Cytochromes P450 for Terpene Functionalisation and Metabolic Engineering

  • Irini Pateraki
  • Allison Maree Heskes
  • Björn Hamberger
Part of the Advances in Biochemical Engineering/Biotechnology book series (ABE, volume 148)

Abstract

Abstract

Plants have evolved the capacity to produce a striking array of specialised metabolites. Terpenoids are the oldest and most diverse class of such compounds and have attracted interest for industrial and pharmaceutical applications. The development of biotechnological alternatives for their production is the focus of intense research. Photosynthetic systems provide new strategies for autotrophic metabolic engineering. Focusing on cytochromes P450, involved in the functionalisation of the core terpene molecules, this review highlights the latest approaches in this field and looks towards recent discoveries that have the potential to shape the future of terpenoid bioengineering.

Graphical Abstract

Keywords

Cytochromes P450 Biotechnology Terpenoids Production hosts Pathway engineering Terpenoid biosynthesis 

Abbreviations

P450

Cytochrome P450 dependent mono-oxygenase

POR

NADPH dependent cytochrome P450 oxidoreductase

CYP71A1 to CYP71 clan

Example of classification of P450s into subfamilies to clans

EST

Expressed sequence tag

Fsp3

Fraction of carbon atoms in compound with sp3 hybridisation

ER

Endoplasmatic reticulum

Notes

Acknowledgments

Financial support was provided by the UNIK [Universitetsforskningens Investeringskapital (Investment Capital for University Research)] Center for Synthetic Biology “bioSYNergy” at the University of Copenhagen, funded by the Research Initiative of the Danish Ministry of Science, Technology and Innovation (BH), and the Novo Nordisk Foundation (BH). Additional support was provided by a personal postdoctoral stipend awarded by the FP7 PEOPLE MARIE CURIE ACTIONS Intra-European Fellowships (IP).

