药学学报, 2019, 54(6): 1000-1009
引用本文:
张福生, 孔冉冉, 陈彤垚, 王倩玉, 秦雪梅, 杜晨晖, 马存根. P450s介导远志皂苷等齐墩果烷型植物三萜生物合成的研究进展[J]. 药学学报, 2019, 54(6): 1000-1009.
ZHANG Fu-sheng, KONG Ran-ran, CHEN Tong-yao, WANG Qian-yu, QIN Xue-mei, DU Chen-hui, MA Cun-gen. Advance in biosynthesis of plant-derived oleanane type triterpenoids such as Polygala saponins with catalysis by cytochrome P450s[J]. Acta Pharmaceutica Sinica, 2019, 54(6): 1000-1009.

P450s介导远志皂苷等齐墩果烷型植物三萜生物合成的研究进展
张福生1, 孔冉冉1,2, 陈彤垚1, 王倩玉1,2, 秦雪梅1, 杜晨晖3, 马存根3
1. 山西大学中医药现代研究中心, 山西 太原 030006;
2. 山西大学化学化工学院, 山西 太原 030006;
3. 山西中医药大学, 山西 太原 030024
摘要:
植物三萜是一大类结构多样、具有广泛工业及药用价值的天然产物。齐墩果烷型三萜因拥有良好的药理/生物活性而被广泛熟知,其生物合成历经了前体供应、骨架合成、萜类合成等3个阶段。在齐墩果烷型三萜骨架糖基化之前,细胞色素P450单加氧酶(cytochrome P450 monooxygenase,P450s)会先行对该骨架进行许多结构修饰,而这些修饰对三萜骨架的结构多样性与功能性至关重要。本文综述了齐墩果烷型三萜皂苷生物合成中P450s对β-香树脂醇(β-amyrin)、齐墩果酸(oleanolic acid)的催化作用,探讨了远志皂苷的主要苷元母核——原远志皂苷元的可能生物合成途径,并简要概述了远志(Polygala tenuifolia)中CYP716A249的发现,为齐墩果烷型植物三萜的生物合成途径解析提供一些借鉴。
关键词:    细胞色素P450单加氧酶      植物三萜      齐墩果烷型三萜皂苷      远志皂苷      生物合成     
Advance in biosynthesis of plant-derived oleanane type triterpenoids such as Polygala saponins with catalysis by cytochrome P450s
ZHANG Fu-sheng1, KONG Ran-ran1,2, CHEN Tong-yao1, WANG Qian-yu1,2, QIN Xue-mei1, DU Chen-hui3, MA Cun-gen3
1. Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China;
2. College of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China;
3. Shanxi University of Chinese Medicine, Taiyuan 030024, China
Abstract:
Plant-derived triterpenoids constitute a large and structurally diverse class of natural products with various implications in industrial and pharmaceutical uses. The oleanane type triterpenoids are widely known for their pharmacological and/or biological activities. The biosynthesis pathway of oleanane triterpenoids is divided into three stages:precursor supply, skeleton synthesis, and terpenoids synthesis. Plant cytochrome P450 monooxygenases enzymes (P450s) are involved in the synthesis and diversification of natural products, and are responsible for other modifications of terpenoids, such as formation of triterpenoids. P450s-catalyzed structural modification prior to glycosylation is crucial for diversification and functionalization of triterpenoid scaffolds. In this paper, the catalyses of P450s on β-amyrin and oleanolic acid in oleanane type triterpenoid saponins biosynthesis were reviewed. Presenegenin is a major aglycon of Polygala saponins. The CYP716A249 in Polygala tenuifolia was used as an example to other P450s participating in the possible biosynthetic pathways of presenegenin. These results provide references for elucidation of the biosynthesis pathways of plant-derived oleanane type triterpenoids.
Key words:    cytochrome P450 monooxygenase    plant-derived triterpenoid    oleanane type triterpenoid saponin    Polygala saponin    biosynthesis   
收稿日期: 2019-03-20
DOI: 10.16438/j.0513-4870.2019-0187
基金项目: 山西省科技厅应用基础研究项目(201601D011064);山西省科技开发计划资助项目(20140313010-1);国家中药标准化项目(ZYBZH-Y-JIN-34);山西省重点研究开发计划资助项目(201603D3111003).
