Abstract
Saponins are specialized plant terpenoids derived from the mevalonic acid pathway. Triterpenoid saponin cores are decorated with sugar residues, conferring a highly amphipathic nature to these molecules, which show hypocholesterolemic, immunoadjuvant and anti-inflammatory activities, among others. Natural sources of bioactive saponins are relevant in light of the technical challenges of chemical synthesis of these compounds. Current supply of high quality, homogeneous and renewable plant material falls short of industrial demand. Research regarding molecular regulation of saponin metabolism has advanced considerably in recent years. Recent studies have focused on transcriptome analysis and identification of key transcription factors regulating gene expression patterns related to saponin biosynthesis. Biotechnological approaches to engineer saponin production in plants, organ and cell cultures, as well as development of heterologous expression systems, are being actively pursued as alternative sources of these high value plant terpenoids. It is expected that these efforts will impact industrial scale sustainable production systems in the coming years.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- AcCoA:
-
Acetyl-CoA
- BAS:
-
Beta amyrin synthase
- DMADP:
-
Dimethylallyl diphosphate
- DS:
-
Dammarenediol synthase
- FDP:
-
Farnesyl diphosphate
- FDS:
-
Farnesyl diphosphate synthase
- HMG-CoA:
-
3-hydroxy-3-methylglutaryl-CoA
- HMGR:
-
3-hydroxy-3-methylglutaryl-CoA reductase
- HMGS:
-
3-hydroxy-3-methylglutaryl-CoA synthase
- IDP:
-
Isopentenyl diphosphate
- MEP:
-
2C-methyl-d-erythritol-4-phosphate
- MVA:
-
Mevalonic acid
- SE:
-
Squalene epoxidase
- SS:
-
Squalene synthase
- OSC:
-
Oxidosqualene cyclase
- SCPL:
-
Serine-carboxypeptidase-like acyltransferase
References
Ahumada I, Cairó A, Hemmerlin A et al (2008) Characterisation of the gene family encoding acetoacetyl-CoA thiolase in Arabidopsis. Funct Plant Biol 35:1100–1111. https://doi.org/10.1071/FP08012
Allen MD, Yamasaki K, Ohme-Takagi M et al (1998) A novel mode of DNA recognition by a β-sheet revealed by the solution structure of the GCC-box binding domain in complex with DNA. EMBO J 17:5484–5496. https://doi.org/10.1093/emboj/17.18.5484
Alsoufi ASM, Pączkowski C, Szakiel A, Długosz M (2019) Effect of jasmonic acid and chitosan on triterpenoid production in Calendula officinalis hairy root cultures. Phytochem Lett 31:5–11. https://doi.org/10.1016/j.phytol.2019.02.030
Arendt P, Miettinen K, Pollier J, De Rycke R (2017) An endoplasmic reticulum-engineered yeast platform for overproduction of triterpenoids. Metab Eng 40:165–175. https://doi.org/10.1016/j.ymben.2017.02.007
Atchley WR, Fitch WM (1997) A natural classification of the basic helix-loop-helix class of transcription factors. Proc Natl Acad Sci U S A 94:5172–5176. https://doi.org/10.1073/pnas.94.10.5172
Augustin JM, Drok S, Shinoda T et al (2012) UDP-glycosyltransferases from the UGT73C subfamily in Barbarea vulgaris catalyze sapogenin 3-O-glucosylation in saponin-mediated insect resistance. Plant Physiol 160:1881–1895. https://doi.org/10.1104/pp.112.202747
Avato P, Bucci R, Tava A, Ferrer A (2006) Antimicrobial activity of saponins from Medicago sp.: structure-activity relationship. Phytother Res 20:454–457. https://doi.org/10.1002/ptr.1876
Bach TJ, Boronat A, Campos N et al (1999) Mevalonate biosynthesis in plants. Crit Rev Biochem Mol Biol 34:107–122. https://doi.org/10.1080/10409239991209237
Baeg IH, So SH (2013) The world ginseng market and the ginseng (Korea). J Ginseng Res 37:1–7. https://doi.org/10.5142/jgr.2013.37.1
Barbosa AdP (2014) An overview on the biological and pharmacological activities of saponins. Int J Pharm Pharm Sci 6:47–50
Biswas T, Dwivedi UN (2019) Plant triterpenoid saponins: biosynthesis, in vitro production, and pharmacological relevance. Protoplasma 256(6):1463–1486. https://doi.org/10.1007/s00709-019-01411-0
Bowles D, Lim E-K, Poppenberger B, Vaistij FE (2006) Glycosyltransferases of lipophilic small molecules. Annu Rev Plant Biol 57:567–597. https://doi.org/10.1146/annurev.arplant.57.032905.105429
Bowyer P, Clarke BR, Lunness P et al (1995) Host range of a plant pathogenic fungus determined by a saponin detoxifying enzyme. Science 267:371–374. https://doi.org/10.1126/science.7824933
Cao H, Nuruzzaman M, Xiu H et al (2015) Transcriptome analysis of methyl jasmonate-elicited Panax ginseng adventitious roots to discover putative ginsenoside biosynthesis and transport genes. Int J Mol Sci 16:3035–3057. https://doi.org/10.3390/ijms16023035
Cardenas PD, Almeida A, Bak S (2019) Evolution of structural diversity of triterpenoids. Front Plant Sci 10:1–10. https://doi.org/10.3389/FPLS.2019.01523
Carelli M, Biazzi E, Panara F et al (2011) Medicago truncatula CYP716A12 is a multifunctional oxidase involved in the biosynthesis of hemolytic saponins. Plant Cell 23:3070–3081. https://doi.org/10.1105/tpc.111.087312
Cho JY, Yoo ES, Baik KU et al (2001) In vitro inhibitory effect of protopanaxadiol ginsenosides on tumour necrosis factor (TNF)-alpha production and its modulation by known TNF-alpha antagonists. Planta Med 67:213–218. https://doi.org/10.1055/s-2001-12005
Chu Y, Xiao S, Su H et al (2018) Genome-wide characterization and analysis of bHLH transcription factors in Panax ginseng. Acta Pharm Sin B 8:666–677. https://doi.org/10.1016/j.apsb.2018.04.004
