Skip to main content

Advertisement

SpringerLink
Log in

Plant diterpenoid metabolism for manufacturing the biopharmaceuticals of tomorrow: prospects and challenges

  • Published:
Phytochemistry Reviews Aims and scope Submit manuscript

Abstract

Plant diterpenoids encompass a diverse group of more than ten thousand specialized (traditionally termed ‘secondary’) metabolites with significant ecological functions and industrial uses. Bioactive diterpenoids form an important source of bio-based pharmaceuticals, as exemplified by the approved anti-cancer drugs paclitaxel and ingenol mebutate. Advanced genomics, metabolomics and enzyme discovery technologies have spawned a new era of exploring traditional medicinal plants for novel or improved therapeutics. Across the plant kingdom numerous diterpene synthase and cytochrome P450 enzymes with key roles in generating diterpenoid chemical diversity have been identified in recent years. This catalog of enzyme catalysts and a deeper knowledge of specialized diterpenoid metabolism can now be applied to modern microbial and photosynthetic production systems, offering alternative avenues for the sustainable manufacture of plant-based medicines important to humanity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

diTPS:

Diterpene synthase

GGPP:

Geranylgeranyl diphosphate

P450:

Cytochrome P450-dependent monooxygenase

CPP:

Copalyl diphosphate

MS:

Mass spectrometry

References

  • 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 330:70–74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Andersen-Ranberg J, Kongstad KT, Nielsen MT, Jensen NB, Pateraki I, Bach SS, Hamberger B, Zerbe P, Staerk D, Bohlmann J, Møller BL (2016) Expanding the landscape of diterpene structural diversity through stereochemically controlled combinatorial biosynthesis. Angew Chem Int Ed Engl 55:2142–2146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anterola A, Shanle E, Perroud PF, Quatrano R (2009) Production of taxa-4(5),11(12)-diene by transgenic Physcomitrella patens. Transgenic Res 18:655–660

    Article  CAS  PubMed  Google Scholar 

  • Banerjee S, Saluja A (2015) Minnelide, a novel drug for pancreatic and liver cancer. Pancreatology 15:S39–S43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beale MH (1990) The biosynthesis of C5-C20 terpenoid compounds. Nat Prod Rep 7:25–39

    Article  CAS  PubMed  Google Scholar 

  • Birtić S, Dussort P, Pierre FX, Bily AC, Roller M (2015) Carnosic acid. Phytochemistry 115:9–19

    Article  PubMed  CAS  Google Scholar 

  • Bjarnholt N, Li B, D’Alvise J, Janfelt C (2014) Mass spectrometry imaging of plant metabolites: principles and possibilities. Nat Prod Rep 31:818–837

    Article  CAS  PubMed  Google Scholar 

  • Bohlmann J (2012) Pine terpenoid defences in the mountain pine beetle epidemic and in other conifer pest interactions: specialized enemies are eating holes into a diverse, dynamic and durable defence system. Tree Physiol 32:943–945

    Article  PubMed  Google Scholar 

  • Bohlmann J, Keeling CI (2008) Terpenoid biomaterials. Plant J 54:656–669

    Article  CAS  PubMed  Google Scholar 

  • Boutanaev AM, Moses T, Zi J, Nelson DR, Mugford ST, Peters RJ, Osbourn A (2015) Investigation of terpene diversification across multiple sequenced plant genomes. Proc Natl Acad Sci USA 112:E81–E88

    Article  CAS  PubMed  Google Scholar 

  • Božić D, Papaefthimiou D, Brückner K, de Vos RC, Tsoleridis CA, Katsarou D, Papanikolaou A, Pateraki I, Chatzopoulou FM, Dimitriadou E, Kostas S, Manzano D, Scheler U, Ferrer A, Tissier A, Makris AM, Kampranis SC, Kanellis AK (2015) Towards elucidating carnosic acid biosynthesis in Lamiaceae: functional characterization of the three first steps of the pathway in Salvia fruticosa and Rosmarinus officinalis. PLoS ONE 10:e0124106

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Brinker AM, Ma J, Lipsky PE, Raskin I (2007) Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae). Phytochemistry 68:732–766

    Article  CAS  PubMed  Google Scholar 

  • Brückner K, Tissier A (2013) High-level diterpene production by transient expression in Nicotiana benthamiana. Plant Methods 9:46

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Brückner K, Božić D, Manzano D, Papaefthimiou D, Pateraki I, Scheler U, Ferrer A, de Vos RC, Kanellis AK, Tissier A (2014) Characterization of two genes for the biosynthesis of abietane-type diterpenes in rosemary (Rosmarinus officinalis) glandular trichomes. Phytochemistry 101:52–64

    Article  PubMed  CAS  Google Scholar 

  • Cahoon EB, Ripp KG, Hall SE, McGonigle B (2002) Transgenic production of epoxy fatty acids by expression of a cytochrome P450 enzyme from Euphorbia lagascae seed. Plant Physiol 128:615–624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caniard A, Zerbe P, Legrand S, Cohade A, Valot N, Magnard JL, Bohlmann J, Legendre L (2012) Discovery and functional characterization of two diterpene synthases for sclareol biosynthesis in Salvia sclarea (L.) and their relevance for perfume manufacture. BMC Plant Biol 12:119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen F, Tholl D, Bohlmann J, Pichersky E (2011) The family of terpene synthases in plants: a mid-size family of genes for specialized metabolism that is highly diversified throughout the kingdom. Plant J 66:212–229