通讯作者: 张福生, 马存根
Email: ample1007@sxu.edu.cn;macungen2001@163.com
相关功能
PDF(683KB) Free
打印本文
0
作者相关文章
张福生  在本刊中的所有文章
孔冉冉  在本刊中的所有文章
陈彤垚  在本刊中的所有文章
王倩玉  在本刊中的所有文章
秦雪梅  在本刊中的所有文章
杜晨晖  在本刊中的所有文章
马存根  在本刊中的所有文章

参考文献:
[1] Hill RA, Connolly JD. Triterpenoids[J]. Nat Prod Rep, 2017, 34:90-122.
[2] Phillips DR, Rasbery JM, Bartel B, et al. Biosynthetic diversity in plant triterpene cyclization[J]. Curr Opin Plant Biol, 2006, 9:305-314.
[3] Misra RC, Maiti P, Chanotiya CS, et al. Methyl jasmonate-elicited transcriptional responses and pentacyclic triterpene biosynthesis in sweet basil[J]. Plant Physiology, 2014, 164:1028-1044.
[4] Moses T, Pollier J, Faizal A, et al. Unraveling the triterpenoid saponin biosynthesis of the African shrub Maesa lanceolata[J]. Mol Plant, 2015, 8:122-135.
[5] Moses T, Pollier J, Shen Q, et al. OSC2 and CYP716A14v2 catalyze the biosynthesis of triterpenoids for the cuticle of aerial organs of Artemisia annua[J]. Plant Cell Online, 2015, 27:286-301.
[6] Papadopoulou K, Melton RE, Leggett M, et al. Compromised disease resistance in saponin-deficient plants[J]. Proc Natl Acad Sci U S A, 1999, 96:12923-12928.
[7] Delis C, Krokida A, Georgiou S, et al. Role of lupeol synthase in Lotus japonicus nodule formation[J]. New Phytol, 2011, 189:335-346.
[8] Confalonieri M, Cammareri M, Biazzi E, et al. Enhanced triterpene saponin biosynthesis and root nodulation in transgenic barrel medic (Medicago truncatula Gaertn.) expressing a novel β-amyrin synthase (AsOXA1) gene[J]. Plant Biotechnol J, 2009, 7:172-182.
[9] Kemen AC, Honkanen S, Melton RE, et al. Investigation of triterpene synthesis and regulation in oats reveals a role for β-amyrin in determining root epidermal cell patterning[J]. Proc Natl Acad Sci U S A, 2014, 111:8679-8684.
[10] Ben F, Osbourn AE. Metabolic diversification——independent assembly of operon-like gene clusters in different plants[J]. Science, 2008, 320:543-547.
[11] Krokida A, Delis C, Geisler K, et al. A metabolic gene cluster in Lotus japonicus discloses novel enzyme functions and products in triterpene biosynthesis[J]. New Phytol, 2013, 200:675-690.
[12] Go YS, Lee SB, Kim HJ, et al. Identification of marneral synthase, which is critical for growth and development in Arabidopsis[J]. Plant J, 2012, 72:791-804.
[13] Laszczyk MN. Pentacyclic triterpenes of the lupane, oleanane and ursane group as tools in cancer therapy[J]. Planta Med, 2009, 75:1549-1560.
[14] Sawai S, Saito K. Triterpenoid biosynthesis and engineering in plants[J]. Front Plant Sci, 2011, 2:25.
[15] Salvador JAR, Moreira VM, Gonçalves BMF, et al. Ursane-type pentacyclic triterpenoids as useful platforms to discover anticancer drugs[J]. Nat Prod Rep, 2012, 29:1463-1479.
[16] Moses T, Pollier J, Thevelein JM, et al. Bioengineering of plant (tri)terpenoids:from metabolic engineering of plants to synthetic biology in vivo and in vitro[J]. New Phytol, 2013, 200:27-43.
[17] Sheng H, Sun H. Synthesis, biology and clinical significance of pentacyclic triterpenes:a multi-target approach to prevention and treatment of metabolic and vascular diseases[J]. Cheminform, 2011, 28:543-593.
[18] Dai Z, Wang B, Liu Y, et al. Producing aglycons of ginsenosides in bakers' yeast[J]. Sci Rep, 2014, 4:3698.
[19] Luo Y, Li BZ, Liu D, et al. Engineered biosynthesis of natural products in heterologous hosts[J]. Chem Soc Rev, 2015, 46:5265-5290.
[20] Arendt P, Miettinen K, Pollier J, et al. An endoplasmic reticulum-engineered yeast platform for overproduction of triterpenoids[J]. Metab Eng, 2017, 40:165-175.