Cordier H, Karst F, Bergès T (1999) Heterologous expression in Saccharomyces cerevisiae of an Arabidopsis thaliana cDNA encoding mevalonate diphosphate decarboxylase. Plant Mol Biol 39:953–967. https://doi.org/10.1023/A:1006181720100
Crombie WML, Crombie L (1986) Distribution of avenacins A-1, A-2, B-1 and B-2 in oat roots: their fungicidal activity towards “take-all” fungus. Phytochemistry 25:2069–2073. https://doi.org/10.1016/0031-9422(86)80068-1
Crombie L, Crombie WML, Whiting DA (1984) Structures of the four avenacins, oat root resistance factors to “take-all” disease. J Chem Soc Chem Commun 1:246–248. https://doi.org/10.1039/C39840000246
Cunillera N, Arró M, Delourme D et al (1996) Arabidopsis thaliana contains two differentially expressed farnesyl-diphosphate synthase genes. J Biol Chem 271:7774–7780. https://doi.org/10.1074/jbc.271.13.7774
Dalsgaard K (1974) Saponin adjuvants. 3. Isolation of a substance from Quillaja saponaria Molina with adjuvant activity in food-and-mouth disease vaccines. Arch Gesamte Virusforsch 44:243–254
De Boer K, Tilleman S, Pauwels L et al (2011) APETALA2/ETHYLENE RESPONSE FACTOR and basic helix-loop-helix tobacco transcription factors cooperatively mediate jasmonate-elicited nicotine biosynthesis. Plant J 66:1053–1065. https://doi.org/10.1111/j.1365-313X.2011.04566.x
De Brito Francisco R, Martinoia E (2018) The vacuolar transportome of plant specialized metabolites. Plant Cell Physiol 59:1326–1336. https://doi.org/10.1093/pcp/pcy039
de Costa F, Yendo ACA, Fleck JD et al (2011) Immunoadjuvant and anti-inflammatory plant saponins: characteristics and biotechnological approaches towards sustainable production. Mini Rev Med Chem 11:857–880. https://doi.org/10.2174/138955711796575470
de Costa F, Yendo ACA, Fleck JD et al (2013) Accumulation of a bioactive triterpene saponin fraction of Quillaja brasiliensis leaves is associated with abiotic and biotic stresses. Plant Physiol Biochem 66:56–62. https://doi.org/10.1016/j.plaphy.2013.02.003
de Costa F, Barber CJS, Kim Yb et al (2017) Molecular cloning of an ester-forming triterpenoid: UDP-glucose 28-O-glucosyltransferase involved in saponin biosynthesis from the medicinal plant Centella asiatica. Plant Sci 262:9–17. https://doi.org/10.1016/j.plantsci.2017.05.009
De Geyter E, Swevers L, Caccia S et al (2012) Saponins show high entomotoxicity by cell membrane permeation in Lepidoptera. Pest Manag Sci 68:1199–1205. https://doi.org/10.1002/ps.3284
Deng B, Huang Z, Ge F et al (2017a) An AP2/ERF Family transcription factor PnERF1 raised the biosynthesis of saponins in Panax notoginseng. J Plant Growth Regul 36:691–701. https://doi.org/10.1007/s00344-017-9672-z
Deng B, Zhang P, Ge F et al (2017b) Enhancement of triterpenoid saponins biosynthesis in Panax notoginseng cells by co-overexpressions of 3-hydroxy-3-methylglutaryl CoA reductase and squalene synthase genes. Biochem Eng J 122:38–46. https://doi.org/10.1016/j.bej.2017.03.001
Długosz M, Markowski M, Pączkowski C (2018) Source of nitrogen as a factor limiting saponin production by hairy root and suspension cultures of Calendula officinalis L. Acta Physiol Plant 40:1–14. https://doi.org/10.1007/s11738-018-2610-2
Dubos C, Grotewold E, Weisshaar B et al (2010) MYB transcription factors in Arabidopsis. Trends Plant Sci 15:573–581. https://doi.org/10.1016/j.tplants.2010.06.005
Enomoto Y, Ito K, Kawagoe Y et al (1986) Positive inotropic action of saponins on isolated atrial and papillary muscles from the guinea-pig. Br J Pharmacol 88:259–267. https://doi.org/10.1111/j.1476-5381.1986.tb09494.x
Faizal A, Geelen D (2013) Saponins and their role in biological processes in plants. Phytochem Rev 12:877–893. https://doi.org/10.1007/s11101-013-9322-4
Fleck JD, Schwambach J, Almeida ME et al (2009) Immunoadjuvant saponin production in seedlings and micropropagated plants of Quillaja brasiliensis. Vitr Cell Dev Biol Plant 45:715–720. https://doi.org/10.1007/s11627-009-9222-x
Fleck JD, De Costa F, Yendo ACA et al (2013) Determination of new immunoadjuvant saponin named QB-90, and analysis of its organ-specific distribution in Quillaja brasiliensis by HPLC. Nat Prod Res 27:907–910. https://doi.org/10.1080/14786419.2012.666751
Gantait A, Pandit S, Nema NK, Mukjerjee PK (2010) Quantification of glycyrrhizin in Glycyrrhiza glabra extract by validated HPTLC densitometry. J AOAC Int 93:492–495
Geisler K, Hughes RK, Sainsbury F et al (2013) Biochemical analysis of a multifunctional cytochrome P450 (CYP51) enzyme required for synthesis of antimicrobial triterpenes in plants. Proc Natl Acad Sci U S A 110:E3360–E3367. https://doi.org/10.1073/pnas.1309157110
Gholami A, De Geyter N, Pollier J et al (2014) Natural product biosynthesis in Medicago species. Nat Prod Rep 31:356–380. https://doi.org/10.1039/c3np70104b
Ghosh S (2017) Triterpene structural diversification by plant cytochrome P450 enzymes. Front Plant Sci 8:1–15. https://doi.org/10.3389/fpls.2017.01886
Goossens J, Mertens J, Goossens A (2017) Role and functioning of bHLH transcription factors in jasmonate signalling. J Exp Bot 68:1333–1347. https://doi.org/10.1093/jxb/erw440
Gringhuis SI, Kaptein TM, Wevers BA et al (2014) Fucose-specific DC-SIGN signalling directs T helper cell type-2 responses via IKKε-and CYLD-dependent Bcl3 activation. Nat Commun 5:1–7. https://doi.org/10.1038/ncomms4898
