Diverse triterpene skeletons are derived from the expansion and divergent evolution of 2,3-oxidosqualene cyclases in plants

References

• Abe I. 2007. Enzymatic synthesis of cyclic triterpenes. Nat Prod Rep. 24(6):1311–1331.
   PubMed Web of Science ®Google Scholar
• Ajikumar PK, Xiao WH, Tyo KE, Wang Y, Simeon F, Leonard E, Mucha O, Phon TH, Pfeifer B, Stephanopoulos G. 2010. Isoprenoid pathway optimization for Taxol precursor overproduction in Escherichia coli. Science. 330(6000):70–74.
   PubMed Web of Science ®Google Scholar
• Akihisa T, Arai K, Kimura Y, Koike K, Kokke W, Shibata T, Nikaido T. 1999. Camelliols A-C, three novel incompletely cyclized triterpene alcohols from sasanqua oil (Camellia sasanqua). J Nat Prod. 62(2):265–268.
   PubMed Web of Science ®Google Scholar
• Alves TB, Souza-Moreira TM, Valentini SR, Zanelli CF, Furlan M. 2018. Friedelin in Maytenus ilicifolia is produced by friedelin synthase isoforms. Molecules. 23(3):700.
   PubMed Web of Science ®Google Scholar
• Andre CM, Legay S, Deleruelle A, Nieuwenhuizen N, Punter M, Brendolise C, Cooney JM, Lateur M, Hausman JF, Larondelle Y, et al. 2016. Multifunctional oxidosqualene cyclases and cytochrome P450 involved in the biosynthesis of apple fruit triterpenic acids. New Phytol. 211(4):1279–1294.
   PubMed Web of Science ®Google Scholar
• Anthonsen T, Bruun T, Hemmer E, Holme D, Lamvik A, Sunde E, Sørensen NA. 1970. Baccharis Oxide, a new Triterpenoid from Baccharis halimifolia L. Acta Chem Scand. 24(7):2479–2488.
   Google Scholar
• Augustin JM, Kuzina V, Andersen SB, Bak S. 2011. Molecular activities, biosynthesis and evolution of triterpenoid saponins. Phytochemistry. 72(6):435–457.
   PubMed Web of Science ®Google Scholar
• Banta AB, Wei JH, Gill CC, Giner JL, Welander PV. 2017. Synthesis of arborane triterpenols by a bacterial oxidosqualene cyclase. Proc Natl Acad Sci USA. 114(2):245–250.
   PubMed Web of Science ®Google Scholar
• Basyuni M, Oku H, Tsujimoto E, Baba S. 2007. Cloning and functional expression of cycloartenol synthases from mangrove species Rhizophora stylosa Griff. and Kandelia candel (L.) Druce. Biosci Biotechnol Biochem. 71(7):1788–1792.
   PubMed Web of Science ®Google Scholar
• Basyuni M, Oku H, Tsujimoto E, Kinjo K, Baba S, Takara K. 2007. Triterpene synthases from the Okinawan mangrove tribe, Rhizophoraceae. FEBS J. 274(19):5028–5042.
   PubMed Web of Science ®Google Scholar
• Bennett GJ, Harrison LJ, Sia GL, Sim KY. 1993. Triterpenoids, tocotrienols and xanthones from the bark of cratoxylum-cochinchinense. Phytochemistry. 32(5):1245–1251.
   Web of Science ®Google Scholar
• Benveniste P. 2004. Biosynthesis and accumulation of sterols. Annu Rev Plant Biol. 55:429–457.
   PubMed Web of Science ®Google Scholar
• Boar RB, Couchman LA, Jaques AJ, Perkins MJ. 1984. Isolation from Pistacia resins of a bicyclic triterpenoid representing an apparent trapped intermediate of squalene 2,3-epoxide cyclization. J Am Chem Soc. 106(8):2477–2479.
   Web of Science ®Google Scholar
• Brendolise C, Yauk YK, Eberhard ED, Wang M, Chagne D, Andre C, Greenwood DR, Beuning LL. 2011. An unusual plant triterpene synthase with predominant α-amyrin-producing activity identified by characterizing oxidosqualene cyclases from Malus × domestica. FEBS J. 278(14):2485–2499.
   PubMed Web of Science ®Google Scholar
• Broker JN, Muller B, van Deenen N, Prufer D, Schulze Gronover C. 2018. Upregulating the mevalonate pathway and repressing sterol synthesis in Saccharomyces cerevisiae enhances the production of triterpenes. Appl Microbiol Biotechnol. 102(16):6923–6934.
   PubMed Web of Science ®Google Scholar
• Chang CH, Chen YC, Tseng SW, Liu YT, Wen HY, Li WH, Huang CY, Ko CY, Wang TT, Wu TK. 2012. The cysteine 703 to isoleucine or histidine mutation of the oxidosqualene-lanosterol cyclase from Saccharomyces cerevisiae generates an iridal-type triterpenoid. Biochimie. 94(11):2376–2381.
   PubMed Web of Science ®Google Scholar
• Chaturvedi PK, Bhui K, Shukla Y. 2008. Lupeol: connotations for chemoprevention. Cancer Lett. 263(1):1–13.
   PubMed Web of Science ®Google Scholar
• Chen JC, Chiu MH, Nie RL, Cordell GA, Qiu SX. 2005. Cucurbitacins and cucurbitane glycosides: structures and biological activities. Nat Prod Rep. 22(3):386–399.
   PubMed Web of Science ®Google Scholar
• Chen SR, Dai Y, Zhao J, Lin LG, Wang YT, Wang Y. 2018. A mechanistic overview of triptolide and Celastrol, natural products from Tripterygium wilfordii Hook F. Front Pharmacol. 9:104.
   PubMed Web of Science ®Google Scholar
• Corey EJ, Cheng H, Baker CH, Matsuda SPT, Li D, Song X. 1997. Studies on the substrate binding segments and catalytic action of lanosterol synthase. affinity labeling with carbocations derived from mechanism-based analogs of 2,3-oxidosqualene and site-directed mutagenesis probes. J Am Chem Soc. 119(6):1289–1296.
