive analyses of big biological data. Mol Plant 2020; 13:1194-1202
    [34] Keeling CI, Dullat HK, Yuen M, Ralph SG, Jancsik S, Bohlmann J. Identification and functional characterization of monofunctional ent-copalyl diphosphate and ent-kaurene synthases in white spruce reveal different patterns for diterpene synthase evolution for primary and secondary metabolism in gymnosperms. Plant Physiol 2010; 152:1197-1208
    [35] Yamaguchi S, Sun T, Kawaide H, Kamiya Y. The GA2 locus of Arabidopsis thaliana encodes ent-kaurene synthase of gibberellin biosynthesis. Plant Physiol 1998; 116:1271-1278
    [36] Yang J, Zhang Y. I-TASSER server:new development for protein structure and function predictions. Nucleic Acids Res 2015; 43:W174-W181
    [37] Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4:automated docking with selective receptor flexibility. J Comput Chem 2009; 30:2785-2791
    [38] Qiao X, Li Q, Yin H, Qi K, Li L, Wang R, et al. Gene duplication and evolution in recurring polyploidization-diploidization cycles in plants. Genome Biol 2019; 20:38
    [39] Irmisch S, Muller AT, Schmidt L, Gunther J, Gershenzon J, Kollner TG. One amino acid makes the difference:the formation of ent-kaurene and 16α-hydroxy-ent-kaurane by diterpene synthases in poplar. BMC Plant Biol 2015; 15:262
    [40] Hansen NL, Nissen JN, Hamberger B. Two residues determine the product profile of the class II diterpene synthases TPS14 and TPS21 of Tripterygium wilfordii. Phytochemistry 2017; 138:52-56
    [41] Koksal M, Hu H, Coates RM, Peters RJ, Christianson DW. Structure and mechanism of the diterpene cyclase ent-copalyl diphosphate synthase. Nat Chem Biol 2011; 7:431-433
    [42] Koksal M, Potter K, Peters RJ, Christianson DW. 1.55A-resolution structure of ent-copalyl diphosphate synthase and exploration of general acid function by site-directed mutagenesis. Biochim Biophys Acta 2014; 1840:184-190
    [43] Fleet CM, Sun TP. A DELLAcate balance:the role of gibberellin in plant morphogenesis. Curr Opin Plant Biol 2005; 8:77-85
    [44] Yamaguchi S. Gibberellin metabolism and its regulation. Annu Rev Plant Biol 2008; 59:225-251
    [45] Hedden P, Thomas SG. Gibberellin biosynthesis and its regulation. Biochem J 2012; 444:11-25
    [46] Su P, Guan H, Zhang Y, Wang X, Gao L, Zhao Y, et al. Probing the single key amino acid responsible for the novel catalytic function of ent-kaurene oxidase supported by NADPH-cytochrome P450 reductases in Tripterygium wilfordii. Front Plant Sci 2017; 8:1756
    [47] Dougherty DA. Cation-pi interactions in chemistry and biology:a new view of benzene, Phe, Tyr, and Trp. Science 1996; 271:163-168
    [48] Kawaide H, Hayashi K, Kawanabe R, Sakigi Y, Matsuo A, Natsume M, et al. Identification of the single amino acid involved in quenching the ent-kauranyl cation by a water molecule in ent-kaurene synthase of Physcomitrella patens. FEBS J 2011; 278:123-133
    [49] Bozic D, Papaefthimiou D, Bruckner K, de Vos RC, Tsoleridis CA, Katsarou D, et al. Towards elucidating carnosic acid biosynthesis in Lamiaceae:functional characterization of the three first steps of the pathway in Salvia fruticosa and Rosmarinus officinalis. PLoS One 2015; 10:e0124106
    [50] Bruckner K, Bozic D, Manzano D, Papaefthimiou D, Pateraki I, Scheler U, et al. Characterization of two genes for the biosynthesis of abietane-type diterpenes in rosemary (Rosmarinus officinalis) glandular trichomes. Phytochemistry 2014; 101:52-64
    [51] Gao W, Hillwig ML, Huang L, Cui GH, Wang XY, Kong JQ, et al. A functional genomics approach to tanshinone biosynthesis provides stereochemical insights. Org Lett 2009; 11:5170-5173
    [52] Hu T, Zhou J, Tong Y, Su P, Li X, Liu Y, et al. Engineering chimeric diterpene synthases and isoprenoid biosynthetic pathways enables high-level production of miltiradiene in yeast. Metab Eng 2020; 60:87-96
    [53] Zhou YJ, Gao W, Rong Q, Jin G, Chu H, Liu W, et al. Modular pathway engineering of diterpenoid synthases and the mevalonic acid pathway for miltiradiene production. J Am Chem Soc 2012; 134:3234-3241
    [54] Jia M, O'Brien TE, Zhang Y, Siegel JB, Tantillo DJ, Peters RJ. Changing face:a key residue for the addition of water by sclareol synthase. ACS Catal 2018; 8:3133-3137
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  • 收稿日期:  2021-10-20
  • 修回日期:  2022-01-24
  • 录用日期:  2022-02-05
  • 网络出版日期:  2023-03-17

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