References

  1. 1.
    Ajikumar PK, Xiao W-H, Tyo KEJ, Wang Y, Simeon F, Leonard E, Mucha O, Phon TH, Pfeifer B, Stephanopoulos G (2010) Isoprenoid Pathway Optimization for Taxol Precursor Overproduction in Escherichia coli. Science 330(6000):70–74Google Scholar
  2. 2.
    Alonso-Gutierrez J, Chan R, Batth TS, Adams PD, Keasling JD, Petzold CJ, Lee TS (2013) Metabolic engineering of Escherichia coli for limonene and perillyl alcohol production. Metab Eng 19:33–41Google Scholar
  3. 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(4):655–660Google Scholar
  4. 4.
    Augustin JM, Kuzina V, Andersen SB, Bak S (2011) Molecular activities, biosynthesis and evolution of triterpenoid saponins. Phytochemistry 72(6):435–457Google Scholar
  5. 5.
    Bach SS, Bassard JE, Andersen-Ranberg J, Moldrup ME, Simonsen HT, Hamberger B (2014) High-throughput testing of terpenoid biosynthesis candidate genes using transient expression in Nicotiana benthamiana. Methods Mol Biol 1153:245–255Google Scholar
  6. 6.
    Bach SS, King BC, Zhan X, Simonsen HT, Hamberger B (2014) Heterologous stable expression of terpenoid biosynthetic genes using the moss Physcomitrella patens. Methods Mol Biol 1153:257–271Google Scholar
  7. 7.
    Bak S, Kahn RA, Nielsen HL, Moller BL, Halkier BA (1998) Cloning of three A-type cytochromes P450, CYP71E1, CYP98, and CYP99 from Sorghum bicolor (L.) Moench by a PCR approach and identification by expression in Escherichia coli of CYP71E1 as a multifunctional cytochrome P450 in the biosynthesis of the cyanogenic glucoside dhurrin. Plant Mol Biol 36(3):393–405Google Scholar
  8. 8.
    Barnes HJ, Arlotto MP, Waterman MR (1991) Expression and enzymatic activity of recombinant cytochrome P450 17 alpha-hydroxylase in Escherichia coli. Proc Natl Acad Sci 88(13):5597–5601Google Scholar
  9. 9.
    Bertea CM, Freije JR, van der Woude H, Verstappen FW, Perk L, Marquez V, De Kraker JW, Posthumus MA, Jansen BJ, de Groot A, Franssen MC, Bouwmeester HJ (2005) Identification of intermediates and enzymes involved in the early steps of artemisinin biosynthesis in Artemisia annua. Planta Med 71(1):40–47Google Scholar
  10. 10.
    Bock R (2014) Genetic engineering of the chloroplast: novel tools and new applications. Curr Opin Biotechnol 26:7–13Google Scholar
  11. 11.
    Bohlmann J, Keeling CI (2008) Terpenoid biomaterials. Plant J Cell Mol Biol 54(4):656–669Google Scholar
  12. 12.
    Boutanaev AM, Moses T, Zi J, Nelson DR, Mugford ST, Peters RJ, Osbourn A (2014) Investigation of terpene diversification across multiple sequenced plant genomes. Proc Natl Acad Sci Google Scholar
  13. 13.
    Bruckner K, Tissier A (2013) High-level diterpene production by transient expression in Nicotiana benthamiana. Plant Methods 9(1):46Google Scholar
  14. 14.
    Butler MS (2008) Natural products to drugs: natural product-derived compounds in clinical trials. Nat Prod Rep 25(3):475–516Google Scholar
  15. 15.
    Butler CF, Peet C, McLean KJ, Baynham MT, Blankley RT, Fisher K, Rigby SE, Leys D, Voice MW, Munro AW (2014) Human P450-like oxidation of diverse proton pump inhibitor drugs by ‘gatekeeper’ mutants of flavocytochrome P450 BM3. Biochem J 460(2):247–259. LID—210.1042/BJ20140030 [doi]Google Scholar
  16. 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 12:119Google Scholar
  17. 17.
    Cankar K, van Houwelingen A, Bosch D, Sonke T, Bouwmeester H, Beekwilder J (2011) A chicory cytochrome P450 mono-oxygenase CYP71AV8 for the oxidation of (+)-valencene. FEBS Lett 585(1):178–182Google Scholar
  18. 18.
    Cankar K, van Houwelingen A, Goedbloed M, Renirie R, de Jong RM, Bouwmeester H, Bosch D, Sonke T, Beekwilder J (2014) Valencene oxidase CYP706M1 from Alaska cedar (Callitropsis nootkatensis). FEBS Lett 588(6):1001–1007Google Scholar
  19. 19.