Guo S, Kenne L (2000a) Structural studies of triterpenoid saponins with new acyl components from Quillaja saponaria Molina. Phytochemistry 55:419–428. https://doi.org/10.1016/S0031-9422(00)00340-X
Guo S, Kenne L (2000b) Characterization of some O-acetylated saponins from Quillaja saponaria Molina. Phytochemistry 54:615–623. https://doi.org/10.1016/S0031-9422(00)00161-8
Guo HB, Cui XM, An N, Cai GP (2010) Sanchi ginseng (Panax notoginseng (Burkill) F. H. Chen) in China: distribution, cultivation and variations. Genet Resour Crop Evol 57:453–460. https://doi.org/10.1007/s10722-010-9531-2
Han JY, In JG, Kwon YS, Choi YE (2010) Regulation of ginsenoside and phytosterol biosynthesis by RNA interferences of squalene epoxidase gene in Panax ginseng. Phytochemistry 71:36–46. https://doi.org/10.1016/j.phytochem.2009.09.031
Han JY, Wang HY, Choi YE (2014) Production of dammarenediol-II triterpene in a cell suspension culture of transgenic tobacco. Plant Cell Rep 33:225–233. https://doi.org/10.1007/s00299-013-1523-1
Han JY, Baek SH, Jo HJ et al (2019) Genetically modified rice produces ginsenoside aglycone (protopanaxadiol). Planta 250:1103–1110. https://doi.org/10.1007/s00425-019-03204-4
Haralampidis K, Bryan G, Qi X et al (2001) A new class of oxidosqualene cyclases directs synthesis of antimicrobial phytoprotectants in monocots. Proc Natl Acad Sci U S A 98:13431–13436. https://doi.org/10.1073/pnas.231324698
Hayashi H, Sudo H (2009) Economic importance of licorice. Plant Biotechnol 26:101–104. https://doi.org/10.5511/plantbiotechnology.26.101
Hayashi H, Fukui H, Tabata M (1988) Examination of triterpenoids produced by callus and cell suspension cultures of Glycyrrhiza glabra. Plant Cell Rep 7:508–511. https://doi.org/10.1007/BF00272743
Hayashi H, Huang P, Kirakosyan A et al (2001) Cloning and characterization of a cDNA encoding β-amyrin synthase involved in glycyrrhizin and soyasaponin biosyntheses in licorice. Biol Pharm Bull 24:912–916. https://doi.org/10.1248/bpb.24.912
Heim MA, Jakoby M, Werber M et al (2003) The basic helix-loop-helix transcription factor family in plants: a genome-wide study of protein structure and functional diversity. Mol Biol Evol 20:735–747. https://doi.org/10.1093/molbev/msg088
Huang L, Li J, Ye H et al (2012) Molecular characterization of the pentacyclic triterpenoid biosynthetic pathway in Catharanthus roseus. Planta 236:1571–1581. https://doi.org/10.1007/s00425-012-1712-0
Huang C, Qian ZG, Zhong JJ (2013) Enhancement of ginsenoside biosynthesis in cell cultures of Panax ginseng by N, N’-dicyclohexylcarbodiimide elicitation. J Biotechnol 165:30–36. https://doi.org/10.1016/j.jbiotec.2013.02.012
Hui Z, Sha DJ, Wang SL et al (2017) Panaxatriol saponins promotes angiogenesis and enhances cerebral perfusion after ischemic stroke in rats. BMC Complement Altern Med 17:1–10. https://doi.org/10.1186/s12906-017-1579-5
Hussain M, Debnath B, Qasim M et al (2019) Role of saponins in plant defense against specialist herbivores. Molecules 24:1–21. https://doi.org/10.3390/molecules24112067
Jo HJ, Han JY, Hwang HS, Choi YE (2017) β-Amyrin synthase (EsBAS) and β-amyrin 28-oxidase (CYP716A244) in oleanane-type triterpene saponin biosynthesis in Eleutherococcus senticosus. Phytochemistry 135:53–63. https://doi.org/10.1016/j.phytochem.2016.12.011
Kao TC, Wu CH, Yen GC (2014) Bioactivity and potential health benefits of licorice. J Agric Food Chem 62:542–553. https://doi.org/10.1021/jf404939f
Kapusta I, Stochmal A, Perrone A et al (2005) Triterpene saponins from barrel medic (Medicago truncatula) aerial parts. J Agric Food Chem 53:2164–2170. https://doi.org/10.1021/jf048178i
Kemen AC, Honkanen S, Melton RE et al (2014) Investigation of triterpene synthesis and regulation in oats reveals a role for β-amyrin in determining root epidermal cell patterning. Proc Natl Acad Sci U S A 111:8679–8684. https://doi.org/10.1073/pnas.1401553111
Khakimov B, Kuzina V, Erthmann P et al (2015) Identification and genome organization of saponin pathway genes from a wild crucifer, and their use for transient production of saponins in Nicotiana benthamiana. Plant J 84:478–490. https://doi.org/10.1111/tpj.13012
Kim S, Park S, Kang S, Kang H (2003) Hypocholesterolemic property of Yucca schidigera and Quillaja saponaria extracts in human body. Arch Pharm Res 26:1042–1046. https://doi.org/10.1007/BF02994756
Kim YJ, Zhang D, Yang DC (2015) Biosynthesis and biotechnological production of ginsenosides. Biotechnol Adv 33:717–735. https://doi.org/10.1016/j.biotechadv.2015.03.001
Kim OT, Jin ML, Lee DY, Jetter R (2017) Characterization of the asiatic acid glucosyltransferase, UGT73AH1, involved in asiaticoside biosynthesis in Centella asiatica (L.) Urban. Int J Mol Sci 18:1–11. https://doi.org/10.3390/ijms18122630
Kochan E, Szymczyk P, Kúzma Ł et al (2018) The increase of triterpene saponin production induced by trans-Anethole in hairy root cultures of Panax quinquefolium. Molecules 23:1–10. https://doi.org/10.3390/molecules23102674
Kojoma M, Ohyama K, Seki H et al (2010) In vitro proliferation and triterpenoid characteristics of licorice (Glycyrrhiza uralensis Fischer, Leguminosae) stolons. Plant Biotechnol 27:59–66. https://doi.org/10.5511/plantbiotechnology.27.59