   Web of Science ®Google Scholar
• Corey EJ, Matsuda SP, Bartel B. 1993. Isolation of an Arabidopsis thaliana gene encoding cycloartenol synthase by functional expression in a yeast mutant lacking lanosterol synthase by the use of a chromatographic screen. Proc Natl Acad Sci USA. 90(24):11628–11632.
   PubMed Web of Science ®Google Scholar
• Corey EJ, Matsuda SP, Bartel B. 1994. Molecular cloning, characterization, and overexpression of ERG7, the Saccharomyces cerevisiae gene encoding lanosterol synthase. Proc Natl Acad Sci USA. 91(6):2211–2215.
   PubMed Web of Science ®Google Scholar
• Dai L, Liu C, Zhu Y, Zhang J, Men Y, Zeng Y, Sun Y. 2015. Functional characterization of cucurbitadienol synthase and triterpene glycosyltransferase involved in biosynthesis of mogrosides from Siraitia grosvenorii. Plant Cell Physiol. 56(6):1172–1182.
   PubMed Web of Science ®Google Scholar
• Dai Z, Liu Y, Zhang X, Shi M, Wang B, Wang D, Huang L, Zhang X. 2013. Metabolic engineering of Saccharomyces cerevisiae for production of ginsenosides. Metab Eng. 20:146–156.
   PubMed Web of Science ®Google Scholar
• Dai Z, Wang B, Liu Y, Shi M, Wang D, Zhang X, Liu T, Huang L, Zhang X. 2014. Producing aglycons of ginsenosides in bakers’ yeast. Sci Rep. 4:3698.
   PubMed Web of Science ®Google Scholar
• Davidovich-Rikanati R, Shalev L, Baranes N, Meir A, Itkin M, Cohen S, Zimbler K, Portnoy V, Ebizuka Y, Shibuya M, et al. 2015. Recombinant yeast as a functional tool for understanding bitterness and cucurbitacin biosynthesis in watermelon (Citrullus spp.). Yeast. 32(1):103–114.
   PubMed Web of Science ®Google Scholar
• Dhar N, Rana S, Razdan S, Bhat WW, Hussain A, Dhar RS, Vaishnavi S, Hamid A, Vishwakarma R, Lattoo SK. 2014. Cloning and functional characterization of three branch point oxidosqualene cyclases from Withania somnifera (L.) dunal. J Biol Chem. 289(24):17249–17267.
   PubMed Web of Science ®Google Scholar
• Diao HJ, Chen NH, Wang K, Zhang F, Wang YH, Wu RB. 2020. Biosynthetic mechanism of lanosterol: a completed story. ACS Catal. 10(3):2157–2168.
   Web of Science ®Google Scholar
• Domínguez XA, Quintanilla JAG, Rojas MP. 1974. Sterols and triterpenes from Eupatorium perfoliatum. Phytochemistry. 13(3):673–674.
   Web of Science ®Google Scholar
• Farhi M, Marhevka E, Masci T, Marcos E, Eyal Y, Ovadis M, Abeliovich H, Vainstein A. 2011. Harnessing yeast subcellular compartments for the production of plant terpenoids. Metab Eng. 13(5):474–481. doi:https://doi.org/10.1016/j.ymben.2011.05.001. 21601648
   PubMed Web of Science ®Google Scholar
• Fazio GC, Xu R, Matsuda SP. 2004. Genome mining to identify new plant triterpenoids. J Am Chem Soc. 126(18):5678–5679.
   PubMed Web of Science ®Google Scholar
• Ferreira M, Lobo A, O’ahoney C, Williams D, Wyler H. 1990. Euferol and melliferol: two novel triterpenoids from Euphorbia mellifera. J Chem Soc Perkin Trans. 1(1):185–187.
   Google Scholar
• Forestier E, Romero-Segura C, Pateraki I, Centeno E, Compagnon V, Preiss M, Berna A, Boronat A, Bach TJ, Darnet S, et al. 2019. Distinct triterpene synthases in the laticifers of Euphorbia lathyris. Sci Rep. 9(1):4840.
   PubMedGoogle Scholar
• Fukushima EO, Seki H, Ohyama K, Ono E, Umemoto N, Mizutani M, Saito K, Muranaka T. 2011. CYP716A subfamily members are multifunctional oxidases in triterpenoid biosynthesis. Plant Cell Physiol. 52(12):2050–2061.
   PubMed Web of Science ®Google Scholar
• Gauthier C, Legault J, Piochon-Gauthier M, Pichette A. 2011. Advances in the synthesis and pharmacological activity of lupane-type triterpenoid saponins. Phytochem Rev. 10(4):521–544.
   Web of Science ®Google Scholar
• Godzina SM, Lovato MA, Meyer MM, Foster KA, Wilson WK, Gu W, de Hostos EL, Matsuda SP. 2000. Cloning and characterization of the Dictyostelium discoideum cycloartenol synthase cDNA. Lipids. 35(3):249–255.
   PubMed Web of Science ®Google Scholar
• Guhling O, Hobl B, Yeats T, Jetter R. 2006. Cloning and characterization of a lupeol synthase involved in the synthesis of epicuticular wax crystals on stem and hypocotyl surfaces of Ricinus communis. Arch Biochem Biophys. 448(1–2):60–72.
   PubMed Web of Science ®Google Scholar
• Han JY, Ahn CH, Adhikari PB, Kondeti S, Choi YE. 2019. Functional characterization of an oxidosqualene cyclase (PdFRS) encoding a monofunctional friedelin synthase in Populus davidiana. Planta. 249(1):95–111.
   PubMed Web of Science ®Google Scholar
• Han JY, Chun JH, Oh SA, Park SB, Hwang HS, Lee H, Choi YE. 2018. Transcriptomic analysis of kalopanax septemlobus and characterization of KsBAS, CYP716A94 and CYP72A397 genes involved in hederagenin saponin biosynthesis. Plant Cell Physiol. 59(2):319–330.
   PubMed Web of Science ®Google Scholar
• Haralampidis K, Bryan G, Qi X, Papadopoulou K, Bakht S, Melton R, Osbourn A. 2001. A new class of oxidosqualene cyclases directs synthesis of antimicrobial phytoprotectants in monocots. Proc Natl Acad Sci USA. 98(23):13431–13436.