    Article  CAS  PubMed  Google Scholar 

  • Chen X, Berim A, Dayan FE, Gang DR (2017) A (-)-kolavenyl diphosphate synthase catalyzes the first step of salvinorin A biosynthesis in Salvia divinorum. J Exp Bot 68:1109–1122

    Article  PubMed  PubMed Central  Google Scholar 

  • Choi HW, Lee BG, Kim NH, Park Y, Lim CW, Song HK, Hwang BK (2008) A role for a menthone reductase in resistance against microbial pathogens in plants. Plant Physiol 148:383–401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chow JY, Tian BX, Ramamoorthy G, Hillerich BS, Seidel RD, Almo SC, Jacobson MP, Poulter CD (2015) Computational-guided discovery and characterization of a sesquiterpene synthase from Streptomyces clavuligerus. Proc Natl Acad Sci USA 112:5661–5666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Criswell J, Potter K, Shephard F, Beale MH, Peters RJ (2012) A single residue change leads to a hydroxylated product from the class II diterpene cyclization catalyzed by abietadiene synthase. Org Lett 14:5828–5831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dai Z, Liu Y, Huang L, Zhang X (2012) Production of miltiradiene by metabolically engineered Saccharomyces cerevisiae. Biotechnol Bioeng 109:2845–2853

    Article  CAS  PubMed  Google Scholar 

  • De Luca V, Salim V, Atsumi SM, Yu F (2012) Mining the biodiversity of plants: a revolution in the making. Science 336:1658–1661

    Article  PubMed  CAS  Google Scholar 

  • Dueber MT, Adolf W, West CA (1978) Biosynthesis of the diterpene phytoalexin casbene: partial purification and characterization of casbene synthetase from Ricinis communis. Plant Physiol 62:598–603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Engels B, Dahm P, Jennewein S (2008) Metabolic engineering of taxadiene biosynthesis in yeast as a first step towards Taxol (Paclitaxel) production. Metab Eng 10:201–206

    Article  CAS  PubMed  Google Scholar 

  • Englund E, Andersen-Ranberg J, Miao R, Hamberger B, Lindberg P (2015) Metabolic Engineering of Synechocystis sp. PCC 6803 for Production of the plant diterpenoid manoyl oxide. ACS Synth Biol 4:1270–1278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Facchini PJ, Bohlmann J, Covello PS, De Luca V, Mahadevan R, Page JE, Ro DK, Sensen CW, Storms R, Martin VJ (2012) Synthetic biosystems for the production of high-value plant metabolites. Trends Biotechnol 30:127–131

    Article  CAS  PubMed  Google Scholar 

  • Formighieri C, Melis A (2017) Heterologous synthesis of geranyllinalool, a diterpenol plant product, in the cyanobacterium Synechocystis. Appl Microbiol Biotechnol 101:2791–2800

    Article  CAS  PubMed  Google Scholar 

  • Galanie S, Thodey K, Trenchard IJ, Filsinger Interrante M, Smolke CD (2015) Complete biosynthesis of opioids in yeast. Science 349:1095–1100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao W, Sun HX, Xiao H, Cui G, Hillwig ML, Jackson A, Wang X, Shen Y, Zhao N, Zhang L, Wang XJ, Peters RJ, Huang L (2014) Combining metabolomics and transcriptomics to characterize tanshinone biosynthesis in Salvia miltiorrhiza. BMC Genom 15:73

    Article  Google Scholar 

  • Gao J, Chen T, Zhao D, Zheng J, Liu Z (2016) Ginkgolide B exerts cardioprotective properties against doxorubicin-Induced cardiotoxicity by regulating reactive oxygen species, akt and calcium signaling pathways in vitro and in vivo. PLoS ONE 11:e0168219

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • George KW, Thompson MG, Kang A, Baidoo E, Wang G, Chan LJ, Adams PD, Petzold CJ, Keasling JD, Lee TS (2015) Metabolic engineering for the high-yield production of isoprenoid-based C(5) alcohols in E. coli. Sci Rep 5:11128

    Article  PubMed  PubMed Central  Google Scholar 

  • Gershenzon J, Dudareva N (2007) The function of terpene natural products in the natural world. Nat Chem Biol 3:408–414

    Article  CAS  PubMed  Google Scholar 

  • Gnanasekaran T, Vavitsas K, Andersen-Ranberg J, Nielsen AZ, Olsen CE, Hamberger B, Jensen PE (2015) Heterologous expression of the isopimaric acid pathway in Nicotiana benthamiana and the effect of N-terminal modifications of the involved cytochrome P450 enzyme. J Biol Eng 9:24

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Guo J, Zhou YJ, Hillwig ML, Shen Y, Yang L, Wang Y, Zhang X, Liu W, Peters RJ, Chen X, Zhao ZK, Huang L (2013) CYP76AH1 catalyzes turnover of miltiradiene in tanshinones biosynthesis and enables heterologous production of ferruginol in yeasts. Proc Natl Acad Sci USA 110:12108–12113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo J, Ma X, Cai Y, Ma Y, Zhan Z, Zhou YJ, Liu W, Guan M, Yang J, Cui G, Kang L, Yang L, Shen Y, Tang J, Lin H, Ma X, Jin B, Liu Z, Peters RJ, Zhao ZK, Huang L (2016) Cytochrome P450 promiscuity leads to a bifurcating biosynthetic pathway for tanshinones. New Phytol 210:525–534