Kümmritz S, Louis M, Haas C et al (2016) Fungal elicitors combined with a sucrose feed significantly enhance triterpene production of a Salvia fruticosa cell suspension. Appl Microbiol Biotechnol 100:7071–7082. https://doi.org/10.1007/s00253-016-7432-9
Lambert E, Faizal A, Geelen D (2011) Modulation of triterpene saponin production: in vitro cultures, elicitation, and metabolic engineering. Appl Biochem Biotechnol 164:220–237. https://doi.org/10.1007/s12010-010-9129-3
Leveau A, Reed J, Qiao X et al (2019) Towards take-all control: a C-21β oxidase required for acylation of triterpene defence compounds in oat. New Phytol 221:1544–1555. https://doi.org/10.1111/nph.15456
Li JN, Yu Y, Zhang YF et al (2017) Synergy of Raddeanin A and cisplatin induced therapeutic effect enhancement in human hepatocellular carcinoma. Biochem Biophys Res Commun 485:335–341. https://doi.org/10.1016/j.bbrc.2017.02.079
Liao P, Wang H, Hemmerlin A et al (2014) Past achievements, current status and future perspectives of studies on 3-hydroxy-3-methylglutaryl-CoA synthase (HMGS) in the mevalonate (MVA) pathway. Plant Cell Rep 33:1005–1022. https://doi.org/10.1007/s00299-014-1592-9
Lin X, Huang R, Zhang S et al (2013) Beneficial effects of asiaticoside on cognitive deficits in senescence-accelerated mice. Fitoterapia 87:69–77. https://doi.org/10.1016/j.fitote.2013.03.023
Liu Q, Khakimov B, Cárdenas PD et al (2019a) The cytochrome P450 CYP72A552 is key to production of hederagenin-based saponins that mediate plant defense against herbivores. New Phytol 222:1599–1609. https://doi.org/10.1111/nph.15689
Liu T, Luo T, Guo X et al (2019b) PgMYB2, a MeJA-responsive transcription factor, positively regulates the dammarenediol synthase gene expression in Panax ginseng. Int J Mol Sci 20:2219. https://doi.org/10.3390/ijms20092219
Lluch MA, Masferrer A, Arró M et al (2000) Molecular cloning and expression analysis of the mevalonate kinase gene from Arabidopsis thaliana. Plant Mol Biol 42:365–376. https://doi.org/10.1023/A:1006325630792
Loh YC, Tan CS, Ch’ng YS, Ng CH (2019) Mechanisms of action of Panax notoginseng ethanolic extract for its vasodilatory effects and partial characterization of vasoactive compounds. Hypertens Res 42:182–194. https://doi.org/10.1038/s41440-018-0139-9
Lorent JH, Quetin-Leclercq J, Mingeot-Leclercq MP (2014) The amphiphilic nature of saponins and their effects on artificial and biological membranes and potential consequences for red blood and cancer cells. Org Biomol Chem 12:8803–8822. https://doi.org/10.1039/c4ob01652a
Louveau T, Orme A, Pfalzgraf H et al (2018) Analysis of two new arabinosyltransferases belonging to the carbohydrate-active enzyme (CAZY) glycosyl transferase family1 provides insights into disease resistance and sugar donor specificity. Plant Cell 30:3038–3057. https://doi.org/10.1105/tpc.18.00641
Luebert F (2014) Taxonomy and distribution of the genus Quillaja Molina (Quillajaceae). Feddes Repert 124:157–162. https://doi.org/10.1002/fedr.201400029
Lv H, Li J, Wu Y et al (2016) Transporter and its engineering for secondary metabolites. Appl Microbiol Biotechnol 100:6119–6130. https://doi.org/10.1007/s00253-016-7605-6
Ma CH, Gao ZJ, Zhang JJ et al (2016) Candidate genes involved in the biosynthesis of triterpenoid saponins in Platycodon grandiflorum identified by transcriptome analysis. Front Plant Sci 7:1–14. https://doi.org/10.3389/fpls.2016.00673
Magedans YVS, Yendo AC, de Costa F et al (2019) Foamy matters: an update on Quillaja saponins and their use as immunoadjuvants. Future Med Chem 11:1485–1499. https://doi.org/10.4155/fmc-2018-0438
Marciani DJ (2018) Elucidating the mechanisms of action of saponin-derived adjuvants. Trends Pharmacol Sci 39:573–585. https://doi.org/10.1016/j.tips.2018.03.005
Marsik P, Langhansova L, Dvorakova M et al (2014) Increased ginsenosides production by elicitation of in vitro cultivated Panax ginseng adventitious roots. Med Aromat Plants 03:1–5. https://doi.org/10.4172/2167-0412.1000147
Matsuda H, Samukawa K, Kubo M (1990) Anti-inflammatory activity of Ginsenoside Ro1. J Planta Medica 56:19–23. https://doi.org/10.1055/s-2006-960875
Matsuura HN, Malik S, de Costa F et al (2018) Specialized plant metabolism characteristics and impact on target molecule biotechnological production. Mol Biotechnol 60:169–183. https://doi.org/10.1007/s12033-017-0056-1
Mazahery-Laghab H, Yazdi-Samadi B, Bagheri M, Bagheri AR (2011) Alfalfa (Medicago sativa L.) shoot saponins: identification and bio-activity by the assessment of aphid feeding. Br J Nutr 105:62–70. https://doi.org/10.1017/S0007114510003120
Meesapyodsuk D, Balsevich J, Reed DW, Covello PS (2007) Saponin biosynthesis in Saponaria vaccaria. cDNAs encoding β-amyrin synthase and a triterpene carboxylic acid glucosyltransferase. Plant Physiol 143:959–969. https://doi.org/10.1104/pp.106.088484
Mertens J, Pollier J, Vanden Bossche R et al (2016a) The bHLH transcription factors TSAR1 and TSAR2 regulate triterpene saponin biosynthesis in Medicago truncatula. Plant Physiol 170:194–210. https://doi.org/10.1104/pp.15.01645
Mertens J, Van Moerkercke A, Vanden Bossche R et al (2016b) Clade IVa basic helix-loop-helix transcription factors form part of a conserved jasmonate signaling circuit for the regulation of bioactive plant terpenoid biosynthesis. Plant Cell Physiol 57:2564–2575. https://doi.org/10.1093/pcp/pcw168