   PubMed Web of Science ®Google Scholar
• Hayashi H, Huang P, Inoue K, Hiraoka N, Ikeshiro Y, Yazaki K, Tanaka S, Kushiro T, Shibuya M, Ebizuka Y. 2001. Molecular cloning and characterization of isomultiflorenol synthase, a new triterpene synthase from Luffa cylindrica, involved in biosynthesis of bryonolic acid. Eur J Biochem. 268(23):6311–6317.
   PubMedGoogle Scholar
• Hayashi H, Huang P, Kirakosyan A, Inoue K, Hiraoka N, Ikeshiro Y, Kushiro T, Shibuya M, Ebizuka Y. 2001. Cloning and characterization of a cDNA encoding beta-amyrin synthase involved in glycyrrhizin and soyasaponin biosyntheses in licorice. Biol Pharm Bull. 24(8):912–916.
   PubMed Web of Science ®Google Scholar
• Hayashi H, Huang P, Takada S, Obinata M, Inoue K, Shibuya M, Ebizuka Y. 2004. Differential expression of three oxidosqualene cyclase mRNAs in Glycyrrhiza glabra. Biol Pharm Bull. 27(7):1086–1092.
   PubMed Web of Science ®Google Scholar
• Herrera JB, Bartel B, Wilson WK, Matsuda SP. 1998. Cloning and characterization of the Arabidopsis thaliana lupeol synthase gene. Phytochemistry. 49(7):1905–1911.
   PubMed Web of Science ®Google Scholar
• Heupel RC. 1985. Varietal similarities and differences in the polycyclic isopentenoid composition of sorghum. Phytochemistry. 24(12):2929–2937.
   Web of Science ®Google Scholar
• Hill RA, Connolly JD. 2013. Triterpenoids. Nat Prod Rep. 30(7):1028–1065.
   PubMed Web of Science ®Google Scholar
• Hodgson H, De La Pena R, Stephenson MJ, Thimmappa R, Vincent JL, Sattely ES, Osbourn A. 2019. Identification of key enzymes responsible for protolimonoid biosynthesis in plants: opening the door to azadirachtin production. Proc Natl Acad Sci USA. 116(34):17096–17104.
   PubMed Web of Science ®Google Scholar
• Huang L, Li J, Ye H, Li C, Wang H, Liu B, Zhang Y. 2012. Molecular characterization of the pentacyclic triterpenoid biosynthetic pathway in Catharanthus roseus. Planta. 236(5):1571–1581.
   PubMed Web of Science ®Google Scholar
• Huang Z, Lin J, Cheng Z, Xu M, Guo M, Huang X, Yang Z, Zheng J. 2015. Production of oleanane-type sapogenin in transgenic rice via expression of β-amyrin synthase gene from Panax japonicus C. A. Mey. BMC Biotechnol. 15:45.
   PubMed Web of Science ®Google Scholar
• Husselstein-Muller T, Schaller H, Benveniste P. 2001. Molecular cloning and expression in yeast of 2,3-oxidosqualene-triterpenoid cyclases from Arabidopsis thaliana. Plant Mol Biol. 45(1):75–92.
   PubMed Web of Science ®Google Scholar
• Inayama S, Hori H, Pang GM, Nagasawa H, Ageta HJC, Bulletin P. 1989. Isolation of a hopane-type triterpenoid, zeorin, from a higher plant, Tripterygium regelii. Chem Pharm Bull. 37(10):2836–2837.
   Web of Science ®Google Scholar
• Ito R, Hashimoto I, Masukawa Y, Hoshino T. 2013. Effect of cation-π interactions and steric bulk on the catalytic action of oxidosqualene cyclase: a case study of Phe728 of β-amyrin synthase from Euphorbia tirucalli L. Chemistry. 19(50):17150–17158.
   PubMed Web of Science ®Google Scholar
• Ito R, Masukawa Y, Nakada C, Amari K, Nakano C, Hoshino T. 2014. β-amyrin synthase from Euphorbia tirucalli. Steric bulk, not the π-electrons of Phe, at position 474 has a key role in affording the correct folding of the substrate to complete the normal polycyclization cascade. Org Biomol Chem. 12(23):3836–3846.
   PubMed Web of Science ®Google Scholar
• Ito R, Mori K, Hashimoto I, Nakano C, Sato T, Hoshino T. 2011. Triterpene cyclases from Oryza sativa L.: cycloartenol, parkeol and achilleol B synthases. Org Lett. 13(10):2678–2681.
   PubMed Web of Science ®Google Scholar
• Ito R, Nakada C, Hoshino T. 2016. β-amyrin synthase from Euphorbia tirucalli L. functional analyses of the highly conserved aromatic residues Phe413, Tyr259 and Trp257 disclose the importance of the appropriate steric bulk, and cation-π and CH-π interactions for the efficient catalytic action of the polyolefin cyclization cascade. Org Biomol Chem. 15(1):177–188.
   PubMed Web of Science ®Google Scholar
• Iturbe-Ormaetxe I, Haralampidis K, Papadopoulou K, Osbourn AE. 2003. Molecular cloning and characterization of triterpene synthases from Medicago truncatula and Lotus japonicus. Plant Mol Biol. 51(5):731–743.
   PubMed Web of Science ®Google Scholar
• Kajikawa M, Yamato KT, Fukuzawa H, Sakai Y, Uchida H, Ohyama K. 2005. Cloning and characterization of a cDNA encoding beta-amyrin synthase from petroleum plant Euphorbia tirucalli L. Phytochemistry. 66(15):1759–1766.
   PubMed Web of Science ®Google Scholar
• Kawano N, Ichinose K, Ebizuka Y. 2002. Molecular cloning and functional expression of cDNAs encoding oxidosqualene cyclases from Costus speciosus. Biol Pharm Bull. 25(4):477–482.
   PubMed Web of Science ®Google Scholar
• Kerr RG, Chen Z. 1995. In vivo and in vitro biosynthesis of saponins in sea cucumbers. J Nat Prod. 58(2):172–176.
   PubMed Web of Science ®Google Scholar
• Khan AQ, Ahmed Z, Kazmi SUH, Malik A. 1988. A new pentacyclic triterpene from calotropis procera. J Nat Prod. 51(5):925–928.