    Article  CAS  PubMed  Google Scholar 

  • Hamberger B, Bak S (2013) Plant P450 s as versatile drivers for evolution of species-specific chemical diversity. Philos Trans R Soc Lond B Biol Sci 368:20120426

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hansen NL, Heskes AM, Hamberger B, Olsen CE, Hallström BM, Andersen-Ranberg J (2016) The terpene synthase gene family in Tripterygium wilfordii harbors a labdane-type diterpene synthase among the monoterpene synthase TPS-b subfamily. Plant J. 89:429–441

    Article  CAS  Google Scholar 

  • Hardy K, Buckley S, Collins MJ, Estalrrich A, Brothwell D, Copeland L, Garcia-Tabernero A, Garcia-Vargas S, de la Rasilla M, Lalueza-Fox C, Huguet R, Bastir M, Santamaria D, Madella M, Wilson J, Cortes AF, Rosas A (2012) Neanderthal medics? Evidence for food, cooking, and medicinal plants entrapped in dental calculus. Naturwissenschaften 99:617–626

    Article  CAS  PubMed  Google Scholar 

  • Hasan MM, Kim HS, Jeon JH, Kim SH, Moon B, Song JY, Shim SH, Baek KH (2014) Metabolic engineering of Nicotiana benthamiana for the increased production of taxadiene. Plant Cell Rep 33:895–904

    Article  CAS  PubMed  Google Scholar 

  • Hayashi K, Kawaide H, Notomi M, Sakigi Y, Matsuo A, Nozaki H (2006) Identification and functional analysis of bifunctional ent-kaurene synthase from the moss Physcomitrella patens. FEBS Lett 580:6175–6181

    Article  CAS  PubMed  Google Scholar 

  • Helmstädter A (2013) Tripterygium wilfordii Hook. f.—how a traditional Taiwanese medicinal plant found its way to the West. Pharmazie 68:643–646

    PubMed  Google Scholar 

  • Henry LK, Gutensohn M, Thomas ST, Noel JP, Dudareva N (2015) Orthologs of the archaeal isopentenyl phosphate kinase regulate terpenoid production in plants. Proc Natl Acad Sci USA 112:10050–10055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hirai S, Utsugi M, Iwamoto M, Nakada M (2015) Formal total synthesis of (-)-taxol through Pd-catalyzed eight-membered carbocyclic ring formation. Chemistry 21:355–359

    Article  CAS  PubMed  Google Scholar 

  • Ignea C, Trikka FA, Nikolaidis AK, Georgantea P, Ioannou E, Loupassaki S, Kefalas P, Kanellis AK, Roussis V, Makris AM, Kampranis SC (2015a) Efficient diterpene production in yeast by engineering Erg20p into a geranylgeranyl diphosphate synthase. Metab Eng 27:65–75

    Article  CAS  PubMed  Google Scholar 

  • Ignea C, Ioannou E, Georgantea P, Loupassaki S, Trikka FA, Kanellis AK, Makris AM, Roussis V, Kampranis SC (2015b) Reconstructing the chemical diversity of labdane-type diterpene biosynthesis in yeast. Metab Eng 28:91–103

    Article  CAS  PubMed  Google Scholar 

  • Ignea C, Athanasakoglou A, Ioannou E, Georgantea P, Trikka FA, Loupassaki S, Roussis V, Makris AM, Kampranis SC (2016a) Carnosic acid biosynthesis elucidated by a synthetic biology platform. Proc Natl Acad Sci USA 113:3681–3686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ignea C, Ioannou E, Georgantea P, Trikka FA, Athanasakoglou A, Loupassaki S, Roussis V, Makris AM, Kampranis SC (2016b) Production of the forskolin precursor 11β-hydroxy-manoyl oxide in yeast using surrogate enzymatic activities. Microb Cell Fact 15:46

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ikram NK, Zhan X, Pan XW, King BC, Simonsen HT (2015) Stable heterologous expression of biologically active terpenoids in green plant cells. Front Plant Sci 6:129

    Article  PubMed  PubMed Central  Google Scholar 

  • Jia M, Peters RJ (2016) Extending a Single Residue Switch for Abbreviating Catalysis in Plant ent-Kaurene Synthases. Front Plant Sci. 7:1765

    PubMed  PubMed Central  Google Scholar 

  • Jia M, Peters RJ (2017) Cis or trans with class II diterpene cyclases. Org Biomol Chem 15:3158–3160

    Article  CAS  PubMed  Google Scholar 

  • Jia M, Potter KC, Peters RJ (2016) Extreme promiscuity of a bacterial and a plant diterpene synthase enables combinatorial biosynthesis. Metab Eng 37:24–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jia M, Zhou K, Tufts S, Schulte S, Peters RJ (2017) A Pair of Residues That Interactively Affect Diterpene Synthase Product Outcome. ACS Chem Biol 12:862–867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jin B, Cui G, Guo J, Tang J, Duan L, Lin H, Shen Y, Chen T, Zhang H, Huang L (2017) Functional diversification of kaurene synthase-like genes. Plant Physiol. doi:10.1104/pp.17.00202

    Google Scholar 

  • Johnson HE, Banack SA, Cox PA (2008) Variability in content of the anti-AIDS drug candidate prostratin in Samoan populations of Homalanthus nutans. J Nat Prod 71:2041–2044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jørgensen L, McKerrall SJ, Kuttruff CA, Ungeheuer F, Felding J, Baran PS (2013) 14-step synthesis of (+)-ingenol from (+)-3-carene. Science 341:878–882