Mugford ST, Milkowski C (2012) Serine carboxypeptidase-like acyltransferases from plants, 1st edn. Elsevier Inc., Amsterdam
Mugford ST, Qi X, Bakht S et al (2009) A serine carboxypeptidase-like acyltransferase is required for synthesis of antimicrobial compounds and disease resistance in oats. Plant Cell 21:2473–2484. https://doi.org/10.1105/tpc.109.065870
Mugford ST, Louveau T, Melton R et al (2013) Modularity of plant metabolic gene clusters: a trio of linked genes that are collectively required for acylation of triterpenes in oat. Plant Cell 25:1078–1092. https://doi.org/10.1105/tpc.113.110551
Mylona P, Owatworakit A, Papadopoulou K et al (2008) Sad3 and Sad4 are required for saponin biosynthesis and root development in oat. Plant Cell 20:201–212. https://doi.org/10.1105/tpc.107.056531
Nakashima T, Inoue T, Oka A et al (1995) Cloning, expression, and characterization of cDNAs encoding Arabidopsis thaliana squalene synthase. Proc Natl Acad Sci U S A 92:2328–2332. https://doi.org/10.1073/pnas.92.6.2328
Netala VR, Ghosh SB, Bobbu P et al (2015) Triterpenoid saponins: a review on biosynthesis, applications and mechanism of their action. Int J Pharm Pharm Sci 7:24–28
Nomura Y, Seki H, Suzuki T, Ohyama K (2019) Functional specialization of UDP-glycosyltransferase 73P12 in licorice to produce a sweet triterpenoid saponin, glycyrrhizin. Plant J 99:1127–1143. https://doi.org/10.1111/tpj.14409
Oh JY, Kim YJ, Jang MG et al (2014) Investigation of ginsenosides in different tissues after elicitor treatment in Panax ginseng. J Ginseng Res 38:270–277. https://doi.org/10.1016/j.jgr.2014.04.004
Oleszek W (1996) Alfalfa saponins: structure, biological activity, and chemotaxonomy. In: Waller GR, Yamasaki K (eds) Saponins used in food and agriculture. In: Advances in experimental medicine and biology (series), vol 405. Plenum Press, New York, pp 155–170
Orme A, Louveau T, Stephenson MJ et al (2019) A noncanonical vacuolar sugar transferase required for biosynthesis of antimicrobial defense compounds in oat. Proc Natl Acad Sci U S A 116:27105–27114. https://doi.org/10.1073/pnas.1914652116
Osbourn AE (2003) Saponins in cereals. Phytochemistry 62:1–4. https://doi.org/10.1016/S0031-9422(02)00393-X
Osbourn AE, Clarke BR, Lunness P et al (1994) An oat species lacking avenacin is susceptible to infection by Gaeumannomyces graminis var. tritici. Physiol Mol Plant Pathol 45:457–467. https://doi.org/10.1016/S0885-5765(05)80042-6
Papadopoulou K, Melton RE, Leggett M et al (1999) Compromised disease resistance in saponin-deficient plants. Proc Natl Acad Sci U S A 96:12923–12928. https://doi.org/10.1073/pnas.96.22.12923
Park SB, Chun JH, Ban YW et al (2016) Alteration of Panax ginseng saponin composition by overexpression and RNA interference of the protopanaxadiol 6-hydroxylase gene (Cyp716a53v2). J Ginseng Res 40:47–54. https://doi.org/10.1016/j.jgr.2015.04.010
Pateraki I, Heskes AM, Hamberger B (2015) Cytochromes P450 for terpene functionalisation and metabolic engineering. In: Schrader J, Bohlmann J (eds) Biotechnology of isoprenoids. Springer, Switzerland, pp 107–139
Patra B, Schluttenhofer C, Wu Y et al (2013) Transcriptional regulation of secondary metabolite biosynthesis in plants. Biochim Biophys Acta Gene Regul Mech 1829:1236–1247. https://doi.org/10.1016/j.bbagrm.2013.09.006
Phillips MA, D’Auria JC, Gershenzon J, Pichersky E (2008) The Arabidopsis thaliana type I isopentenyl diphosphate isomerases are targeted to multiple subcellular compartments and have overlapping functions in isoprenoid biosynthesis. Plant Cell 20:677–696. https://doi.org/10.1105/tpc.107.053926
Phukan UJ, Jeena GS, Tripathi V, Shukla RK (2017) Regulation of Apetala2/Ethylene response factors in plants. Front Plant Sci 8:1–18. https://doi.org/10.3389/fpls.2017.00150
Pollier J, Morreel K, Geelen D, Goossens A (2011) Metabolite profiling of triterpene saponins in Medicago truncatula hairy roots by liquid chromatography fourier transform ion cyclotron resonance mass spectrometry. J Nat Prod 74:1462–1476. https://doi.org/10.1021/np200218r
Potter SM, Jimenez-Flores R, Pollack JA et al (1993) Protein-saponin interaction and its influence on blood lipids. J Agric Food Chem 41:1287–1291. https://doi.org/10.1021/jf00032a023
Ramilowski JA, Sawai S, Seki H et al (2013) Glycyrrhiza uralensis transcriptome landscape and study of phytochemicals. Plant Cell Physiol 54:697–710. https://doi.org/10.1093/pcp/pct057
Reed J, Stephenson MJ, Miettinen K, Brouwer B (2017) A translational synthetic biology platform for rapid access to gram-scale quantities of novel drug-like molecules. Metab Eng 42:185–193. https://doi.org/10.1016/j.ymben.2017.06.012
Reichert CL, Salminen H, Weiss J (2019) Quillaja saponin characteristics and functional properties. Annu Rev Food Sci Technol 10:43–73. https://doi.org/10.1146/annurev-food-032818-122010
Ribeiro B, Erffelinck M-L, Colinas M, Williams C (2020a) ER-anchored transcription factors bZIP17 and bZIP60 regulate triterpene saponin biosynthesis in Medicago truncatula. bioRxiv. https://doi.org/10.1101/2020.01.17.910802
Ribeiro B, Lacchini E, Bicalho KU et al (2020b) A seed-specific regulator of triterpene saponin biosynthesis in Medicago truncatula. Plant Cell 32:2020–2042. https://doi.org/10.1105/tpc.19.00609