   Web of Science ®Google Scholar
• Kim J-E, Jang I-S, Son S-H, Ko Y-J, Cho B-K, Kim SC, Lee JY. 2019. Tailoring the Saccharomyces cerevisiae endoplasmic reticulum for functional assembly of terpene synthesis pathway. Metab Eng. 56:50–59. doi:https://doi.org/10.1016/j.ymben.2019.08.013. 31445083
   PubMed Web of Science ®Google Scholar
• Kirby J, Romanini DW, Paradise EM, Keasling JD. 2008. Engineering triterpene production in Saccharomyces cerevisiae-beta-amyrin synthase from Artemisia annua. FEBS J. 275(8):1852–1859.
   PubMed Web of Science ®Google Scholar
• Kitagawa I. 2002. Licorice root. A-natural sweetener and an important ingredient in Chinese medicine. Pure Appl Chem. 74(7):1189–1198.
   Web of Science ®Google Scholar
• Kolesnikova MD, Wilson WK, Lynch DA, Obermeyer AC, Matsuda SP. 2007. Arabidopsis camelliol C synthase evolved from enzymes that make pentacycles. Org Lett. 9(25):5223–5226.
   PubMed Web of Science ®Google Scholar
• Kolesnikova MD, Xiong Q, Lodeiro S, Hua L, Matsuda SP. 2006. Lanosterol biosynthesis in plants. Arch Biochem Biophys. 447(1):87–95.
   PubMed Web of Science ®Google Scholar
• Kumar S, Stecher G, and Tamura K. 2016. MEGA7: Molecular evolutionary genetics analysis version 7.0 for bigger datasets. Mol Biol Evol. 33(7):1870–1874.
   PubMed Web of Science ®Google Scholar
• Kushiro T, Shibuya M, Ebizuka Y. 1998. Beta-amyrin synthase-cloning of oxidosqualene cyclase that catalyzes the formation of the most popular triterpene among higher plants. Eur J Biochem. 256(1):238–244.
   PubMedGoogle Scholar
• Kushiro T, Shibuya M, Ebizuka Y. 1999. Chimeric triterpene synthase. A possible model for multifunctional triterpene synthase. J Am Chem Soc. 121(6):1208–1216.
   Web of Science ®Google Scholar
• Kushiro T, Shibuya M, Masuda K, Ebizuka Y. 2000. Mutational studies on triterpene synthases: engineering lupeol synthase into β-amyrin Synthase. J Am Chem Soc. 122(29):6816–6824.
   Web of Science ®Google Scholar
• Ladhari A, Chappell J. 2019. Unravelling triterpene biosynthesis through functional characterization of an oxidosqualene cyclase (OSC) from Cleome arabica L. Plant Physiol Biochem. 144:73–84.
   PubMed Web of Science ®Google Scholar
• Li J, Mutanda I, Wang K, Yang L, Wang J, Wang Y. 2019. Chloroplastic metabolic engineering coupled with isoprenoid pool enhancement for committed taxanes biosynthesis in Nicotiana benthamiana. Nat Comm. 10(1):4850.
   PubMedGoogle Scholar
• Li Y, Wang R, Xun X, Wang J, Bao L, Thimmappa R, Ding J, Jiang J, Zhang L, Li T, et al. 2018. Sea cucumber genome provides insights into saponin biosynthesis and aestivation regulation. Cell Discov. 4:29.
   PubMed Web of Science ®Google Scholar
• Liu J, Henkel T. 2002. Traditional Chinese medicine (TCM): are polyphenols and saponins the key ingredients triggering biological activities? Curr Med Chem. 9(15):1483–1485.
   PubMed Web of Science ®Google Scholar
• Liu J, Lee J, Salazar Hernandez MA, Mazitschek R, Ozcan U. 2015. Treatment of obesity with celastrol. Cell. 161(5):999–1011.
   PubMed Web of Science ®Google Scholar
• Liu Y, Cai Y, Zhao Z, Wang J, Li J, Xin W, Xia G, Xiang F. 2009. Cloning and Functional Analysis of a beta-amyrin synthase gene associated with oleanolic acid biosynthesis in Gentiana straminea MAXIM. Biol Pharm Bull. 32(5):818–824.
   PubMed Web of Science ®Google Scholar
• Liu Y, Zhao Z, Xue Z, Wang L, Cai Y, Wang P, Wei T, Gong J, Liu Z, Li J, et al. 2016. An intronless β-amyrin synthase gene is more efficient in oleanolic acid accumulation than its paralog in Gentiana straminea . Sci Rep. 6:33364.
   PubMed Web of Science ®Google Scholar
• Liu YT, Hu TC, Chang CH, Shie WS, Wu TK. 2012. Protein engineering of saccharomyces cerevisiae oxidosqualene-lanosterol cyclase into parkeol synthase. Org Lett. 14(20):5222–5225.
   PubMed Web of Science ®Google Scholar
• Liu Z, Suarez Duran HG, Harnvanichvech Y, Stephenson MJ, Schranz ME, Nelson D, Medema MH, Osbourn A. 2020. Drivers of metabolic diversification: how dynamic genomic neighbourhoods generate new biosynthetic pathways in the Brassicaceae. New Phytol. 227(4):1109–1994.
   PubMed Web of Science ®Google Scholar
• Lodeiro S, Wilson WK, Shan H, Matsuda SP. 2006. A putative precursor of isomalabaricane triterpenoids from lanosterol synthase mutants. Org Lett. 8(3):439–442.
   PubMed Web of Science ®Google Scholar
• Lodeiro S, Xiong Q, Wilson WK, Kolesnikova MD, Onak CS, Matsuda SP. 2007. An oxidosqualene cyclase makes numerous products by diverse mechanisms: a challenge to prevailing concepts of triterpene biosynthesis. J Am Chem Soc. 129(36):11213–11222.
   PubMed Web of Science ®Google Scholar
• Lou H, Li X, Onda M, Konda Y, Urano M, Harigaya Y, Takayanagi H, Ogura HJC, Bulletin P. 1991. Stereochemistry of novel triterpenes from Cynanchum hancokianum. Chem Pharm Bull. 39(9):2271–2276.