[21] Reed J, Stephenson MJ, Miettinen K, et al. A translational synthetic biology platform for rapid access to gram-scale quantities of novel drug-like molecules[J]. Metab Eng, 2017, 42:185-193.
[22] Xu XS, Zhang FS, Qin XM. Research advances on triterpenoid saponins biosynthesis and its key enzymes[J]. World Sci Technol/Mod Tradit Chin Med Mater Med (世界科学技术-中医药现代化), 2014, 16:2440-2448.
[23] Osbourn A, Goss RJM, Field RA. The saponins-polar isoprenoids with important and diverse biological activities[J]. Nat Prod Rep, 2011, 28:1261-1268.
[24] Moses T, Papadopoulou KK, Osbourn A. Metabolic and functional diversity of saponins, biosynthetic intermediates and semi-synthetic derivatives[J]. Crit Rev Biochem Mol Biol, 2014, 49:439-462.
[25] Thimmappa R, Geisler K, Louveau T, et al. Triterpene biosynthesis in plants[J]. Ann Rev Plant Biol, 2014, 65:225-257.
[26] Ghosh S. Biosynthesis of structurally diverse triterpenes in plants:the role of oxidosqualene cyclases[J]. Proc Indian Natl Sci Acad. 2016, 82:1189-1210.
[27] Matsui S, Matsumoto H, Sonoda Y, et al. Glycyrrhizin and related compounds down-regulate production of inflammatory chemokines IL-8 and eotaxin 1 in a human lung fibroblast cell line[J]. Int Immunopharmacol, 2004, 4:1633-1644.
[28] Sun SX, Li YM, Fang WR, et al. Effect and mechanism of AR-6 in experimental rheumatoid arthritis[J]. Clin Exp Med, 2010, 10:113-121.
[29] Man S, Gao W, Zhang Y, et al. Chemical study and medical application of saponins as anti-cancer agents[J]. Fitoterapia, 2010, 81:703-714.
[30] Cinatl J, Morgenstern B, Bauer G, et al. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus[J]. Lancet, 2003, 361:2045-2046.
[31] Zhao YL, Cai GM, Hong X, et al. Antihepatitis B virus activities of triterpenoid saponin compound from Potentilla anserine L[J]. Phytomedicine, 2008, 15:253-258.
[32] Suzuki H, Achnine L, Xu R, et al. A genomics approach to the early stages of triterpene saponin biosynthesis in Medicago truncatula[J]. Plant J, 2010, 32:1033-1048.
[33] Sparg SG, Light ME, Staden JV. Biological activities and distribution of plant saponins[J]. J Ethnopharmacol, 2004, 94:219-243.
[34] Huhman DV, Berhow MA, Sumner LW. Quantification of saponins in aerial and subterranean tissues of Medicago truncatula[J]. J Agric Food Chem, 2005, 53:1914-1920.
[35] Buchanan B, Gruissem W, Jones R. Biochemistry and Molecular Biology of Plants[M]. Beijing:Science Press, 2000:1250-1318.
[36] Nelson D, Werckreichhart D. A P450-centric view of plant evolution[J]. Plant J, 2011, 66:194-211.
[37] Urlacher VB, Girhard M. Cytochrome P450 monooxygenases:an update on perspectives for synthetic application[J]. Trends Biotechnol, 2012, 30:26-36.
[38] Bernhardt R. Cytochromes P450 as versatile biocatalysts[J]. J Biotechnol, 2006, 124:128-145.
[39] Nelson DR. Progress in tracing the evolutionary paths of cytochrome P450[J]. Biochim Biophys Acta, 2011, 1814:14-18.
[40] Miettinen K, Iñigo Sabrina, Kreft L, et al. The TriForC database:a comprehensive up-to-date resource of plant triterpene biosynthesis[J]. Nucleic Acids Res, 2017, 46:586-594.
[41] Ghosh S. Triterpene structural diversification by plant cytochrome P450 enzymes[J]. Front Plant Sci, 2017, 8:1886.
[42] Zhou Y, Ma Y, Zeng J, et al. Convergence and divergence of bitterness biosynthesis and regulation in Cucurbitaceae[J]. Nat Plants, 2016, 2:16183.
[43] Li Z. Research on Mechanisms underlying the Anti-cancer Activities of Triazolyl-napthyl Derivative of β-Amyrin in Nasopharyngeal Carcinoma (β-香树醇酯奈基三唑衍生物对人鼻咽癌抗癌作用机制的研究)[D]. Shandong:Shandong University, 2018.
