Phytochemistry Reviews

, Volume 17, Issue 1, pp 113–130 | Cite as

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

  • Sibongile Mafu
  • Philipp ZerbeEmail author


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.


Diterpenoids Plant specialized metabolism Biopharmaceuticals Plant natural products Diterpene synthases 



Diterpene synthase


Geranylgeranyl diphosphate


Cytochrome P450-dependent monooxygenase


Copalyl diphosphate


Mass spectrometry



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.


  1. 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 330:70–74PubMedPubMedCentralCrossRefGoogle Scholar
  2. 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 55:2142–2146PubMedPubMedCentralCrossRefGoogle Scholar
  3. Anterola A, Shanle E, Perroud PF, Quatrano R (2009) Production of taxa-4(5),11(12)-diene by transgenic Physcomitrella patens. Transgenic Res 18:655–660PubMedCrossRefGoogle Scholar
  4. Banerjee S, Saluja A (2015) Minnelide, a novel drug for pancreatic and liver cancer. Pancreatology 15:S39–S43PubMedPubMedCentralCrossRefGoogle Scholar
  5. Beale MH (1990) The biosynthesis of C5-C20 terpenoid compounds. Nat Prod Rep 7:25–39PubMedCrossRefGoogle Scholar
  6. Birtić S, Dussort P, Pierre FX, Bily AC, Roller M (2015) Carnosic acid. Phytochemistry 115:9–19PubMedCrossRefGoogle Scholar
  7. Bjarnholt N, Li B, D’Alvise J, Janfelt C (2014) Mass spectrometry imaging of plant metabolites: principles and possibilities. Nat Prod Rep 31:818–837PubMedCrossRefGoogle Scholar
  8. 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 32:943–945PubMedCrossRefGoogle Scholar
  9. Bohlmann J, Keeling CI (2008) Terpenoid biomaterials. Plant J 54:656–669PubMedCrossRefGoogle Scholar
  10. 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–E88PubMedCrossRefGoogle Scholar
  11. 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:e0124106PubMedPubMedCentralCrossRefGoogle Scholar
  12. Brinker AM, Ma J, Lipsky PE, Raskin I (2007) Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae). Phytochemistry 68:732–766PubMedCrossRefGoogle Scholar
  13. Brückner K, Tissier A (2013) High-level diterpene production by transient expression in Nicotiana benthamiana. Plant Methods 9:46PubMedPubMedCentralCrossRefGoogle Scholar
  14. 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 101:52–64PubMedCrossRefGoogle Scholar
  15. 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 128:615–624PubMedPubMedCentralCrossRefGoogle Scholar
  16. 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 12:119PubMedPubMedCentralCrossRefGoogle Scholar
  17. 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 66:212–229PubMedCrossRefGoogle Scholar
  18. 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 68:1109–1122PubMedPubMedCentralCrossRefGoogle Scholar
  19. 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 148:383–401PubMedPubMedCentralCrossRefGoogle Scholar
  20. 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 112:5661–5666PubMedPubMedCentralCrossRefGoogle Scholar
  21. 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 14:5828–5831PubMedPubMedCentralCrossRefGoogle Scholar
  22. Dai Z, Liu Y, Huang L, Zhang X (2012) Production of miltiradiene by metabolically engineered Saccharomyces cerevisiae. Biotechnol Bioeng 109:2845–2853PubMedCrossRefGoogle Scholar
  23. De Luca V, Salim V, Atsumi SM, Yu F (2012) Mining the biodiversity of plants: a revolution in the making. Science 336:1658–1661PubMedCrossRefGoogle Scholar
  24. 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 62:598–603PubMedPubMedCentralCrossRefGoogle Scholar
  25. Engels B, Dahm P, Jennewein S (2008) Metabolic engineering of taxadiene biosynthesis in yeast as a first step towards Taxol (Paclitaxel) production. Metab Eng 10:201–206PubMedCrossRefGoogle Scholar
  26. 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 4:1270–1278PubMedPubMedCentralCrossRefGoogle Scholar
  27. 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 30:127–131PubMedCrossRefGoogle Scholar
  28. Formighieri C, Melis A (2017) Heterologous synthesis of geranyllinalool, a diterpenol plant product, in the cyanobacterium Synechocystis. Appl Microbiol Biotechnol 101:2791–2800PubMedCrossRefGoogle Scholar
  29. Galanie S, Thodey K, Trenchard IJ, Filsinger Interrante M, Smolke CD (2015) Complete biosynthesis of opioids in yeast. Science 349:1095–1100PubMedPubMedCentralCrossRefGoogle Scholar
  30. 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 15:73CrossRefGoogle Scholar
  31. 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:e0168219PubMedPubMedCentralCrossRefGoogle Scholar
  32. 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 5:11128PubMedPubMedCentralCrossRefGoogle Scholar