    Article  PubMed  CAS  Google Scholar 

  • Keasling JD (2012) Synthetic biology and the development of tools for metabolic engineering. Metab Eng 14:189–195

    Article  CAS  PubMed  Google Scholar 

  • Keeling CI, Bohlmann J (2006a) Diterpene resin acids in conifers. Phytochemistry 67:2415–2423

    Article  CAS  PubMed  Google Scholar 

  • Keeling CI, Bohlmann J (2006b) Genes, enzymes and chemicals of terpenoid diversity in the constitutive and induced defence of conifers against insects and pathogens. New Phytol 170:657–675

    Article  CAS  PubMed  Google Scholar 

  • Keeling CI, Weisshaar S, Lin RP, Bohlmann J (2008) Functional plasticity of paralogous diterpene synthases involved in conifer defense. Proc Natl Acad Sci USA 105:1085–1090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • King AJ, Brown GD, Gilday AD, Larson TR, Graham IA (2014) Production of bioactive diterpenoids in the Euphorbiaceae depends on evolutionarily conserved gene clusters. Plant Cell 26:3286–3298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kirby J, Nishimoto M, Park JG, Withers ST, Nowroozi F, Behrendt D, Rutledge EJ, Fortman JL, Johnson HE, Anderson JV, Keasling JD (2010) Cloning of casbene and neocembrene synthases from Euphorbiaceae plants and expression in Saccharomyces cerevisiae. Phytochemistry 71:1466–1473

    Article  CAS  PubMed  Google Scholar 

  • Kitaoka N, Lu X, Yang B, Peters RJ (2015) The application of synthetic biology to elucidation of plant mono-, sesqui-, and diterpenoid metabolism. Mol Plant 8:6–16

    Article  CAS  PubMed  Google Scholar 

  • Kivell B, Uzelac Z, Sundaramurthy S, Rajamanickam J, Ewald A, Chefer V, Jaligam V, Bolan E, Simonson B, Annamalai B, Mannangatti P, Prisinzano TE, Gomes I, Devi LA, Jayanthi LD, Sitte HH, Ramamoorthy S, Shippenberg TS (2014a) Salvinorin A regulates dopamine transporter function via a kappa opioid receptor and ERK1/2-dependent mechanism. Neuropharmacology 86:228–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kivell BM, Ewald AW, Prisinzano TE (2014b) Salvinorin A analogs and other kappa-opioid receptor compounds as treatments for cocaine abuse. Adv Pharmacol 69:481–511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klein AT, Yagnik GB, Hohenstein JD, Ji Z, Zi J, Reichert MD, MacIntosh GC, Yang B, Peters RJ, Vela J, Lee YJ (2015) Investigation of the chemical interface in the soybean-aphid and rice-bacteria interactions using MALDI-mass spectrometry imaging. Anal Chem 87:5294–5301

    Article  CAS  PubMed  Google Scholar 

  • Köksal M, Jin Y, Coates RM, Croteau R, Christianson DW (2011) Taxadiene synthase structure and evolution of modular architecture in terpene biosynthesis. Nature 469:116–120

    Article  PubMed  CAS  Google Scholar 

  • Köksal M, Potter K, Peters RJ, Christianson DW (2014) 1.55A-resolution structure of ent-copalyl diphosphate synthase and exploration of general acid function by site-directed mutagenesis. Biochim Biophys Acta 1840:184–190

    Article  PubMed  CAS  Google Scholar 

  • Kong MK, Kang HJ, Kim JH, Oh SH, Lee PC (2015) Metabolic engineering of the Stevia rebaudiana ent-kaurene biosynthetic pathway in recombinant Escherichia coli. J Biotechnol 214:95–102

    Article  CAS  PubMed  Google Scholar 

  • Kuhlbrandt W (2014) Cryo-EM enters a new era. Elife 3:e03678

    PubMed  Google Scholar 

  • Kutrzeba L, Dayan FE, Howell J, Feng J, Giner JL, Zjawiony JK (2007) Biosynthesis of salvinorin A proceeds via the deoxyxylulose phosphate pathway. Phytochemistry 68:1872–1881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lange BM, Fischedick JT, Lange MF, Srividya N, Šamec D, Poirier BC (2017) Integrative approaches for the identification and localization of specialized metabolites in Tripterygium roots. Plant Physiol 173:456–469

    Article  CAS  PubMed  Google Scholar 

  • Laule O, Furholz A, Chang HS, Zhu T, Wang X, Heifetz PB, Gruissem W, Lange M (2003) Crosstalk between cytosolic and plastidial pathways of isoprenoid biosynthesis in Arabidopsis thaliana. Proc Natl Acad Sci USA 100:6866–6871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laursen T, Borch J, Knudsen C, Bavishi K, Torta F, Martens HJ, Silvestro D, Hatzakis NS, Wenk MR, Dafforn TR, Olsen CE, Motawia MS, Hamberger B, Møller BL, Bassard JE (2016) Characterization of a dynamic metabolon producing the defense compound dhurrin in sorghum. Science 354:890–893