[44] Shuhei Y, Hikaru S, Yuko S, et al. Functional characterization of CYP716 family P450 enzymes in triterpenoid biosynthesis in tomato[J]. Front Plant Sci, 2017, 8:21.
[45] Seki H, Ohyama K, Sawai S, et al. Licorice beta-amyrin 11-oxidase, a cytochrome P450 with a key role in the biosynthesis of the triterpene sweetener glycyrrhizin[J]. Proc Natl Acad Sci U S A, 2008, 105:14204-14209.
[46] Miettinen K, Pollier J, Buyst D, et al. The ancient CYP716 family is a major contributor to the diversification of eudicot triterpenoid biosynthesis[J]. Nat Commun, 2017, 8:14153.
[47] Geisler K, Hughes RK, Sainsbury F, et al. Biochemical analysis of a multifunctional cytochrome P450(CYP51) enzyme required for synthesis of antimicrobial triterpenes in plants[J]. Proc Natl Acad Sci U S A, 2013, 110:3360-3367.
[48] Moses T, Pollier J, Almagro L, et al. Combinatorial biosynthesis of sapogenins and saponins in Saccharomyces cerevisiae using a C-16 hydroxylase from Bupleurum falcatum[J]. Proc Natl Acad Sci U S A, 2014, 111:1634-1639.
[49] Yasumoto S, Fukushima EO, Seki H, et al. Novel triterpene oxidizing activity of Arabidopsis thaliana CYP716A subfamily enzymes[J]. FEBS Lett, 2016, 590:533-540.
[50] Tamura K, Seki H, Suzuki H, et al. CYP716A179 functions as a triterpene C-28 oxidase in tissue-cultured stolons of Glycyrrhiza uralensis[J]. Plant Cell Rep, 2017, 36:437-445.
[51] Moses T, Thevelein JM, Goossens A, et al. Comparative analysis of CYP93E proteins for improved microbial synthesis of plant triterpenoids[J]. Phytochemistry, 2014, 108:47-56.
[52] Shibuya M, Hoshino M, Katsube Y, et al. Identification of β-amyrin and sophoradiol 24-hydroxylase by expressed sequence tag mining and functional expression assay[J]. FEBS J, 2006, 273:948-959.
[53] Fukushima EO, Seki H, Ohyama K, et al. CYP716A subfamily members are multifunctional oxidases in triterpenoid biosynthesis[J]. Plant Cell Physiol, 2011, 52:2050-2061.
[54] Carelli M, Biazzi E, Panara F, et al. Medicago truncatula CYP716A12 is a multifunctional oxidase involved in the biosynthesis of hemolytic saponins[J]. Plant Cell, 2011, 23:3070-3081.
[55] Han JY, Kim MJ, Ban YW, et al. The involvement of β-amyrin 28-oxidase (CYP716A52v2) in oleanane-type ginsenoside biosynthesis in Panax ginseng[J]. Plant Cell Physiol, 2013, 54:2034-2046.
[56] Fiallos-Jurado J, Pollier J, Moses T, et al. Saponin determination, expression analysis and functional characterization of saponin biosynthetic genes in Chenopodium quinoa leaves[J]. Plant Sci, 2016, 250:188-197.
[57] Jo HJ, Han JY, Hwang HS, et al. β-Amyrin synthase (EsBAS) and β-amyrin 28-oxidase (CYP716A244) in oleanane-type triterpene saponin biosynthesis in Eleutherococcus senticosus[J]. Phytochemistry, 2017, 135:53-63.
[58] Misra RC, Sharma S,Sandeep, et al. Two CYP716A subfamily cytochrome P450 monooxygenases of sweet basil play similar but nonredundant roles in ursane-and oleanane-type pentacyclic triterpene biosynthesis[J]. New Phytol, 2017, 214:706-720.
[59] Andre CM, Legay S, Deleruelle, et al. Multifunctional oxidosqualene cyclases and cytochrome P450 involved in the biosynthesis of apple fruit triterpenic acids[J]. New Phytol, 2016, 211:1279-1294.
[60] Huang L, Li J, Ye H, et al. Note added in proof to:molecular characterization of the pentacyclic triterpenoid biosynthetic pathway in Catharanthus roseus[J]. Planta, 2012, 236:1571-1581.
[61] Khakimov B, Kuzina V, Erthmann PØ, et al. Identification and genome organization of saponin pathway genes from a wild crucifer, and their use for transient production of saponins in Nicotiana benthamiana[J]. Plant J, 2015, 84:478-490.