    Castilho A, Bohorova N, Grass J, Bohorov O, Zeitlin L, Whaley K, Altmann F, Steinkellner H (2011) Rapid high yield production of different glycoforms of Ebola virus monoclonal antibody. PLoS ONE 6(10):e26040Google Scholar
  20. 20.
    Chang MCY, Eachus RA, Trieu W, Ro D-K, Keasling JD (2007) Engineering Escherichia coli for production of functionalized terpenoids using plant P450s. Nat Chem Biol 3(5):274–277Google Scholar
  21. 21.
    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(1):212–229Google Scholar
  22. 22.
    Coelho PS, Brustad EM, Kannan A, Arnold FH (2013) Olefin cyclopropanation via carbene transfer catalyzed by engineered cytochrome P450 enzymes. Science 339(6117):307–310Google Scholar
  23. 23.
    Cragg GM (1998) Paclitaxel (Taxol): a success story with valuable lessons for natural product drug discovery and development. Med Res Rev 18(5):315–331Google Scholar
  24. 24.
    Croteau R, Ketchum RB, Long R, Kaspera R, Wildung M (2006) Taxol biosynthesis and molecular genetics. Phytochem Rev 5(1):75–97Google Scholar
  25. 25.
    Cyr A, Wilderman PR, Determan M, Peters RJ (2007) A modular approach for facile biosynthesis of labdane-related diterpenes. J Am Chem Soc 129(21):6684–6685Google Scholar
  26. 26.
    Dai Z, Wang B, Liu Y, Shi M, Wang D, Zhang X, Liu T, Huang L, Zhang X (2014) Producing aglycons of ginsenosides in bakers’ yeast. Sci Rep 4:3698. doi: 10.1038/srep03698
  27. 27.
    de Kraker JW, Franssen MC, Joerink M, de Groot A, Bouwmeester HJ (2002) Biosynthesis of costunolide, dihydrocostunolide, and leucodin. Demonstration of cytochrome p450-catalyzed formation of the lactone ring present in sesquiterpene lactones of chicory. Plant Physiol 129(1):257–268Google Scholar
  28. 28.
    DeJong JM, Liu Y, Bollon AP, Long RM, Jennewein S, Williams D, Croteau RB (2006) Genetic engineering of taxol biosynthetic genes in Saccharomyces cerevisiae. Biotechnol Bioeng 93(2):212–224Google Scholar
  29. 29.
    Diaz-Chavez ML, Moniodis J, Madilao LL, Jancsik S, Keeling CI, Barbour EL, Ghisalberti EL, Plummer JA, Jones CG, Bohlmann J (2013) Biosynthesis of sandalwood oil: Santalum album CYP76F cytochromes P450 produce santalols and bergamotol. PLoS ONE 8(9):e75053Google Scholar
  30. 30.
    Dietrich JA, Yoshikuni Y, Fisher KJ, Woolard FX, Ockey D, McPhee DJ, Renninger NS, Chang MCY, Baker D, Keasling JD (2009) A novel semi-biosynthetic route for artemisinin production using engineered substrate-promiscuous P450BM3. ACS Chem Biol 4(4):261–267Google Scholar
  31. 31.
    Englund E, Pattanaik B, Ubhayasekera SJ, Stensjo K, Bergquist J, Lindberg P (2014) Production of squalene in Synechocystis sp. PCC 6803. PLoS ONE 9(3):e90270Google Scholar
  32. 32.
    Feller T, Thom P, Koch N, Spiegel H, Addai-Mensah O, Fischer R, Reimann A, Pradel G, Fendel R, Schillberg S, Scheuermayer M, Schinkel H (2013) Plant-based production of recombinant Plasmodium surface protein pf38 and evaluation of its potential as a vaccine candidate. PLoS ONE 8(11):e79920Google Scholar
  33. 33.
    Feyereisen R (2011) Arthropod CYPomes illustrate the tempo and mode in P450 evolution. Biochim Biophys Acta 1814(1):19–28Google Scholar
  34. 34.
    Frense D (2007) Taxanes: perspectives for biotechnological production. Appl Microbiol Biotechnol 73(6):1233–1240Google Scholar
  35. 35.
    Fukushima EO, Seki H, Ohyama K, Ono E, Umemoto N, Mizutani M, Saito K, Muranaka T (2011) CYP716A subfamily members are multifunctional oxidases in triterpenoid biosynthesis. Plant Cell Physiol 52(12):2050–2061Google Scholar
  36. 36.
    Fukushima EO, Seki H, Sawai S, Suzuki M, Ohyama K, Saito K, Muranaka T (2013) Combinatorial biosynthesis of legume natural and rare triterpenoids in engineered yeast. Plant Cell Physiol 54(5):740–749Google Scholar
  37. 37.
    Gavira C, Höfer R, Lesot A, Lambert F, Zucca J, Werck-Reichhart D (2013) Challenges and pitfalls of P450-dependent (+)-valencene bioconversion by Saccharomyces cerevisiae. Metab Eng 18:25–35Google Scholar