Rodriguez-Concepción M (2014) Plant isoprenoids: a general overview. In: Rodríguez-Concepción M (ed) Plant isoprenoids. Methods and protocols. Humana Press, pp 1–8
Santos FN, Borja-Cabrera GP, Miyashiro LM et al (2007) Immunotherapy against experimental canine visceral leishmaniasis with the saponin enriched-Leishmune®vaccine. Vaccine 25:6176–6190. https://doi.org/10.1016/j.vaccine.2007.06.005
Sawai S, Saito K (2011) Triterpenoid biosynthesis and engineering in plants. Front Plant Sci 2:1–8. https://doi.org/10.3389/fpls.2011.00025
Scott GI, Colligan PB, Ren BH, Ren J (2001) Ginsenosides Rb1 and Re decrease cardiac contraction in adult rat ventricular myocytes: role of nitric oxide. Br J Pharmacol 134:1159–1165. https://doi.org/10.1038/sj.bjp.0704377
Seki H, Ohyama K, Sawai S et al (2008) Licorice β-amyrin 11-oxidase, a cytochrome P450 with a key role in the biosynthesis of the triterpene sweetener glycyrrhizin. Proc Natl Acad Sci U S A 105:14204–14209. https://doi.org/10.1073/pnas.0803876105
Seki H, Sawai S, Ohyama K et al (2011) Triterpene functional genomics in licorice for identification of CYP72A154 involved in the biosynthesis of glycyrrhizin. Plant Cell 23:4112–4123. https://doi.org/10.1105/tpc.110.082685
Sewelam N, Kazan K, Schenk PM (2016) Global plant stress signaling: reactive oxygen species at the cross-road. Front Plant Sci 7:1–21. https://doi.org/10.3389/fpls.2016.00187
Shabani L, Ehsanpour AA, Asghari G, Emami J (2009) Glycyrrhizin production by in vitro cultured Glycyrrhiza glabra elicited by methyl jasmonate and salicylic acid. Russ J Plant Physiol 56:621–626. https://doi.org/10.1134/S1021443709050069
Shang Y, Huang S (2019) Multi-omics data-driven investigations of metabolic diversity of plant triterpenoids. Plant J 97:101–111. https://doi.org/10.1111/tpj.14132
Shi Y, Wang H, Shi F (2019a) Ginsenoside Rg3 suppresses the NLRP3 inflammasome activation through inhibition of its assembly. FASEB J 34:208–221. https://doi.org/10.1096/fj.201901537R
Shi Y, Zhang S, Peng D et al (2019b) Transcriptome analysis of Clinopodium chinense (Benth.) O. Kuntze and identification of genes involved in triterpenoid saponin biosynthesis. Int J Mol Sci 20:2643. https://doi.org/10.3390/ijms20112643
Shibuya M, Katsube Y, Otsuka M et al (2009) Identification of a product specific β-amyrin synthase from Arabidopsis thaliana. Plant Physiol Biochem 47:26–30. https://doi.org/10.1016/j.plaphy.2008.09.007
Shin BK, Kwon SW, Park JH (2015) Chemical diversity of ginseng saponins from Panax ginseng. J Ginseng Res 39:287–298. https://doi.org/10.1016/j.jgr.2014.12.005
Shirazi Z, Aalami A, Tohidfar M, Sohani MM (2018) Metabolic engineering of glycyrrhizin pathway by over-expression of beta-amyrin 11-oxidase in transgenic roots of Glycyrrhiza glabra. Mol Biotechnol 60:412–419. https://doi.org/10.1007/s12033-018-0082-7
Shirley AM, Chapple C (2003) Biochemical characterization of sinapoylglucose:choline sinapoyltransferase, a serine carboxypeptidase-like protein that functions as an acyltransferase in plant secondary metabolism. J Biol Chem 278:19870–19877. https://doi.org/10.1074/jbc.M302362200
Shitan N (2016) Secondary metabolites in plants: transport and self-tolerance mechanisms. Biosci Biotechnol Biochem 80:1283–1293. https://doi.org/10.1080/09168451.2016.1151344
Shoji T (2019) The recruitment model of metabolic evolution: jasmonate-responsive transcription factors and a conceptual model for the evolution of metabolic pathways. Front Plant Sci 10:1–12. https://doi.org/10.3389/fpls.2019.00560
Singh D, Chaudhuri PK (2018) Structural characteristics, bioavailability and cardioprotective potential of saponins. Integr Med Res 7:33–43. https://doi.org/10.1016/j.imr.2018.01.003
Singh B, Kaur A (2018) Control of insect pests in crop plants and stored food grains using plant saponins: a review. LWT Food Sci Technol 87:93–101. https://doi.org/10.1016/j.lwt.2017.08.077
Soltysik S, Wu JY, Recchia J et al (1995) Structure/function studies of QS-21 adjuvant: assessment of triterpene aldehyde and glucuronic acid roles in adjuvant function. Vaccine 13:1403–1410. https://doi.org/10.1016/0264-410X(95)00077-E
Srisawat P, Fukushima EO, Yasumoto S, Robertlee J (2019) Identification of oxidosqualene cyclases from the medicinal legume tree Bauhinia forficata: a step toward discovering preponderant alpha-amyrin-producing activity. New Phytol 224:352–366. https://doi.org/10.1111/nph.16013
Srisawat P, Yasumoto S, Fukushima EO et al (2020) Production of the bioactive plant-derived triterpenoid morolic acid in engineered Saccharomyces cerevisiae. Biotechnol Bioeng 117:2198–2208. https://doi.org/10.1002/bit.27357
Srivastava M, Singh G, Sharma S et al (2019) Elicitation enhanced the yield of glycyrrhizin and antioxidant activities in hairy root cultures of Glycyrrhiza glabra L. J Plant Growth Regul 38:373–384. https://doi.org/10.1007/s00344-018-9847-2
Srivastava G, Garg A, Chandra R et al (2020) Transcriptome analysis and functional characterization of oxidosqualene cyclases of the Arjuna triterpene saponin pathway. Plant Sci 292:110382. https://doi.org/10.1016/j.plantsci.2019.110382
Sun Y, Niu Y, Xu J et al (2013a) Discovery of WRKY transcription factors through transcriptome analysis and characterization of a novel methyl jasmonate-inducible PqWRKY1 gene from Panax quinquefolius. Plant Cell Tissue Organ Cult 114:269–277. https://doi.org/10.1007/s11240-013-0323-1