  33. Gershenzon J, Dudareva N (2007) The function of terpene natural products in the natural world. Nat Chem Biol 3:408–414PubMedCrossRefGoogle Scholar
  34. 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 9:24PubMedPubMedCentralCrossRefGoogle Scholar
  35. 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 110:12108–12113PubMedPubMedCentralCrossRefGoogle Scholar
  36. 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 210:525–534PubMedCrossRefGoogle Scholar
  37. 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 368:20120426PubMedPubMedCentralCrossRefGoogle Scholar
  38. 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. 89:429–441CrossRefGoogle Scholar
  39. 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 99:617–626PubMedCrossRefGoogle Scholar
  40. 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 33:895–904PubMedCrossRefGoogle Scholar
  41. 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 580:6175–6181PubMedCrossRefGoogle Scholar
  42. Helmstädter A (2013) Tripterygium wilfordii Hook. f.—how a traditional Taiwanese medicinal plant found its way to the West. Pharmazie 68:643–646PubMedGoogle Scholar
  43. 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 112:10050–10055PubMedPubMedCentralCrossRefGoogle Scholar
  44. Hirai S, Utsugi M, Iwamoto M, Nakada M (2015) Formal total synthesis of (-)-taxol through Pd-catalyzed eight-membered carbocyclic ring formation. Chemistry 21:355–359PubMedCrossRefGoogle Scholar
  45. 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 27:65–75PubMedCrossRefGoogle Scholar
  46. 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 28:91–103PubMedCrossRefGoogle Scholar
  47. 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 113:3681–3686PubMedPubMedCentralCrossRefGoogle Scholar
  48. 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 15:46PubMedPubMedCentralCrossRefGoogle Scholar
  49. 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 6:129PubMedPubMedCentralCrossRefGoogle Scholar
  50. Jia M, Peters RJ (2016) Extending a Single Residue Switch for Abbreviating Catalysis in Plant ent-Kaurene Synthases. Front Plant Sci. 7:1765PubMedPubMedCentralGoogle Scholar
  51. Jia M, Peters RJ (2017) Cis or trans with class II diterpene cyclases. Org Biomol Chem 15:3158–3160PubMedCrossRefGoogle Scholar
  52. Jia M, Potter KC, Peters RJ (2016) Extreme promiscuity of a bacterial and a plant diterpene synthase enables combinatorial biosynthesis. Metab Eng 37:24–34PubMedPubMedCentralCrossRefGoogle Scholar
  53. 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 12:862–867PubMedPubMedCentralCrossRefGoogle Scholar
  54. 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
  55. 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 71:2041–2044PubMedPubMedCentralCrossRefGoogle Scholar
  56. Jørgensen L, McKerrall SJ, Kuttruff CA, Ungeheuer F, Felding J, Baran PS (2013) 14-step synthesis of (+)-ingenol from (+)-3-carene. Science 341:878–882PubMedCrossRefGoogle Scholar
  57. Keasling JD (2012) Synthetic biology and the development of tools for metabolic engineering. Metab Eng 14:189–195PubMedCrossRefGoogle Scholar
  58. Keeling CI, Bohlmann J (2006a) Diterpene resin acids in conifers. Phytochemistry 67:2415–2423PubMedCrossRefGoogle Scholar
  59. 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 170:657–675PubMedCrossRefGoogle Scholar
  60. Keeling CI, Weisshaar S, Lin RP, Bohlmann J (2008) Functional plasticity of paralogous diterpene synthases involved in conifer defense. Proc Natl Acad Sci USA 105:1085–1090PubMedPubMedCentralCrossRefGoogle Scholar
  61. 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 26:3286–3298PubMedPubMedCentralCrossRefGoogle Scholar
  62. 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 71:1466–1473PubMedCrossRefGoogle Scholar
  63. 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 8:6–16PubMedCrossRefGoogle Scholar
  64. 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 86:228–240PubMedPubMedCentralCrossRefGoogle Scholar
  65. Kivell BM, Ewald AW, Prisinzano TE (2014b) Salvinorin A analogs and other kappa-opioid receptor compounds as treatments for cocaine abuse. Adv Pharmacol 69:481–511PubMedPubMedCentralCrossRefGoogle Scholar
  66. 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 87:5294–5301PubMedCrossRefGoogle Scholar
  67. Köksal M, Jin Y, Coates RM, Croteau R, Christianson DW (2011) Taxadiene synthase structure and evolution of modular architecture in terpene biosynthesis. Nature 469:116–120PubMedCrossRefGoogle Scholar
  68. 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 1840:184–190PubMedCrossRefGoogle Scholar
  69. 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 214:95–102PubMedCrossRefGoogle Scholar
  70. Kuhlbrandt W (2014) Cryo-EM enters a new era. Elife 3:e03678PubMedGoogle Scholar