  38. 38.
    Geisler K, Hughes RK, Sainsbury F, Lomonossoff GP, Rejzek M, Fairhurst S, Olsen C-E, Motawia MS, Melton RE, Hemmings AM, Bak S, Osbourn A (2013) Biochemical analysis of a multifunctional cytochrome P450 (CYP51) enzyme required for synthesis of antimicrobial triterpenes in plants. Proc Natl Acad Sci 110(35):E3360–E3367Google Scholar
  39. 39.
    Gongora-Castillo E, Childs KL, Fedewa G, Hamilton JP, Liscombe DK, Magallanes-Lundback M, Mandadi KK, Nims E, Runguphan W, Vaillancourt B, Varbanova-Herde M, Dellapenna D, McKnight TD, O’Connor S, Buell CR (2012) Development of transcriptomic resources for interrogating the biosynthesis of monoterpene indole alkaloids in medicinal plant species. PLoS ONE 7(12):e52506Google Scholar
  40. 40.
    Guo J et al (2013) PNAS 110(29):12108–12113Google Scholar
  41. 41.
    Hahn S, Giritch A, Bartels D, Bortesi L, Gleba Y (2014) A novel and fully scalable Agrobacterium spray-based process for manufacturing cellulases and other cost-sensitive proteins in plants. Plant Biotechnol J. doi: 10.1111/pbi.12299 Early online version [Epub ahead of print]
  42. 42.
    Hamberger B, Bak S (2013) Plant P450s as versatile drivers for evolution of species-specific chemical diversity. Philos Trans R Soc B: Biol Sci 368(1612):20120426. doi: 10.1098/rstb.2012.0426
  43. 43.
    Hamberger B, Ohnishi T, Hamberger B, Séguin A, Bohlmann J (2011) Evolution of diterpene metabolism: sitka spruce CYP720B4 catalyzes multiple oxidations in resin acid biosynthesis of conifer defense against insects. Plant Physiol 157(4):1677–1695Google Scholar
  44. 44.
    Han JY, Kim HJ, Kwon YS, Choi YE (2011) The Cyt P450 enzyme CYP716A47 catalyzes the formation of protopanaxadiol from dammarenediol-II during ginsenoside biosynthesis in Panax ginseng. Plant Cell Physiol 52(12):2062–2073Google Scholar
  45. 45.
    Han J-Y, Hwang H-S, Choi S-W, Kim H-J, Choi Y-E (2012) Cytochrome P450 CYP716A53v2 catalyzes the formation of protopanaxatriol from protopanaxadiol during ginsenoside biosynthesis in Panax Ginseng. Plant Cell Physiol 53(9):1535–1545Google Scholar
  46. 46.
    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(8):617–626Google Scholar
  47. 47.
    Ikezawa N, Göpfert JC, Nguyen DT, Kim S-U, O’Maille PE, Spring O, Ro D-K (2011) Lettuce costunolide synthase (CYP71BL2) and its homolog (CYP71BL1) from sunflower catalyze distinct regio- and stereoselective hydroxylations in sesquiterpene lactone metabolism. J Biol Chem 286(24):21601–21611Google Scholar
  48. 48.
    Jackson CJ, Lamb DC, Marczylo TH, Warrilow AGS, Manning NJ, Lowe DJ, Kelly DE, Kelly SL (2002) A novel sterol 14α-demethylase/ferredoxin fusion protein (MCCYP51FX) from Methylococcus capsulatus represents a new class of the cytochrome P450 superfamily. J Biol Chem 277(49):46959–46965Google Scholar
  49. 49.
    Jennewein S, Rithner CD, Williams RM, Croteau RB (2001) Taxol biosynthesis: taxane 13α-hydroxylase is a cytochrome P450-dependent monooxygenase. Proc Natl Acad Sci 98(24):13595–13600Google Scholar
  50. 50.
    Jennewein S, Rithner CD, Williams RM, Croteau R (2003) Taxoid metabolism: taxoid 14β-hydroxylase is a cytochrome P450-dependent monooxygenase. Arch Biochem Biophys 413(2):262–270Google Scholar
  51. 51.
    Jennewein S, Long RM, Williams RM, Croteau R (2004) Cytochrome P450 taxadiene 5α-hydroxylase, a mechanistically unusual monooxygenase catalyzing the first oxygenation step of taxol biosynthesis. Chem Biol 11(3):379–387Google Scholar
  52. 52.
    Jensen K, Møller BL (2010) Plant NADPH-cytochrome P450 oxidoreductases. Phytochemistry 71(2–3):132–141Google Scholar
  53. 53.
    Jiang M, Stephanopoulos G, Pfeifer BA (2012) Toward biosynthetic design and implementation of Escherichia coli-derived paclitaxel and other heterologous polyisoprene compounds. Appl Environ Microbiol 78(8):2497–2504Google Scholar