   Web of Science ®Google Scholar
• Matsuda SP, Darr LB, Hart EA, Herrera JB, McCann KE, Meyer MM, Pang J, Schepmann HG. 2000. Steric bulk at cycloartenol synthase position 481 influences cyclization and deprotonation. Org Lett. 2(15):2261–2263.
   PubMed Web of Science ®Google Scholar
• Meesapyodsuk D, Balsevich J, Reed DW, Covello PS. 2007. Saponin biosynthesis in Saponaria vaccaria. cDNAs encoding beta-amyrin synthase and a triterpene carboxylic acid glucosyltransferase. Plant Physiol. 143(2):959–969.
   PubMed Web of Science ®Google Scholar
• Miller MB, Haubrich BA, Wang Q, Snell WJ, Nes WD. 2012. Evolutionarily conserved Delta(25(27))-olefin ergosterol biosynthesis pathway in the alga Chlamydomonas reinhardtii. J Lipid Res. 53(8):1636–1645.
   PubMed Web of Science ®Google Scholar
• Misra T, Singh R, Srivastava R, Pandey H, Prasad C, Singh S. 1993. A new triterpenoidal from Vernonia cinerea. Planta Med. 59(5):458–460.
   PubMed Web of Science ®Google Scholar
• Misra TN, Singh RS, Upadhyay J, Srivastava R. 1984. Chemical constituents of Vernonia cinerea, Part I. isolation and spectral studies of triterpenes. J Nat Prod. 47(2):368–372.
   Web of Science ®Google Scholar
• Morita M, Shibuya M, Kushiro T, Masuda K, Ebizuka Y. 2000. Molecular cloning and functional expression of triterpene synthases from pea (Pisum sativum) new alpha-amyrin-producing enzyme is a multifunctional triterpene synthase. Eur J Biochem. 267(12):3453–3460.
   PubMedGoogle Scholar
• Morita M, Shibuya M, Lee MS, Sankawa U, Ebizuka Y. 1997. Molecular cloning of pea cDNA encoding cycloartenol synthase and its functional expression in yeast. Biol Pharm Bull. 20(7):770–775.
   PubMed Web of Science ®Google Scholar
• Morlacchi P, Wilson WK, Xiong Q, Bhaduri A, Sttivend D, Kolesnikova MD, Matsuda SP. 2009. Product profile of PEN3: the last unexamined oxidosqualene cyclase in Arabidopsis thaliana. Org Lett. 11(12):2627–2630.
   PubMed Web of Science ®Google Scholar
• Moser S, Strohmeier GA, Leitner E, Plocek TJ, Vanhessche K, Pichler H. 2018. Whole-cell (+)-ambrein production in the yeast Pichia pastoris. Metab Eng Commun. 7:e00077.
   PubMedGoogle Scholar
• Moses T, Papadopoulou KK, Osbourn A. 2014. Metabolic and functional diversity of saponins, biosynthetic intermediates and semi-synthetic derivatives. Crit Rev Biochem Mol Biol. 49(6):439–462.
   PubMed Web of Science ®Google Scholar
• Moses T, Pollier J, Shen Q, Soetaert S, Reed J, Erffelinck ML, Van Nieuwerburgh FCW, Vanden Bossche R, Osbourn A, Thevelein JM, et al. 2015. OSC2 and CYP716A14v2 catalyze the biosynthesis of triterpenoids for the cuticle of aerial organs of Artemisia annua. Plant Cell. 27(1):286–301.
   PubMed Web of Science ®Google Scholar
• Naim Z, Khan M, Nizami S. 1985. Isolation of a new triterpenic alcohol from of Carissa carandas. Pak J Sci Indus Res. 28:378–381.
   Google Scholar
• Nei M and Kumar S. 2000. Molecular evolution and phylogenetics. New York (NY): Oxford University Press.
   Google Scholar
• Nguyen LHD, Harrison LJ. 1999. Triterpenoid and xanthone constituents of Cratoxylum cochinchinense. Phytochemistry. 50(3):471–476.
   Web of Science ®Google Scholar
• Ohyama K, Suzuki M, Kikuchi J, Saito K, Muranaka T. 2009. Dual biosynthetic pathways to phytosterol via cycloartenol and lanosterol in Arabidopsis. Proc Natl Acad Sci USA. 106(3):725–730.
   PubMed Web of Science ®Google Scholar
• Paddon CJ, Westfall PJ, Pitera DJ, Benjamin K, Fisher K, McPhee D, Leavell MD, Tai A, Main A, Eng D, et al. 2013. High-level semi-synthetic production of the potent antimalarial artemisinin. Nature. 496(7446):528–532.
   PubMed Web of Science ®Google Scholar
• Panosian AG, Mnatsakanian V. 1977. structure of pentacyclic triterpenic alcohol from Centaurea squarrosa. Chem Nat Compd. 13:50–57.
   Google Scholar
• Phillips DR, Rasbery JM, Bartel B, Matsuda SP. 2006. Biosynthetic diversity in plant triterpene cyclization. Curr Opin Plant Biol. 9(3):305–314.
   PubMed Web of Science ®Google Scholar
• Pollier J, Goossens A. 2012. Oleanolic acid. Phytochemistry. 77:10–15.
   PubMed Web of Science ®Google Scholar
• Poralla K, Hewelt A, Prestwich GD, Abe I, Reipen I, Sprenger G. 1994. A specific amino acid repeat in squalene and oxidosqualene cyclases. Trends Biochem Sci. 19(4):157–158.
   PubMed Web of Science ®Google Scholar
• Putter KM, van Deenen N, Muller B, Fuchs L, Vorwerk K, Unland K, Broker JN, Scherer E, Huber C, Eisenreich W, et al. 2019. The enzymes OSC1 and CYP716A263 produce a high variety of triterpenoids in the latex of Taraxacum koksaghyz. Sci Rep. 9(1):5942.
   PubMedGoogle Scholar
• Qi LW, Wang CZ, Yuan CS. 2011. Ginsenosides from American ginseng: chemical and pharmacological diversity. Phytochemistry. 72(8):689–699.
   PubMed Web of Science ®Google Scholar
• Reed J, Stephenson MJ, Miettinen K, Brouwer B, Leveau A, Brett P, Goss RJM, Goossens A, O’Connell MA, Osbourn A. 2017. A translational synthetic biology platform for rapid access to gram-scale quantities of novel drug-like molecules. Metab Eng. 42:185–193.