Sun Y, Zhao SJ, Liang YL et al (2013b) Regulation and differential expression of protopanaxadiol synthase in Asian and American ginseng ginsenoside biosynthesis by RNA interferences. Plant Growth Regul 71:207–217. https://doi.org/10.1007/s10725-013-9821-8
Suzuki H, Fukushima EO, Shimizu Y et al (2019) Lotus japonicus triterpenoid profile and characterization of the CYP716A51 and LjCYP93E1 genes involved in their biosynthesis in planta. Plant Cell Physiol 60:2496–2509. https://doi.org/10.1093/pcp/pcz145
Szakiel A, Janiszowska W (2002) The mechanism of oleanolic acid monoglycosides transport into vacuoles isolated from Calendula officinalis leaf protoplasts. Plant Physiol Biochem 40:203–209. https://doi.org/10.1016/S0981-9428(02)01370-0
Szakiel A, Ruszkowski D, Janiszowska W (2005) Saponins in Calendula officinalis L. - Structure, biosynthesis, transport and biological activity. Phytochem Rev 4:151–158. https://doi.org/10.1007/s11101-005-4053-9
Szakiel A, Pączkowski C, Henry M (2011) Influence of environmental biotic factors on the content of saponins in plants. Phytochem Rev 10:493–502. https://doi.org/10.1007/s11101-010-9164-2
Szczepanik M, Krystokowiak K, Jurzysta M, Bialy Z (2001) Biological activity of saponins from alfalfa tops and roots against Colorado potato beetle larvae. Acta Agrobot 54:33–45. https://doi.org/10.5586/aa.2001.021
Takemura M, Tanaka R, Misawa N (2017) Pathway engineering for the production of β-amyrin and cycloartenol in Escherichia coli—a method to biosynthesize plant-derived triterpene skeletons in E. coli. Appl Microbiol Biotechnol 101:6615–6625. https://doi.org/10.1007/s00253-017-8409-z
Tam KI, Roner MR (2011) Characterization of in vivo anti-rotavirus activities of saponin extracts from Quillaja saponaria Molina. Antivir Res 90:231–241. https://doi.org/10.1016/j.antiviral.2011.04.004
Tamura K, Teranishi Y, Ueda S et al (2017a) Cytochrome P450 monooxygenase CYP716A141 is a unique β-amyrin C-16β oxidase involved in triterpenoid saponin biosynthesis in Platycodon grandiflorus. Plant Cell Physiol 58:874–884. https://doi.org/10.1093/pcp/pcx043
Tamura K, Teranishi Y, Ueda S, Suzuki H, Kawano N, Yoshimatsu K, Saito K, Kawahara N, Muranaka T, Seki H (2017b) Cytochrome P450 monooxygenase CYP716A141 is a unique b-amyrin C-16b oxidase involved in triterpenoid saponin biosynthesis in platycodon grandiflorus. Plant Cell Physiol 58(6):1119. https://doi.org/10.1093/pcp/pcx067
Tamura K, Yoshida K, Hiraoka Y et al (2018) The basic helix-loop-helix transcription factor GubHLH3 positively regulates soyasaponin biosynthetic genes in Glycyrrhiza uralensis. Plant Cell Physiol 59:778–791. https://doi.org/10.1093/pcp/pcy046
Tansakul P, Shibuya M, Kushiro T, Ebizuka Y (2006) Dammarenediol-II synthase, the first dedicated enzyme for ginsenoside biosynthesis in Panax ginseng. Plant Cell Physiol 580:5143–5149. https://doi.org/10.1016/j.febslet.2006.08.044
Tava A, Scotti C, Avato P (2011) Biosynthesis of saponins in the genus Medicago. Phytochem Rev 10:459–469. https://doi.org/10.1007/s11101-010-9169-x
Thimmappa R, Geisler K, Louveau T et al (2014) Triterpene biosynthesis in plants. Annu Rev Plant Biol 65:225–257. https://doi.org/10.1146/annurev-arplant-050312-120229
Tzin V, Snyder JH, Yang DS et al (2019) Integrated metabolomics identifies CYP72A67 and CYP72A68 oxidases in the biosynthesis of Medicago truncatula oleanate sapogenins. Metabolomics 15:1–20. https://doi.org/10.1007/s11306-019-1542-1
Uzayisenga R, Ayeka PA, Wang Y (2014) Anti-diabetic potential of Panax notoginseng saponins (PNS): a review. Phyther Res 28:510–516. https://doi.org/10.1002/ptr.5026
Vermeersch M, Foubert K, Inocêncio da Luz R et al (2009) Selective antileishmania activity of 13,28-epoxy-oleanane and related triterpene saponins from the plant families Myrsinaceae, Primulaceae, Aceraceae and Icacinaceae. Phyther Res 23:1404–1410. https://doi.org/10.1002/ptr
Vincken JP, Heng L, de Groot A, Gruppen H (2007) Saponins, classification and occurrence in the plant kingdom. Phytochemistry 68:275–297. https://doi.org/10.1016/j.phytochem.2006.10.008
Wallace F, Bennadji Z, Ferreira F, Olivaro C (2019) Structural characterisation of new immunoadjuvant saponins from leaves and the first study of saponins from the bark of Quillaja brasiliensis by liquid chromatography electrospray ionisation ion trap mass spectrometry. Phytochem Anal 30:644–652. https://doi.org/10.1002/pca.2837
Wang T, Guo R, Zhou G et al (2016) Traditional uses, botany, phytochemistry, pharmacology and toxicology of Panax notoginseng (Burk.) F.H. Chen: a review. J Ethnopharmacol 188:234–258. https://doi.org/10.1016/j.jep.2016.05.005
Wang N, Wang L, Qi L, Lu X (2018) Construct a gene-to-metabolite network to screen the key genes of triterpene saponin biosynthetic pathway in Panax notoginseng. Biotechnol Appl Biochem 65:119–127. https://doi.org/10.1002/bab.1580
Wasternack C, Hause B (2013) Jasmonates: biosynthesis, perception, signal transduction and action in plant stress response, growth and development. An update to the 2007 review in Annals of Botany. Ann Bot 111:1021–1058. https://doi.org/10.1093/aob/mct067
Watson BS, Bedair MF, Urbanczyk-Wochniak E et al (2015) Integrated metabolomics and transcriptomics reveal enhanced specialized metabolism in Medicago truncatula root border cells. Plant Physiol 167:1699–1716. https://doi.org/10.1104/pp.114.253054