  54. 54.
    Jorgensen K, Rasmussen AV, Morant M, Nielsen AH, Bjarnholt N, Zagrobelny M, Bak S, Moller BL (2005) Metabolon formation and metabolic channeling in the biosynthesis of plant natural products. Curr Opin Plant Biol 8(3):280–291Google Scholar
  55. 55.
    Kaspera R, Croteau R (2006) Cytochrome P450 oxygenases of taxol biosynthesis. Phytochem Rev 5(2–3):433–444Google Scholar
  56. 56.
    Kato-Noguchi H, Peters RJ (2013) The role of momilactones in rice allelopathy. J Chem Ecol 39(2):175–185Google Scholar
  57. 57.
    Kim J-E, Cheng KM, Craft NE, Hamberger B, Douglas CJ (2010) Over-expression of Arabidopsis thaliana carotenoid hydroxylases individually and in combination with a β-carotene ketolase provides insight into in vivo functions. Phytochemistry 71(2–3):168–178Google Scholar
  58. 58.
    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(8):3286–3298Google Scholar
  59. 59.
    Kirby J, Keasling JD (2009) Biosynthesis of plant isoprenoids: perspectives for microbial engineering. Annu Rev Plant Biol 60(1):335–355Google Scholar
  60. 60.
    Krokida A, Delis C, Geisler K, Garagounis C, Tsikou D, Pena-Rodriguez LM, Katsarou D, Field B, Osbourn AE, Papadopoulou KK (2013) A metabolic gene cluster in Lotus japonicus discloses novel enzyme functions and products in triterpene biosynthesis. New Phytol 200(3):675–690Google Scholar
  61. 61.
    Kunii M, Kitahama Y, Fukushima EO, Seki H, Muranaka T, Yoshida Y, Aoyama Y (2012) b-Amyrin oxidation by oat CYP51H10 expressed heterologously in yeast cells: the first example of CYP51-dependent metabolism other than the 14-demethylation of sterol precursors. Biol Pharm Bull 35(5):801–804Google Scholar
  62. 62.
    Lamb DC, Waterman MR (2013) Unusual properties of the cytochrome P450 superfamily. Philos Trans R Soc B: Biol Sci 368(1612):20120434. doi: 10.1098/rstb.2012.0434
  63. 63.
    Landry N, Pillet S, Favre D, Poulin JF, Trepanier S, Yassine-Diab B, Ward BJ (2014) Influenza virus-like particle vaccines made in Nicotiana benthamiana elicit durable, poly-functional and cross-reactive T cell responses to influenza HA antigens. Clin Immunol 154(2):164–177Google Scholar
  64. 64.
    Lassen LM, Nielsen AZ, Olsen CE, Bialek W, Jensen K, Moller BL, Jensen PE (2014) Anchoring a plant cytochrome P450 via PsaM to the thylakoids in Synechococcus sp. PCC 7002: evidence for light-driven biosynthesis. PLoS ONE 9(7):e102184Google Scholar
  65. 65.
    Laursen T, Møller BL, Bassard J-E (2014) Plasticity of specialized metabolism as mediated by dynamic metabolons. Trends Plant Sci. doi: 10.1016/j.tplants.2014.11.002 [Epub ahead of print]
  66. 66.
    Leonard E, Koffas MAG (2007) Engineering of artificial plant cytochrome P450 enzymes for synthesis of isoflavones by Escherichia coli. Appl Environ Microbiol 73(22):7246–7251Google Scholar
  67. 67.
    Leroi-Gourhan A (1975) The flowers found with Shanidar IV, a neanderthal burial in Iraq. Science 190(4214):562–564Google Scholar
  68. 68.
    Li Y, Pfeifer BA (2014) Heterologous production of plant-derived isoprenoid products in microbes and the application of metabolic engineering and synthetic biology. Curr Opin Plant Biol 19:8–13Google Scholar
  69. 69.
    Liu T, Khosla C (2010) A balancing act for taxol precursor pathways in E. coli. Science 330(6000):44–45Google Scholar
  70. 70.
    Liu Q, Majdi M, Cankar K, Goedbloed M, Charnikhova T, Verstappen FW, de Vos RC, Beekwilder J, van der Krol S, Bouwmeester HJ (2011) Reconstitution of the costunolide biosynthetic pathway in yeast and Nicotiana benthamiana. PLoS ONE 6(8):e23255Google Scholar
  71. 71.
    Liu Q, Manzano D, Tanic N, Pesic M, Bankovic J, Pateraki I, Ricard L, Ferrer A, de Vos R, van de Krol S, Bouwmeester H (2014) Elucidation and in planta reconstitution of the parthenolide biosynthetic pathway. Metab Eng 23:145–153Google Scholar