    Article  CAS  PubMed  Google Scholar 

  • Leonard E, Ajikumar PK, Thayer K, Xiao WH, Mo JD, Tidor B, Stephanopoulos G, Prather KL (2010) Combining metabolic and protein engineering of a terpenoid biosynthetic pathway for overproduction and selectivity control. Proc Natl Acad Sci USA 107:13654–13659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li C, Ng A, Xie L, Mao H, Qiu C, Srinivasan R, Yin Z, Hong Y (2016) Engineering low phorbol ester Jatropha curcas seed by intercepting casbene biosynthesis. Plant Cell Rep 35:103–114

    Article  CAS  PubMed  Google Scholar 

  • Line NJ, Burns AC, Butler SC, Casbohm J, Forsyth CJ (2016) Total synthesis of (-)-salvinorin A. Chemistry 22:17983–17986

    Article  CAS  PubMed  Google Scholar 

  • Luo D, Callari R, Hamberger B, Wubshet SG, Nielsen MT, Andersen-Ranberg J, Hallström BM, Cozzi F, Heider H, Lindberg Møller B, Staerk D (2016) Oxidation and cyclization of casbene in the biosynthesis of Euphorbia factors from mature seeds of Euphorbia lathyris L. Proc Natl Acad Sci USA 113(34):E5082–E5089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mafu S, Hillwig ML, Peters RJ (2011) A novel labda-7,13E-dien-15-ol-producing bifunctional diterpene synthase from Selaginella moellendorffii. ChemBioChem 12:1984–1987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mafu S, Jia M, Zi J, Morrone D, Wu Y, Xu M, Hillwig ML, Peters RJ (2016a) Probing the promiscuity of ent-kaurene oxidases via combinatorial biosynthesis. Proc Natl Acad Sci USA 113:2526–2531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mafu S, Fischer E, Addisson B, Riberio Barbosana I, Zerbe P (2016b) Substitution of two active site residues alters C9-hydroxylation in a class II diterpene synthase. ChemBioChem 17:2304–2307

    Article  CAS  PubMed  Google Scholar 

  • Mafu S, Karunanithi PS, Palazzo TA, Harrod BL, Rodriguez SM, Mollhoff IN, O’Brien TE, Tong S, Fiehn O, Tantillo DJ, Bohlmann J, Zerbe P (2017) Biosynthesis of the microtubule-destabilizing diterpene pseudolaric acid B from golden larch involves an unusual diterpene synthase. Proc Natl Acad Sci USA. doi:10.1073/pnas.1612901114

    PubMed  PubMed Central  Google Scholar 

  • Matasci N, Hung LH, Yan Z, Carpenter EJ, Wickett NJ, Mirarab S, Nguyen N, Warnow T, Ayyampalayam S, Barker M, Burleigh JG, Gitzendanner MA, Wafula E, Der JP, dePamphilis CW, Roure B, Philippe H, Ruhfel BR, Miles NW, Graham SW, Mathews S, Surek B, Melkonian M, Soltis DE, Soltis PS, Rothfels C, Pokorny L, Shaw JA, DeGironimo L, Stevenson DW, Villarreal JC, Chen T, Kutchan TM, Rolf M, Baucom RS, Deyholos MK, Samudrala R, Tian Z, Wu X, Sun X, Zhang Y, Wang J, Leebens-Mack J, Wong GK (2014) Data access for the 1,000 Plants (1KP) project. Gigascience 3:17

    Article  PubMed  PubMed Central  Google Scholar 

  • Matsuba Y, Nguyen TT, Wiegert K, Falara V, Gonzales-Vigil E, Leong B, Schäfer P, Kudrna D, Wing RA, Bolger AM, Usadel B, Tissier A, Fernie AR, Barry CS, Pichersky E (2013) Evolution of a complex locus for terpene biosynthesis in solanum. Plant Cell 25:2022–2036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Modi S, Kir D, Giri B, Majumder K, Arora N, Dudeja V, Banerjee S, Saluja AK (2016) Minnelide overcomes oxaliplatin resistance by downregulating the DNA repair pathway in pancreatic cancer. J Gastrointest Surg 20:13–23

    Article  PubMed  Google Scholar 

  • Morani AS, Ewald A, Prevatt-Smith KM, Prisinzano TE, Kivell BM (2013) The 2-methoxy methyl analogue of salvinorin A attenuates cocaine-induced drug seeking and sucrose reinforcements in rats. Eur J Pharmacol 720:69–76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morrone D, Lowry L, Determan MK, Hershey DM, Xu M, Peters RJ (2010) Increasing diterpene yield with a modular metabolic engineering system in E. coli: comparison of MEV and MEP isoprenoid precursor pathway engineering. Appl Microbiol Biotechnol 85:1893–1906

    Article  CAS  PubMed  Google Scholar 

  • Morrone D, Hillwig ML, Mead ME, Lowry L, Fulton DB, Peters RJ (2011) Evident and latent plasticity across the rice diterpene synthase family with potential implications for the evolution of diterpenoid metabolism in the cereals. Biochem J 435:589–595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nielsen MT, Ranberg JA, Christensen U, Christensen HB, Harrison SJ, Olsen CE, Hamberger B, Møller BL, Nørholm MH (2014) Microbial Synthesis of the Forskolin Precursor Manoyl Oxide in an Enantiomerically Pure Form. Appl Environ Microbiol 80:7258–7265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nozawa M, Suka Y, Hoshi T, Suzuki T, Hagiwara H (2008) Total synthesis of the hallucinogenic neoclerodane diterpenoid salvinorin A. Org Lett 10:1365–1368