[62] Boutanaev AM, Moses T, Zi J, et al. Investigation of terpene diversification across multiple sequenced plant genomes[J]. Proc Natl Acad Sci U S A, 2015, 112:81-88.
[63] Seki H, Sawai S, Ohyama K, et al. Triterpene functional genomics in licorice for identification of CYP72A154 involved in the biosynthesis of glycyrrhizin[J]. Plant Cell, 2011, 23:4112-4123.
[64] Tian LT, Ma L, Du NS. Survey of pharmacology of aleanolic acid[J]. China J Chin Mater Med (中国中药杂志), 2002, 27:11-26.
[65] Kim HY, Cho KW, Kang DG, et al. Oleanolic acid increases plasma ANP levels via an accentuation of cardiac ANP synthesis and secretion in rats[J]. Eur J Pharmacol, 2013, 710:73-79.
[66] Pan Y, Zhou F, Song Z, et al. Oleanolic acid protects against pathogenesis of atherosclerosis, possibly via FXR-mediated angiotensin (Ang)-(1-7) upregulation[J]. Biomed Pharmacother, 2018, 97:1694-1700.
[67] Niels HB, Nicolaj CH, Rosalia RR, et al. Antiatherogenic effects of oleanolic acid in apolipoprotein E knockout mice[J]. Eur J Pharmacol, 2011, 670:519-526.
[68] Martín R, Carvalho-Tavares J, Hernández M, et al. Beneficial actions of oleanolic acid in an experimental model of multiple sclerosis:a potential therapeutic role[J]. Biochem Pharmacol, 2010, 79:198-208.
[69] Liu XJ, Han YW, Li XM. Effects of oleanolic acid on early brain injury following subarachnoid hemorrhage in rats by inhibiting NF-κB/ICAM-1 signaling pathway[J]. Chin J Mod Appl Pharm(中国现代应用药学), 2017, 34:1225-1228.
[70] Martín R, Cordova C, San Román JA, et al. Oleanolic acid modulates the immune-inflammatory response in mice with experimental autoimmune myocarditis and protects from cardiac injury. Therapeutic implications for the human disease[J]. J Mol Cell Cardiol, 2014, 72:250-262.
[71] Bai X, Wang X, Nan ML, et al. Research progress on natural pentacyclic triterpenoids and derivatives in anti-cardiovascular and cerebrovascular diseases[J]. Chin Tradit Herb Drugs (中草药), 2019, 50:745-752.
[72] Pollier J, Goossens A. Oleanolic acid[J]. Phytochemistry, 2012, 77:10-15.
[73] Wei J, Liu H, Liu M, et al. Oleanolic acid potentiates the anti-tumor activity of 5-fluorouracil in pancreatic cancer cells[J]. Oncol Rep, 2012, 28:1339-1345.
[74] Biazzi E, Carelli M, Tava A, et al. CYP72A67 catalyzes a key oxidative step in Medicago truncatula hemolytic saponin biosynthesis[J]. Mol Plant, 2015, 8:1493-1506.
[75] Fukushima EO, Seki H, Sawai S, et al. Combinatorial biosynthesis of legume natural and rare triterpenoids in engineered yeast[J]. Plant Cell Physiol, 2013, 54:740-749.
[76] Lin ZH, Gu J, Xiu J, et al. Traditional Chinese medicine for senile dementia[J]. Evid-Based Compl Alt, 2012(1741-427X):692621.
[77] Li CJ. Studies on Chemical Constituents and Biological Activities of Polygala tenuifolia Willdenow and Polygala glomerata Lour (远志和华南远志的化学成分及其生物活性研究)[D]. Beijing:Peking Union Medical College, 2008.
[78] Wang L, Jin GF, Yu HH, et al. Protective effect of tenuifolin against Alzheimer's disease[J]. Neurosci Lett, 2019, 705:195-201.
[79] Cao Q, Jiang Y, Cui SY, et al. Tenuifolin, a saponin derived from Radix Polygalae, exhibits sleep-enhancing effects in mice[J]. Phytomedicine, 2016, 23:1797-1805.
[80] Jin ML, Lee DY, Um Y, et al. Isolation and characterization of an oxidosqualene cyclase gene encoding a β-amyrin synthase involved in Polygala tenuifolia Willd. saponin biosynthesis[J]. Plant Cell Rep, 2014, 33:511-519.
[81] Zhang FS, Wang QY, Pu YJ, et al. PtOAS and its applications (远志齐墩果酸合酶基因PtOAS及其应用):CH, CN109234291A[P]. 2019-01-18.