  72. 72.
    Lovering F (2013) Escape from Flatland 2: complexity and promiscuity. Med Chem Comm 4(3):515–519Google Scholar
  73. 73.
    Lovering F, Bikker J, Humblet C (2009) Escape from Flatland: increasing saturation as an approach to improving clinical success. J Med Chem 52(21):6752–6756Google Scholar
  74. 74.
    Magome H et al (2013) PNAS 110(5):1947–1952Google Scholar
  75. 75.
    Mamedov T, Ghosh A, Jones RM, Mett V, Farrance CE, Musiychuk K, Horsey A, Yusibov V (2012) Production of non-glycosylated recombinant proteins in Nicotiana benthamiana plants by co-expressing bacterial PNGase F. Plant Biotechnol J 10(7):773–782Google Scholar
  76. 76.
    Margulies M, Egholm M, Altman WE, Attiya S, Bader JS, Bemben LA, Berka J, Braverman MS, Chen YJ, Chen Z, Dewell SB, Du L, Fierro JM, Gomes XV, Godwin BC, He W, Helgesen S, Ho CH, Irzyk GP, Jando SC, Alenquer ML, Jarvie TP, Jirage KB, Kim JB, Knight JR, Lanza JR, Leamon JH, Lefkowitz SM, Lei M, Li J, Lohman KL, Lu H, Makhijani VB, McDade KE, McKenna MP, Myers EW, Nickerson E, Nobile JR, Plant R, Puc BP, Ronan MT, Roth GT, Sarkis GJ, Simons JF, Simpson JW, Srinivasan M, Tartaro KR, Tomasz A, Vogt KA, Volkmer GA, Wang SH, Wang Y, Weiner MP, Yu P, Begley RF, Rothberg JM (2005) Genome sequencing in microfabricated high-density picolitre reactors. Nature 437(7057):376–380Google Scholar
  77. 77.
    Miettinen K, Dong L, Navrot N, Schneider T, Burlat V, Pollier J, Woittiez L, van der Krol S, Lugan R, Ilc T, Verpoorte R, Oksman-Caldentey KM, Martinoia E, Bouwmeester H, Goossens A, Memelink J, Werck-Reichhart D (2014) The seco-iridoid pathway from Catharanthus roseus. Nat Commun 5:3606Google Scholar
  78. 78.
    Moses T, Pollier J, Almagro L, Buyst D, Van Montagu M, Pedreno MA, Martins JC, Thevelein JM, Goossens A (2014) Combinatorial biosynthesis of sapogenins and saponins in Saccharomyces cerevisiae using a C-16alpha hydroxylase from Bupleurum falcatum. Proc Natl Acad Sci U S A 111(4):1634–1639Google Scholar
  79. 79.
    Moses T, Pollier J, Almagro L, Buyst D, Van Montagu M, Pedreño MA, Martins JC, Thevelein JM, Goossens A (2014) Combinatorial biosynthesis of sapogenins and saponins in Saccharomyces cerevisiae using a C-16α hydroxylase from Bupleurum falcatum. Proc Natl Acad Sci 111(4):1634–1639Google Scholar
  80. 80.
    Moses T, Pollier J, Faizal A, Apers S, Pieters L, Thevelein JM, Geelen D, Goossens A (2014) Unravelling the triterpenoid saponin biosynthesis of the african shrub Maesa lanceolata. Mol Plant 8(1):122−135. doi: 10.1016/j.molp.2014.11.004
  81. 81.
    Munro AW, Leys DG, McLean KJ, Marshall KR, Ost TWB, Daff S, Miles CS, Chapman SK, Lysek DA, Moser CC, Page CC, Dutton PL (2002) P450 BM3: the very model of a modern flavocytochrome. Trends Biochem Sci 27(5):250–257Google Scholar
  82. 82.
    Naoumkina MA, Modolo LV, Huhman DV, Urbanczyk-Wochniak E, Tang Y, Sumner LW, Dixon RA (2010) Genomic and coexpression analyses predict multiple genes involved in triterpene saponin biosynthesis in Medicago truncatula. Plant Cell 22(3):850–866Google Scholar
  83. 83.
    Nelson DR (1998) Metazoan cytochrome P450 evolution. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 121(1–3):15–22Google Scholar
  84. 84.
    Nelson DR (1999) Cytochrome P450 and the individuality of species. Arch Biochem Biophys 369(1):1–10Google Scholar
  85. 85.
    Nelson D, Werck-Reichhart D (2011) A P450-centric view of plant evolution. Plant J 66(1):194–211Google Scholar
  86. 86.
    Nelson DR, Koymans L, Kamataki T, Stegeman J, Feyereisen R, Waxman D, Waterman M, Gotoh O, Coon M, Estabrook R, Gunsalus I, Nebert D (1996) P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 6(1):1–42Google Scholar
  87. 87.
    Nelson DR, Schuler MA, Paquette SM, Werck-Reichhart D, Bak S (2004) Comparative genomics of rice and arabidopsis. analysis of 727 cytochrome P450 genes and pseudogenes from a monocot and a dicot. Plant Physiol 135(2):756–772Google Scholar