    Article  CAS  PubMed  Google Scholar 

  • Nützmann HW, Osbourn A (2014) Gene clustering in plant specialized metabolism. Curr Opin Biotechnol 26:91–99

    Article  PubMed  CAS  Google Scholar 

  • Okamoto S, Yu F, Harada H, Okajima T, Hattan J, Misawa N, Utsumi R (2011) A short-chain dehydrogenase involved in terpene metabolism from Zingiber zerumbet. FEBS J 278:2892–2900

    Article  CAS  PubMed  Google Scholar 

  • Oliver NJ, Rabinovitch-Deere CA, Carroll AL, Nozzi NE, Case AE, Atsumi S (2016) Cyanobacterial metabolic engineering for biofuel and chemical production. Curr Opin Chem Biol 35:43–50

    Article  CAS  PubMed  Google Scholar 

  • O’Neill EC, Kelly S (2016) Engineering biosynthesis of high-value compounds in photosynthetic organisms. Crit Rev Biotechnol. doi:10.1080/07388551.2016.1237467

  • Paddon CJ, Keasling JD (2014) Semi-synthetic artemisinin: a model for the use of synthetic biology in pharmaceutical development. Nat Rev Microbiol 12:355–367

    Article  CAS  PubMed  Google Scholar 

  • Paddon CJ, Westfall PJ, Pitera DJ, Benjamin K, Fisher K, McPhee D, Leavell MD, Tai A, Main A, Eng D, Polichuk DR, Teoh KH, Reed DW, Treynor T, Lenihan J, Fleck M, Bajad S, Dang G, Dengrove D, Diola D, Dorin G, Ellens KW, Fickes S, Galazzo J, Gaucher SP, Geistlinger T, Henry R, Hepp M, Horning T, Iqbal T, Jiang H, Kizer L, Lieu B, Melis D, Moss N, Regentin R, Secrest S, Tsuruta H, Vazquez R, Westblade LF, Xu L, Yu M, Zhang Y, Zhao L, Lievense J, Covello PS, Keasling JD, Reiling KK, Renninger NS, Newman JD (2013) High-level semi-synthetic production of the potent antimalarial artemisinin. Nature 496:528–532

    Article  CAS  PubMed  Google Scholar 

  • Pan XW, Han L, Zhang YH, Chen DF, Simonsen HT (2015) Sclareol production in the moss Physcomitrella patens and observations on growth and terpenoid biosynthesis. Plant Biotechnol Rep 9:149–159

    Article  Google Scholar 

  • Pateraki I, Andersen-Ranberg J, Hamberger B, Heskes AM, Martens HJ, Zerbe P, Bach SS, Moller BL, Bohlmann J, Hamberger B (2014) Manoyl oxide (13R), the biosynthetic precursor of forskolin, is synthesized in specialized root cork cells in Coleus forskohlii. Plant Physiol 164:1222–1236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pateraki I, Heskes AM, Hamberger B (2015) Cytochromes P450 for terpene functionalisation and metabolic engineering. Adv Biochem Eng Biotechnol 148:107–139

    CAS  PubMed  Google Scholar 

  • Pateraki I, Andersen-Ranberg J, Jensen NB, Wubshet SG, Heskes AM, Forman V, Hallström B, Hamberger B, Motawia MS, Olsen CE, Staerk D, Hansen J, Møller BL, Hamberger B (2017) Total biosynthesis of the cyclic AMP booster forskolin from Coleus forskohlii. Elife 14:6

    Google Scholar 

  • Pelot KA, Mitchell R, Kwon M, Hagelthorn DM, Wardman JF, Chiang A, Bohlmann J, Ro DK, Zerbe P (2017a) Biosynthesis of the psychotropic plant diterpene salvinorin A: discovery and characterization of the Salvia divinorum clerodienyl diphosphate synthase. Plant J. 89:885–897

    Article  CAS  PubMed  Google Scholar 

  • Pelot KA, Hagelthorn DM, Addison JB, Zerbe P (2017b) Biosynthesis of the oxygenated diterpene nezukol in the medicinal plant Isodon rubescens is catalyzed by a pair of diterpene synthases. PLoS ONE 12:e0176507

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Peralta-Yahya PP, Zhang F, del Cardayre SB, Keasling JD (2012) Microbial engineering for the production of advanced biofuels. Nature 488:320–328

    Article  CAS  PubMed  Google Scholar 

  • Peters RJ (2010) Two rings in them all: the labdane-related diterpenoids. Nat Prod Rep 27:1521–1530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Petiwala SM, Johnson JJ (2015) Diterpenes from rosemary (Rosmarinus officinalis): defining their potential for anti-cancer activity. Cancer Lett 367:93–102

    Article  CAS  PubMed  Google Scholar 

  • Philippe RN, De Mey M, Anderson J, Ajikumar PK (2014) Biotechnological production of natural zero-calorie sweeteners. Curr Opin Biotechnol 26:155–161

    Article  CAS  PubMed  Google Scholar 

  • Potter KC, Zi J, Hong YJ, Schulte S, Malchow B, Tantillo DJ, Peters RJ (2016a) Blocking deprotonation with retention of aromaticity in a plant ent-copalyl diphosphate synthase leads to product rearrangement. Angew Chem Int Ed Engl 55:634–638

    Article  CAS  PubMed  Google Scholar 

  • Potter KC, Jia M, Hong YJ, Tantillo D, Peters RJ (2016b) Product rearrangement from altering a single residue in the rice syn-copalyl diphosphate synthase. Org Lett 18:1060–1063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rai A, Saito K (2016) Omics data input for metabolic modeling. Curr Opin Biotechnol 37:127–134