   PubMed Web of Science ®Google Scholar
• Revesz L, Hiestand P, La Vecchia L, Naef R, Naegeli HU, Oberer L, Roth HJ. 1999. Isolation and synthesis of a novel immunosuppressive 17alpha-substituted dammarane from the flour of the Palmyrah palm (Borassus flabellifer) ). Bioorg Med Chem Lett. 9(11):1521–1526.
   PubMed Web of Science ®Google Scholar
• Ro DK, Paradise EM, Ouellet M, Fisher KJ, Newman KL, Ndungu JM, Ho KA, Eachus RA, Ham TS, Kirby J, et al. 2006. Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature. 440(7086):940–943.
   PubMed Web of Science ®Google Scholar
• Ruan JY, Zheng C, Qu L, Liu YX, Han LF, Yu HY, Zhang Y, Wang T. 2016. Plant resources, C-13-NMR spectral characteristic and pharmacological activities of dammarane-type triterpenoids. Molecules. 21(8):1047.
   Web of Science ®Google Scholar
• Saimaru H, Orihara Y, Tansakul P, Kang YH, Shibuya M, Ebizuka Y. 2007. Production of triterpene acids by cell suspension cultures of Olea europaea. Chem Pharm Bull (Tokyo). 55(5):784–788.
   PubMed Web of Science ®Google Scholar
• Sanchez MI, Ting AY. 2020. Directed evolution improves the catalytic efficiency of TEV protease. Nat Methods. 17(2):167–174.
   PubMed Web of Science ®Google Scholar
• Sawai S, Akashi T, Sakurai N, Suzuki H, Shibata D, Ayabe S, Aoki T. 2006. Plant lanosterol synthase: divergence of the sterol and triterpene biosynthetic pathways in eukaryotes. Plant Cell Physiol. 47(5):673–677.
   PubMed Web of Science ®Google Scholar
• Scholz M, Lipinski M, Leupold M, Luftmann H, Harig L, Ofir R, Fischer R, Prufer D, Muller KJ. 2009. Methyl jasmonate induced accumulation of kalopanaxsaponin I in Nigella sativa. Phytochemistry. 70(4):517–522.
   PubMed Web of Science ®Google Scholar
• Shang Y, Ma Y, Zhou Y, Zhang H, Duan L, Chen H, Zeng J, Zhou Q, Wang S, Gu W, et al. 2014. Plant science. Biosynthesis, regulation, and domestication of bitterness in cucumber. Science. 346(6213):1084–1088.
   PubMed Web of Science ®Google Scholar
• Sharma SC, Tandon JS. 1982. A dammarane triterpene from Commelina undulata. Phytochemistry. 21(9):2420–2421.
   Web of Science ®Google Scholar
• Shibuya M, Katsube Y, Otsuka M, Zhang H, Tansakul P, Xiang T, Ebizuka Y. 2009. Identification of a product specific beta-amyrin synthase from Arabidopsis thaliana. Plant Physiol Biochem. 47(1):26–30.
   PubMed Web of Science ®Google Scholar
• Shibuya M, Sagara A, Saitoh A, Kushiro T, Ebizuka Y. 2008. Biosynthesis of baccharis oxide, a triterpene with a 3,10-oxide bridge in the A-ring. Org Lett. 10(21):5071–5074.
   PubMed Web of Science ®Google Scholar
• Shibuya M, Zhang H, Endo A, Shishikura K, Kushiro T, Ebizuka Y. 1999. Two branches of the lupeol synthase gene in the molecular evolution of plant oxidosqualene cyclases. Eur J Biochem. 266(1):302–307.
   PubMedGoogle Scholar
• Shinozaki J, Shibuya M, Masuda K, Ebizuka Y. 2008. Squalene cyclase and oxidosqualene cyclase from a fern. FEBS Lett. 582(2):310–318.
   PubMed Web of Science ®Google Scholar
• Shinozaki J, Shibuya M, Takahata Y, Masuda K, Ebizuka Y. 2010. Molecular evolution of fern squalene cyclases. Chembiochem. 11(3):426–433.
   PubMed Web of Science ®Google Scholar
• Shiojima K, Arai Y, Masuda K, Kamada T, Ageta H. 1983. Fern constituents: Polypodatetraenes, novel bicyclic triterpenoids, isolated from polypodiaceous and aspidiaceous plants. Tetrahedron Lett. 24(51):5733–5736.
   Web of Science ®Google Scholar
• Shoji N, Umeyama A, Taira Z, Takemoto T, Nomoto K, Nizukawa K, Ohizumi Y. 1983. Chemical structure of hosenkol-A, the first example of the natural baccharane triterpenoid of the missing intermediate to shionane and lupane. J Chem Soc Chem Commun. 16(16):871–873.
   Google Scholar
• Singh S, Florez H. 2020. Coronavirus disease 2019 drug discovery through molecular docking. F1000Res. 9:502.
   PubMedGoogle Scholar
• Souza-Moreira TM, Alves TB, Pinheiro KA, Felippe LG, De Lima GMA, Watanabe TF, Barbosa CC, Santos VAFFM, Lopes NP, Valentini SR, et al. 2016. Friedelin synthase from Maytenus ilicifolia: leucine 482 plays an essential role in the production of the most rearranged pentacyclic triterpene. Sci Rep. 6:36858.
   PubMed Web of Science ®Google Scholar
• Stephenson M, Reed J, Brouwer B, Osbourn A. 2017. Transient expression in Nicotiana benthamiana leaves for triterpene production ata preparative scale. J Vis Exp. 138:e58169.
   Google Scholar
• Stephenson MJ, Field RA, Osbourn A. 2019. The protosteryl and dammarenyl cation dichotomy in polycyclic triterpene biosynthesis revisited: has this ‘rule’ finally been broken? Nat Prod Rep. 36(8):1044–1052.
   PubMed Web of Science ®Google Scholar
• Sun J, Xu X, Xue Z, Snyder JH, Qi X. 2013. Functional analysis of a rice oxidosqualene cyclase through total gene synthesis. Mol Plant. 6(5):1726–1729.