  71. Kutrzeba L, Dayan FE, Howell J, Feng J, Giner JL, Zjawiony JK (2007) Biosynthesis of salvinorin A proceeds via the deoxyxylulose phosphate pathway. Phytochemistry 68:1872–1881PubMedPubMedCentralCrossRefGoogle Scholar
  72. 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 173:456–469PubMedCrossRefGoogle Scholar
  73. 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 100:6866–6871PubMedPubMedCentralCrossRefGoogle Scholar
  74. 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 354:890–893PubMedCrossRefGoogle Scholar
  75. 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 107:13654–13659PubMedPubMedCentralCrossRefGoogle Scholar
  76. 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 35:103–114PubMedCrossRefGoogle Scholar
  77. Line NJ, Burns AC, Butler SC, Casbohm J, Forsyth CJ (2016) Total synthesis of (-)-salvinorin A. Chemistry 22:17983–17986PubMedCrossRefGoogle Scholar
  78. 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–E5089PubMedPubMedCentralCrossRefGoogle Scholar
  79. Mafu S, Hillwig ML, Peters RJ (2011) A novel labda-7,13E-dien-15-ol-producing bifunctional diterpene synthase from Selaginella moellendorffii. ChemBioChem 12:1984–1987PubMedPubMedCentralCrossRefGoogle Scholar
  80. 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 113:2526–2531PubMedPubMedCentralCrossRefGoogle Scholar
  81. 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 17:2304–2307PubMedCrossRefGoogle Scholar
  82. 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 PubMedPubMedCentralGoogle Scholar
  83. 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 3:17PubMedPubMedCentralCrossRefGoogle Scholar
  84. 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 25:2022–2036PubMedPubMedCentralCrossRefGoogle Scholar
  85. 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 20:13–23PubMedCrossRefGoogle Scholar
  86. 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 720:69–76PubMedPubMedCentralCrossRefGoogle Scholar
  87. 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 85:1893–1906PubMedCrossRefGoogle Scholar
  88. 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 435:589–595PubMedPubMedCentralCrossRefGoogle Scholar
  89. 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 80:7258–7265PubMedPubMedCentralCrossRefGoogle Scholar
  90. Nozawa M, Suka Y, Hoshi T, Suzuki T, Hagiwara H (2008) Total synthesis of the hallucinogenic neoclerodane diterpenoid salvinorin A. Org Lett 10:1365–1368PubMedCrossRefGoogle Scholar
  91. Nützmann HW, Osbourn A (2014) Gene clustering in plant specialized metabolism. Curr Opin Biotechnol 26:91–99PubMedCrossRefGoogle Scholar
  92. 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 278:2892–2900PubMedCrossRefGoogle Scholar
  93. 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 35:43–50PubMedCrossRefGoogle Scholar
  94. O’Neill EC, Kelly S (2016) Engineering biosynthesis of high-value compounds in photosynthetic organisms. Crit Rev Biotechnol. doi: 10.1080/07388551.2016.1237467
  95. Paddon CJ, Keasling JD (2014) Semi-synthetic artemisinin: a model for the use of synthetic biology in pharmaceutical development. Nat Rev Microbiol 12:355–367PubMedCrossRefGoogle Scholar
  96. 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 496:528–532PubMedCrossRefGoogle Scholar
  97. 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 9:149–159CrossRefGoogle Scholar
  98. 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 164:1222–1236PubMedPubMedCentralCrossRefGoogle Scholar
  99. Pateraki I, Heskes AM, Hamberger B (2015) Cytochromes P450 for terpene functionalisation and metabolic engineering. Adv Biochem Eng Biotechnol 148:107–139PubMedGoogle Scholar
  100. 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 14:6Google Scholar
  101. 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. 89:885–897PubMedCrossRefGoogle Scholar
  102. 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:e0176507PubMedPubMedCentralCrossRefGoogle Scholar
  103. Peralta-Yahya PP, Zhang F, del Cardayre SB, Keasling JD (2012) Microbial engineering for the production of advanced biofuels. Nature 488:320–328PubMedCrossRefGoogle Scholar
  104. Peters RJ (2010) Two rings in them all: the labdane-related diterpenoids. Nat Prod Rep 27:1521–1530PubMedPubMedCentralCrossRefGoogle Scholar
  105. Petiwala SM, Johnson JJ (2015) Diterpenes from rosemary (Rosmarinus officinalis): defining their potential for anti-cancer activity. Cancer Lett 367:93–102PubMedCrossRefGoogle Scholar
  106. Philippe RN, De Mey M, Anderson J, Ajikumar PK (2014) Biotechnological production of natural zero-calorie sweeteners. Curr Opin Biotechnol 26:155–161PubMedCrossRefGoogle Scholar
  107. 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 55:634–638PubMedCrossRefGoogle Scholar
  108. 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 18:1060–1063PubMedPubMedCentralCrossRefGoogle Scholar