    Article  CAS  PubMed  Google Scholar 

  • Raskin I, Ribnicky DM, Komarnytsky S, Ilic N, Poulev A, Borisjuk N, Brinker A, Moreno DA, Ripoll C, Yakoby N, O’Neal JM, Cornwell T, Pastor I, Fridlender B (2002) Plants and human health in the twenty-first century. Trends Biotechnol 20:522–531

    Article  CAS  PubMed  Google Scholar 

  • Reski R, Parsons J, Decker EL (2015) Moss-made pharmaceuticals: from bench to bedside. Plant Biotechnol J 13:1191–1198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Riley AP, Groer CE, Young D, Ewald AW, Kivell BM, Prisinzano TE (2014) Synthesis and kappa-opioid receptor activity of furan-substituted salvinorin A analogues. J Med Chem 57:10464–10475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ro DK, Arimura G, Lau SY, Piers E, Bohlmann J (2005) Loblolly pine abietadienol/abietadienal oxidase PtAO (CYP720B1) is a multifunctional, multisubstrate cytochrome P450 monooxygenase. Proc Natl Acad Sci USA 102:8060–8065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roth BL, Baner K, Westkaemper R, Siebert D, Rice KC, Steinberg S, Ernsberger P, Rothman RB (2002) Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proc Natl Acad Sci USA 99:11934–11939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sallaud C, Giacalone C, Topfer R, Goepfert S, Bakaher N, Rosti S, Tissier A (2012) Characterization of two genes for the biosynthesis of the labdane diterpene Z-abienol in tobacco (Nicotiana tabacum) glandular trichomes. Plant J 72:1–17

    Article  CAS  PubMed  Google Scholar 

  • Schalk M, Pastore L, Mirata MA, Khim S, Schouwey M, Deguerry F, Pineda V, Rocci L, Daviet L (2012) Toward a biosynthetic route to sclareol and amber odorants. J Am Chem Soc 134:18900–18903

    Article  CAS  PubMed  Google Scholar 

  • Scheler U, Brandt W, Porzel A, Rothe K, Manzano D, Božić D, Papaefthimiou D, Balcke GU, Henning A, Lohse S, Marillonnet S, Kanellis AK, Ferrer A, Tissier A (2016) Elucidation of the biosynthesis of carnosic acid and its reconstitution in yeast. Nat Commun 7:12942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schmelz EA, Huffaker A, Sims JW, Christensen SA, Lu X, Okada K, Peters RJ (2014) Biosynthesis, elicitation and roles of monocot terpenoid phytoalexins. Plant J 79:659–678

    Article  CAS  PubMed  Google Scholar 

  • Shen Q, Li L, Jiang Y, Wang Q (2016) Functional characterization of ent-copalyl diphosphate synthase from Andrographis paniculata with putative involvement in andrographolides biosynthesis. Biotechnol Lett 38:131–137

    Article  CAS  PubMed  Google Scholar 

  • Shi M, Luo X, Ju G, Li L, Huang S, Zhang T, Wang H, Kai G (2016) Enhanced Diterpene Tanshinone Accumulation and Bioactivity of Transgenic Salvia miltiorrhiza Hairy Roots by Pathway Engineering. J Agric Food Chem 64:2523–2530

    Article  CAS  PubMed  Google Scholar 

  • Sumner LW, Lei Z, Nikolau BJ, Saito K (2015) Modern plant metabolomics: advanced natural product gene discoveries, improved technologies, and future prospects. Nat Prod Rep 32:212–229

    Article  CAS  PubMed  Google Scholar 

  • Ting HM, Wang B, Rydén AM, Woittiez L, van Herpen T, Verstappen FW, Ruyter-Spira C, Beekwilder J, Bouwmeester HJ, van der Krol A (2013) The metabolite chemotype of Nicotiana benthamiana transiently expressing artemisinin biosynthetic pathway genes is a function of CYP71AV1 type and relative gene dosage. New Phytol 199:352–366

    Article  CAS  PubMed  Google Scholar 

  • Valdes LJ (1994) Salvia divinorum and the unique diterpene hallucinogen, Salvinorin (divinorin) A. J Psychoactive Drugs 26:277–283

    Article  PubMed  Google Scholar 

  • van Herpen TW, Cankar K, Nogueira M, Bosch D, Bouwmeester HJ, Beekwilder J (2010) Nicotiana benthamiana as a production platform for artemisinin precursors. PLoS ONE 5:e14222

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Vaughan MM, Wang Q, Webster FX, Kiemle D, Hong YJ, Tantillo DJ, Coates RM, Wray AT, Askew W, O’Donnell C, Tokuhisa JG, Tholl D (2013) Formation of the unusual semivolatile diterpene rhizathalene by the Arabidopsis class I terpene synthase TPS08 in the root stele is involved in defense against belowground herbivory. Plant Cell 25:1108–1125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vranová E, Coman D, Gruissem W (2013) Network analysis of the MVA and MEP pathways for isoprenoid synthesis. Annu Rev Plant Biol 64:665–700

    Article  PubMed  CAS  Google Scholar 

  • Wang Q, Jia M, Huh JH, Muchlinski A, Peters RJ, Tholl D (2016a) Identification of a dolabellane type diterpene synthase and other root-expressed diterpene synthases in Arabidopsis. Front Plant Sci 7:1761