   PubMed Web of Science ®Google Scholar
• Sun J, Zhang C, Nan W, Li D, Ke D, Lu W. 2019. Glycerol improves heterologous biosynthesis of betulinic acid in engineered Yarrowia lipolytica. Chem Eng Sci. 196:82–90.
   Web of Science ®Google Scholar
• Suzuki A, Aikawa Y, Ito R, Hoshino T. 2019. Oryza sativa parkeol cyclase: changes in the substrate-folding conformation and the deprotonation sites on mutation at Tyr257: importance of the hydroxy group and steric bulk. Chembiochem. 20(22):2862–2875.
   PubMed Web of Science ®Google Scholar
• Suzuki M, Xiang T, Ohyama K, Seki H, Saito K, Muranaka T, Hayashi H, Katsube Y, Kushiro T, Shibuya M, et al. 2006. Lanosterol synthase in dicotyledonous plants. Plant Cell Physiol. 47(5):565–571.
   PubMed Web of Science ®Google Scholar
• Tan QG, Luo XD. 2011. Meliaceous limonoids: chemistry and biological activities. Chem Rev. 111(11):7437–7522.
   PubMed Web of Science ®Google Scholar
• Tansakul P, Shibuya M, Kushiro T, Ebizuka Y. 2006. Dammarenediol-II synthase, the first dedicated enzyme for ginsenoside biosynthesis, in Panax ginseng. FEBS Lett. 580(22):5143–5149.
   PubMed Web of Science ®Google Scholar
• Thimmappa R, Geisler K, Louveau T, O’Maille P, Osbourn A. 2014. Triterpene biosynthesis in plants. Annu Rev Plant Biol. 65:225–257.
   PubMed Web of Science ®Google Scholar
• Thoma R, Schulz-Gasch T, D'Arcy B, Benz J, Aebi J, Dehmlow H, Hennig M, Stihle M, Ruf A. 2004. Insight into steroid scaffold formation from the structure of human oxidosqualene cyclase. Nature. 432(7013):118–122.
   PubMed Web of Science ®Google Scholar
• Turner NJ. 2009. Directed evolution drives the next generation of biocatalysts. Nat Chem Biol. 5(8):567–573.
   PubMed Web of Science ®Google Scholar
• Umehara K, Takagi R, Kuroyanagi M, Ueno A, Taki T, Chen YJ. 1992. Studies on differentiation-inducing activities of triterpenes. Chem Pharm Bull (Tokyo). 40(2):401–405.
   PubMed Web of Science ®Google Scholar
• Vincken JP, Heng L, de Groot A, Gruppen H. 2007. Saponins, classification and occurrence in the plant kingdom. Phytochemistry. 68(3):275–297.
   PubMed Web of Science ®Google Scholar
• Wang P, Wei W, Ye W, Li X, Zhao W, Yang C, Li C, Yan X, Zhou Z. 2019. Synthesizing ginsenoside Rh2 in Saccharomyces cerevisiae cell factory at high-efficiency. Cell Discov. 5:5.
   PubMed Web of Science ®Google Scholar
• Wang P, Wei Y, Fan Y, Liu Q, Wei W, Yang C, Zhang L, Zhao G, Yue J, Yan X, et al. 2015. Production of bioactive ginsenosides Rh2 and Rg3 by metabolically engineered yeasts. Metab Eng. 29:97–105.
   PubMed Web of Science ®Google Scholar
• Wang Z, Guhling O, Yao R, Li F, Yeats TH, Rose JK, Jetter R. 2011. Two oxidosqualene cyclases responsible for biosynthesis of tomato fruit cuticular triterpenoids. Plant Physiol. 155(1):540–552.
   PubMed Web of Science ®Google Scholar
• Wang Z, Yeats T, Han H, Jetter R. 2010. Cloning and characterization of oxidosqualene cyclases from Kalanchoe daigremontiana: enzymes catalyzing up to 10 rearrangement steps yielding friedelin and other triterpenoids. J Biol Chem. 285(39):29703–29712.
   PubMed Web of Science ®Google Scholar
• Wei W, Wang P, Wei Y, Liu Q, Yang C, Zhao G, Yue J, Yan X, Zhou Z. 2015. Characterization of Panax ginseng UDP-glycosyltransferases catalyzing protopanaxatriol and biosyntheses of bioactive ginsenosides F1 and Rh1 in metabolically engineered yeasts . Mol Plant. 8(9):1412–1424.
   PubMed Web of Science ®Google Scholar
• Wu S, Zhang F, Xiong W, Molnár I, Liang J, Ji A, Li Y, Wang C, Wang S, Liu Z, et al. 2020. An unexpected oxidosqualene cyclase active site architecture in the Iris tectorum multifunctional α-amyrin synthase. ACS Catal. 10(16):9515–9520.
   PubMed Web of Science ®Google Scholar
• Wu TK, Chang CH, Liu YT, Wang TT. 2008. Saccharomyces cerevisiae oxidosqualene-lanosterol cyclase: a chemistry-biology interdisciplinary study of the protein's structure-function-reaction mechanism relationships. Chem Rec. 8(5):302–325.
   PubMed Web of Science ®Google Scholar
• Wu TK, Li WH, Chang CH, Wen HY, Liu YT, Chang YC. 2009. Differential stereocontrolled formation of tricyclic triterpenes by mutation of Tyrosine 99 of the oxidosqualene-lanosterol cyclase from Saccharomyces cerevisiae. Eur J Org Chem. 2009(33):5731–5737.
   Web of Science ®Google Scholar
• Wu TK, Liu YT, Chang CH, Yu MT, Wang HJ. 2006. Site-saturated mutagenesis of histidine 234 of Saccharomyces cerevisiae oxidosqualene-lanosterol cyclase demonstrates dual functions in cyclization and rearrangement reactions. J Am Chem Soc. 128(19):6414–6419.
   PubMed Web of Science ®Google Scholar
• Wu TK, Liu YT, Chang CH. 2005. Histidine residue at position 234 of oxidosqualene-lanosterol cyclase from Saccharomyces cerevisiae simultaneously influences cyclization, rearrangement, and deprotonation reactions. Chembiochem. 6(7):1177–1181.