  109. Rai A, Saito K (2016) Omics data input for metabolic modeling. Curr Opin Biotechnol 37:127–134PubMedCrossRefGoogle Scholar
  110. 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 20:522–531PubMedCrossRefGoogle Scholar
  111. Reski R, Parsons J, Decker EL (2015) Moss-made pharmaceuticals: from bench to bedside. Plant Biotechnol J 13:1191–1198PubMedPubMedCentralCrossRefGoogle Scholar
  112. 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 57:10464–10475PubMedPubMedCentralCrossRefGoogle Scholar
  113. 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 102:8060–8065PubMedPubMedCentralCrossRefGoogle Scholar
  114. 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 99:11934–11939PubMedPubMedCentralCrossRefGoogle Scholar
  115. 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 72:1–17PubMedCrossRefGoogle Scholar
  116. 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 134:18900–18903PubMedCrossRefGoogle Scholar
  117. 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 7:12942PubMedPubMedCentralCrossRefGoogle Scholar
  118. 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 79:659–678PubMedCrossRefGoogle Scholar
  119. 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 38:131–137PubMedCrossRefGoogle Scholar
  120. 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 64:2523–2530PubMedCrossRefGoogle Scholar
  121. 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 32:212–229PubMedCrossRefGoogle Scholar
  122. 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 199:352–366PubMedCrossRefGoogle Scholar
  123. Valdes LJ (1994) Salvia divinorum and the unique diterpene hallucinogen, Salvinorin (divinorin) A. J Psychoactive Drugs 26:277–283PubMedCrossRefGoogle Scholar
  124. 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:e14222PubMedPubMedCentralCrossRefGoogle Scholar
  125. 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 25:1108–1125PubMedPubMedCentralCrossRefGoogle Scholar
  126. Vranová E, Coman D, Gruissem W (2013) Network analysis of the MVA and MEP pathways for isoprenoid synthesis. Annu Rev Plant Biol 64:665–700PubMedCrossRefGoogle Scholar
  127. 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 7:1761PubMedPubMedCentralGoogle Scholar
  128. 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 38:159–169PubMedCrossRefGoogle Scholar
  129. 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 113:14225–14230PubMedPubMedCentralCrossRefGoogle Scholar
  130. 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 379:137–146PubMedCrossRefGoogle Scholar
  131. Wilson SA, Roberts SC (2012) Recent advances towards development and commercialization of plant cell culture processes for the synthesis of biomolecules. Plant Biotechnol J 10:249–268PubMedCrossRefGoogle Scholar
  132. Wurtzel ET, Kutchan TM (2016) Plant metabolism, the diverse chemistry set of the future. Science 353:1232–1236PubMedCrossRefGoogle Scholar
  133. 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 104:7397–7401PubMedPubMedCentralCrossRefGoogle Scholar
  134. Zeitlin L, Whaley KJ, Olinger GG, Jacobs M, Gopal R, Qiu X, Kobinger GP (2016) Antibody therapeutics for Ebola virus disease. Curr Opin Virol 17:45–49PubMedPubMedCentralCrossRefGoogle Scholar
  135. Zerbe P, Bohlmann J (2015a) Plant diterpene synthases: exploring modularity and metabolic diversity for bioengineering. Trends Biotechnol 33:419–428PubMedCrossRefGoogle Scholar
  136. Zerbe P, Bohlmann J (2015b) Enzymes for synthetic biology of ambroxide-related diterpenoid fragrance compounds. Adv Biochem Eng Biotechnol 148:427–447PubMedGoogle Scholar
  137. 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 162:1073–1091PubMedPubMedCentralCrossRefGoogle Scholar
  138. 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 79:914–927PubMedCrossRefGoogle Scholar
  139. 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 5:636PubMedPubMedCentralCrossRefGoogle Scholar
  140. 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 287:6840–6850PubMedPubMedCentralCrossRefGoogle Scholar
  141. 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 24:823–834PubMedCrossRefGoogle Scholar
  142. Zi J, Peters RJ (2013) Characterization of CYP76AH4 clarifies phenolic diterpenoid biosynthesis in the Lamiaceae. Org Biomol Chem 11:7650–7652PubMedPubMedCentralCrossRefGoogle Scholar
  143. Zi J, Mafu S, Peters RJ (2014a) To gibberellins and beyond! Surveying the evolution of (di)terpenoid metabolism. Annu Rev Plant Biol 65:259–286PubMedPubMedCentralCrossRefGoogle Scholar
  144. 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 136:16951–16953PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2017

Authors and Affiliations

  1. 1.Department of Plant BiologyUniversity of California-DavisDavisUSA

Personalised recommendations