    PubMed  PubMed Central  Google Scholar 

  • Wang B, Kashkooli AB, Sallets A, Ting HM, de Ruijter NC, Olofsson L, Brodelius P, Pottier M, Boutry M, Bouwmeester H, van der Krol AR (2016b) Transient production of artemisinin in Nicotiana benthamiana is boosted by a specific lipid transfer protein from A. annua. Metab Eng 38:159–169

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Liu W, Xin C, Zheng Y, Cheng Y, Sun S, Li R, Zhu XG, Dai SY, Rentzepis PM, Yuan JS (2016c) Enhanced limonene production in cyanobacteria reveals photosynthesis limitations. Proc Natl Acad Sci USA 113:14225–14230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Williams DC, Wildung MR, Jin AQ, Dalal D, Oliver JS, Coates RM, Croteau R (2000) Heterologous expression and characterization of a “pseudomature” form of taxadiene synthase involved in paclitaxel (Taxol) biosynthesis and evaluation of a potential intermediate and inhibitors of the multistep diterpene cyclization reaction. Arch Biochem Biophys 379:137–146

    Article  CAS  PubMed  Google Scholar 

  • Wilson SA, Roberts SC (2012) Recent advances towards development and commercialization of plant cell culture processes for the synthesis of biomolecules. Plant Biotechnol J 10:249–268

    Article  CAS  PubMed  Google Scholar 

  • Wurtzel ET, Kutchan TM (2016) Plant metabolism, the diverse chemistry set of the future. Science 353:1232–1236

    Article  CAS  PubMed  Google Scholar 

  • Xu M, Wilderman PR, Peters RJ (2007) Following evolution’s lead to a single residue switch for diterpene synthase product outcome. Proc Natl Acad Sci USA 104:7397–7401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zeitlin L, Whaley KJ, Olinger GG, Jacobs M, Gopal R, Qiu X, Kobinger GP (2016) Antibody therapeutics for Ebola virus disease. Curr Opin Virol 17:45–49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zerbe P, Bohlmann J (2015a) Plant diterpene synthases: exploring modularity and metabolic diversity for bioengineering. Trends Biotechnol 33:419–428

    Article  CAS  PubMed  Google Scholar 

  • Zerbe P, Bohlmann J (2015b) Enzymes for synthetic biology of ambroxide-related diterpenoid fragrance compounds. Adv Biochem Eng Biotechnol 148:427–447

    CAS  PubMed  Google Scholar 

  • Zerbe P, Hamberger B, Yuen MM, Chiang A, Sandhu HK, Madilao LL, Nguyen A, Hamberger B, Bach SS, Bohlmann J (2013) Gene discovery of modular diterpene metabolism in nonmodel systems. Plant Physiol 162:1073–1091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zerbe P, Chiang A, Dullat H, O’Neil-Johnson M, Starks C, Hamberger B, Bohlmann J (2014) Diterpene synthases of the biosynthetic system of medicinally active diterpenoids in Marrubium vulgare. Plant J 79:914–927

    Article  CAS  PubMed  Google Scholar 

  • Zhan X, Zhang YH, Chen DF, Simonsen HT (2014) Metabolic engineering of the moss Physcomitrella patens to produce the sesquiterpenoids patchoulol and α/β-santalene. Front Plant Sci 5:636

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhou K, Gao Y, Hoy JA, Mann FM, Honzatko RB, Peters RJ (2012) Insights into diterpene cyclization from structure of bifunctional abietadiene synthase from Abies grandis. J Biol Chem 287:6840–6850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu C, Miao G, Guo J, Huo Y, Zhang X, Xie J, Feng J (2014) Establishment of Tripterygium wilfordii Hook. f. Hairy root culture and optimization of its culture conditions for the production of triptolide and wilforine. J Microbiol Biotechnol 24:823–834

    Article  CAS  PubMed  Google Scholar 

  • Zi J, Peters RJ (2013) Characterization of CYP76AH4 clarifies phenolic diterpenoid biosynthesis in the Lamiaceae. Org Biomol Chem 11:7650–7652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zi J, Mafu S, Peters RJ (2014a) To gibberellins and beyond! Surveying the evolution of (di)terpenoid metabolism. Annu Rev Plant Biol 65:259–286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zi J, Matsuba Y, Hong YJ, Jackson AJ, Tantillo DJ, Pichersky E, Peters RJ (2014b) Biosynthesis of lycosantalonol, a cis-prenyl derived diterpenoid. J Am Chem Soc 136:16951–16953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors acknowledge financial support by start-up funds through University of California-Davis, a UC Davis Academic Senate Research Grant Program, and a 2016 Hellman Fellowship (to PZ). We further gratefully acknowledge Mrs. Margaret Waddell who contributed the original watercolor artwork used Fig. 1.

Author information

Authors and Affiliations

  1. Department of Plant Biology, University of California-Davis, One Shields Avenue, Davis, CA, 95616, USA

    Sibongile Mafu & Philipp Zerbe

Authors
  1. Sibongile Mafu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Philipp Zerbe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Philipp Zerbe.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mafu, S., Zerbe, P. Plant diterpenoid metabolism for manufacturing the biopharmaceuticals of tomorrow: prospects and challenges. Phytochem Rev 17, 113–130 (2018). https://doi.org/10.1007/s11101-017-9513-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11101-017-9513-5

Keywords

Search

Navigation