   PubMed Web of Science ®Google Scholar
• Wu TK, Yu MT, Liu YT, Chang CH, Wang HJ, Diau EWG. 2006. Tryptophan 232 within oxidosqualene-lanosterol cyclase from Saccharomyces cerevisiae influences rearrangement and deprotonation but not cyclization reactions. Org Lett. 8(7):1319–1322.
   PubMed Web of Science ®Google Scholar
• Wu Y, Xu S, Gao X, Li M, Li D, Lu W. 2019. Enhanced protopanaxadiol production from xylose by engineered Yarrowia lipolytica. Microb Cell Fact. 18(1):83.
   PubMedGoogle Scholar
• Xiang T, Shibuya M, Katsube Y, Tsutsumi T, Otsuka M, Zhang H, Masuda K, Ebizuka Y. 2006. A new triterpene synthase from Arabidopsis thaliana produces a tricyclic triterpene with two hydroxyl groups. Org Lett. 8(13):2835–2838.
   PubMed Web of Science ®Google Scholar
• Xiong QB, Wilson WK, Matsuda SPT. 2006. An Arabidopsis oxidosqualene cyclase catalyzes iridal skeleton formation by Grob fragmentation. Angew Chem Int Ed Engl. 45(8):1285–1288.
   PubMed Web of Science ®Google Scholar
• Xu R, Fazio GC, Matsuda SP. 2004. On the origins of triterpenoid skeletal diversity. Phytochemistry. 65(3):261–291.
   PubMed Web of Science ®Google Scholar
• Xue ZY, Duan LX, Liu D, Guo J, Ge S, Dicks J, OMaille P, Osbourn A, Qi XQ. 2012. Divergent evolution of oxidosqualene cyclases in plants. New Phytol. 193(4):1022–1038.
   PubMed Web of Science ®Google Scholar
• Xue ZY, Tan ZW, Huang AC, Zhou Y, Sun JC, Wang XN, Thimmappa RB, Stephenson MJ, Osbourn A, Qi XQ. 2018. Identification of key amino acid residues determining product specificity of 2,3-oxidosqualene cyclase in Oryza species. New Phytol. 218(3):1076–1088.
   PubMed Web of Science ®Google Scholar
• Xue ZY, Xu X, Zhou Y, Wang XN, Zhang YC, Liu D, Zhao BB, Duan LX, Qi XQ. 2018. Deficiency of a triterpene pathway results in humidity-sensitive genic male sterility in rice. Nat Commun. 9:604.
   PubMed Web of Science ®Google Scholar
• Yan X, Fan Y, Wei W, Wang P, Liu Q, Wei Y, Zhang L, Zhao G, Yue J, Zhou Z. 2014. Production of bioactive ginsenoside compound K in metabolically engineered yeast. Cell Res. 24(6):770–773.
   PubMed Web of Science ®Google Scholar
• Yang JL, Shi YP. 2012. Structurally diverse terpenoids from the rhizomes of Cyperus rotundus L. Planta Med. 78(1):59–64.
   PubMed Web of Science ®Google Scholar
• Yang X, Yang Y, Ouyang D, Yang G. 2015. A review of biotransformation and pharmacology of ginsenoside compound K. Fitoterapia. 100:208–220.
   PubMed Web of Science ®Google Scholar
• Yu SP, Zhu YY, Xu JR, Yao GT, Zhang P, Wang MG, Zhao YF, Lin GQ, Chen HZ, Chen LL, et al. 2021. Glycyrrhizic acid exerts inhibitory activity against the spike protein of SARS-CoV-2. Phytomedicine. 85:153364.
   PubMed Web of Science ®Google Scholar
• Yu Y, Chang P, Yu H, Ren H, Hong D, Li Z, Wang Y, Song H, Huo Y, Li C. 2018. Productive amyrin synthases for efficient α-Amyrin Synthesis in Engineered Saccharomyces cerevisiae . ACS Synth Biol. 7(10):2391–2402.
   PubMed Web of Science ®Google Scholar
• Zhang H, Shibuya M, Yokota S, Ebizuka Y. 2003. Oxidosqualene cyclases from cell suspension cultures of Betula platyphylla var. japonica: molecular evolution of oxidosqualene cyclases in higher plants. Biol Pharm Bull. 26(5):642–650.
   PubMed Web of Science ®Google Scholar
• Zhang X, Sun L, Yuan J, Sun Y, Gao Y, Zhang L, Li S, Dai H, Hamel JF, Liu C, et al. 2017. The sea cucumber genome provides insights into morphological evolution and visceral regeneration. PLoS Biol. 15(10):e2003790.
   PubMed Web of Science ®Google Scholar
• Zhao F, Bai P, Liu T, Li D, Zhang X, Lu W, Yuan Y. 2016. Optimization of a cytochrome P450 oxidation system for enhancing protopanaxadiol production in Saccharomyces cerevisiae. Biotechnol Bioeng. 113(8):1787–1795.
   PubMed Web of Science ®Google Scholar
• Zhao F, Du Y, Bai P, Liu J, Lu W, Yuan Y. 2017. Enhancing Saccharomyces cerevisiae reactive oxygen species and ethanol stress tolerance for high-level production of protopanoxadiol. Bioresour Technol. 227:308–316.
   PubMed Web of Science ®Google Scholar
• Zheng X, Luo X, Ye G, Chen Y, Ji X, Wen L, Xu Y, Xu H, Zhan R, Chen W. 2015. Characterisation of two oxidosqualene cyclases responsible for triterpenoid biosynthesis in Ilex asprella. Int J Mol Sci. 16(2):3564–3578.
   PubMed Web of Science ®Google Scholar
• Zhou J, Hu T, Gao L, Su P, Zhang Y, Zhao Y, Chen S, Tu L, Song Y, Wang X, et al. 2019. Friedelane-type triterpene cyclase in celastrol biosynthesis from Tripterygium wilfordii and its application for triterpenes biosynthesis in yeast. New Phytol. 223(2):722–735.
   PubMed Web of Science ®Google Scholar
• Zhuang Y, Yang GY, Chen X, Liu Q, Zhang X, Deng Z, Feng Y. 2017. Biosynthesis of plant-derived ginsenoside Rh2 in yeast via repurposing a key promiscuous microbial enzyme. Metab Eng. 42:25–32.
   PubMed Web of Science ®Google Scholar