WHO (1999) WHO monographs on selected medicinal plants. WHO, Malta
Wongwicha W, Tanaka H, Shoyama Y et al (2008) Production of glycyrrhizin in callus cultures of licorice. Zeitschrift fur Naturforsch - Sect C J Biosci 63c:413–417. https://doi.org/10.1515/znc-2008-5-617
Xie Z, Nolan TM, Jiang H, Yin Y (2019) AP2/ERF transcription factor regulatory networks in hormone and abiotic stress responses in Arabidopsis. Front Plant Sci 10:1–17. https://doi.org/10.3389/fpls.2019.00228
Xu CL, Wang QZ, Sun LM et al (2012) Asiaticoside: attenuation of neurotoxicity induced by MPTP in a rat model of Parkinsonism via maintaining redox balance and up-regulating the ratio of Bcl-2/Bax. Pharmacol Biochem Behav 100:413–418. https://doi.org/10.1016/j.pbb.2011.09.014
Yamamoto Y, Tani T (2005) Field study and pharmaceutical evaluation of Glycyrrhiza uralensis roots cultivated in China. J Trad Med 22:86–97
Yang X, Xiong X, Wang H, Wang J (2014) Protective effects of Panax notoginseng saponins on cardiovascular diseases: a comprehensive overview of experimental studies. Evid Based Complement Altern Med 2014:1–13. https://doi.org/10.1155/2014/204840
Yao Y, Wu WY, Guan SH et al (2008) Proteomic analysis of differential protein expression in rat platelets treated with notoginsengnosides. Phytomedicine 15:800–807. https://doi.org/10.1016/j.phymed.2008.06.013
Yao L, Wang S, Liang W et al (2019) Screening and evaluation of adventitious root lines of Panax notoginseng by morphology, gene expression, and metabolite profiles. Appl Microbiol Biotechnol 103:4405–4415. https://doi.org/10.1007/s00253-019-09778-z
Yao L, Wang J, Sun J et al (2020) A WRKY transcription factor, PgWRKY4X, positively regulates ginsenoside biosynthesis by activating squalene epoxidase transcription in Panax ginseng. Ind Crops Prod 154:112671. https://doi.org/10.1016/j.indcrop.2020.112671
Yendo ACA, de Costa F, Gosmann G, Fett-Neto AG (2010) Production of plant bioactive triterpenoid saponins: elicitation strategies and target genes to improve yields. Mol Biotechnol 46:94–104. https://doi.org/10.1007/s12033-010-9257-6
Yendo ACA, de Costa F, da Costa CT et al (2014) Biosynthesis of plant triterpenoid saponins: genes, enzymes and their regulation. Mini Rev Org Chem 11:292–306. https://doi.org/10.2174/1570193x1103140915111425
Yendo ACA, de Costa F, Cibulski SP et al (2016) A rabies vaccine adjuvanted with saponins from leaves of the soap tree (Quillaja brasiliensis) induces specific immune responses and protects against lethal challenge. Vaccine 34:2305–2311. https://doi.org/10.1016/j.vaccine.2016.03.070
Zeng X, Luo T, Li J et al (2018) Transcriptomics-based identification and characterization of 11 CYP450 genes of Panax ginseng responsive to MeJA. Acta Biochim Biophys Sin (Shanghai) 50:1094–1103. https://doi.org/10.1093/abbs/gmy120
Zhang R, Huang J, Zhu J et al (2013a) Isolation and characterization of a novel PDR-type ABC transporter gene PgPDR3 from Panax ginseng C.A. Meyer induced by methyl jasmonate. Mol Biol Rep 40:6195–6204. https://doi.org/10.1007/s11033-013-2731-z
Zhang R, Zhu J, Cao HZ et al (2013b) Molecular cloning and expression analysis of PDR1-like gene in ginseng subjected to salt and cold stresses or hormonal treatment. Plant Physiol Biochem 71:203–211. https://doi.org/10.1016/j.plaphy.2013.07.011
Zhang S, Wu Y, Jin J et al (2015) De novo characterization of Panax japonicus C. A. Mey transcriptome and genes related to triterpenoid saponin biosynthesis. Biochem Biophys Res Commun 466:450–455. https://doi.org/10.1016/j.bbrc.2015.09.048
Zhang X, Ge F, Deng B et al (2017) Molecular cloning and characterization of PnbHLH1 transcription factor in Panax notoginseng. Molecules 22:1–12. https://doi.org/10.3390/molecules22081268
Zhang X, Yu Y, Jiang S et al (2019) Oleanane-type saponins biosynthesis in Panax notoginseng via transformation of β-amyrin synthase gene from Panax japonicus. J Agric Food Chem 67:1982–1989. https://doi.org/10.1021/acs.jafc.8b07183
Zhao YJ, Li C (2018) Biosynthesis of plant triterpenoid saponins in microbial cell factories. J Agric Food Chem 66:12155–12165. https://doi.org/10.1021/acs.jafc.8b04657
Zhou M, Memelink J (2016) Jasmonate-responsive transcription factors regulating plant secondary metabolism. Biotechnol Adv 34:441–449. https://doi.org/10.1016/j.biotechadv.2016.02.004
Acknowledgements
We thank Dr. Fernanda de Costa (Lupos Biotechnology Inc., North York, Canada) for helping in the preparation of Fig. 3.
Funding
The work was supported by Grants from the National Council for Scientific and Technological Development (CNPq-Brazil/Grant 303560/2017-7) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brazil (CAPES) - Finance Code 001 to A.F.N as well as a grant from the Natural Sciences and Engineering Council of Canada to M. P. (RGPIN-2017-06400).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
None.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
da Silva Magedans, Y.V., Phillips, M.A. & Fett-Neto, A.G. Production of plant bioactive triterpenoid saponins: from metabolites to genes and back. Phytochem Rev 20, 461–482 (2021). https://doi.org/10.1007/s11101-020-09722-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11101-020-09722-4