  88. 88.
    Newman DJ, Cragg GM (2012) Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod 75(3):311–335Google Scholar
  89. 89.
    Nielsen AZ, Ziersen B, Jensen K, Lassen LM, Olsen CE, Møller BL, Jensen PE (2013) Redirecting photosynthetic reducing power toward bioactive natural product synthesis. ACS Synth Biol 2(6):308–315Google Scholar
  90. 90.
    Noble MA, Miles CS, Chapman SK, Lysek DA, MacKay AC, Reid GA, Hanzlik RP, Munro AW (1999) Roles of key active-site residues in flavocytochrome P450 BM3. Biochem J 339:371–379Google Scholar
  91. 91.
    Nomura T, Magome H, Hanada A, Takeda-Kamiya N, Mander LN, Kamiya Y, Yamaguchi S (2013) Functional analysis of arabidopsis CYP714A1 and CYP714A2 reveals that they are distinct gibberellin modification enzymes. Plant Cell Physiol 54(11):1837–1851Google Scholar
  92. 92.
    Olinger GG Jr, Pettitt J, Kim D, Working C, Bohorov O, Bratcher B, Hiatt E, Hume SD, Johnson AK, Morton J, Pauly M, Whaley KJ, Lear CM, Biggins JE, Scully C, Hensley L, Zeitlin L (2012) Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques. Proc Natl Acad Sci U S A 109(44):18030–18035Google Scholar
  93. 93.
    Paddon CJ, Keasling JD (2014) Semi-synthetic artemisinin: a model for the use of synthetic biology in pharmaceutical development. Nat Rev Micro 12(5):355–367Google Scholar
  94. 94.
    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, Jiang H, 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, 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(7446):528–532Google Scholar
  95. 95.
    Panella NA, Dolan MC, Karchesy JJ, Xiong Y, Peralta-Cruz J, Khasawneh M, Montenieri JA, Maupin GO (2005) Use of novel compounds for pest control: insecticidal and acaricidal activity of essential oil components from heartwood of Alaska yellow cedar. J Med Entomol 42(3):352–358Google Scholar
  96. 96.
    Papadopoulou K, Melton RE, Leggett M, Daniels MJ, Osbourn AE (1999) Compromised disease resistance in saponin-deficient plants. Proc Natl Acad Sci U S A 96(22):12923–12928Google Scholar
  97. 97.
    Peters RJ (2006) Uncovering the complex metabolic network underlying diterpenoid phytoalexin biosynthesis in rice and other cereal crop plants. Phytochemistry 67(21):2307–2317Google Scholar
  98. 98.
    Qi X, Bakht S, Leggett M, Maxwell C, Melton R, Osbourn A (2004) A gene cluster for secondary metabolism in oat: implications for the evolution of metabolic diversity in plants. Proc Natl Acad Sci U S A 101(21):8233–8238Google Scholar
  99. 99.
    Quinlan RF, Shumskaya M, Bradbury LMT, Beltrán J, Ma C, Kennelly EJ, Wurtzel ET (2012) Synergistic interactions between carotene ring hydroxylases drive lutein formation in plant carotenoid biosynthesis. Plant Physiol 160(1):204–214Google Scholar
  100. 100.
    Renault H, Bassard JE, Hamberger B, Werck-Reichhart D (2014) Cytochrome P450-mediated metabolic engineering: current progress and future challenges. Curr Opin Plant Biol 19:27–34Google Scholar
  101. 101.
    Ro D-K, Arimura G-I, Lau SYW, Piers E, Bohlmann J (2005) Loblolly pine abietadienol/abietadienal oxidase PtAO (CYP720B1) is a multifunctional, multisubstrate cytochrome P450 monooxygenase. Proc Natl Acad Sci 102(22):8060–8065Google Scholar
  102. 102.
    Ro D-K, Paradise EM, Ouellet M, Fisher KJ, Newman KL, Ndungu JM, Ho KA, Eachus RA, Ham TS, Kirby J, Chang MCY, Withers ST, Shiba Y, Sarpong R, Keasling JD (2006) Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 440(7086):940–943Google Scholar
  103. 103.
    Saklani A, Kutty SK (2008) Plant-derived compounds in clinical trials. Drug Discov Today 13(3–4):161–171Google Scholar
  104. 104.
    Salim V, Yu F, Altarejos J, De Luca V (2013) Virus-induced gene silencing identifies Catharanthus roseus 7-deoxyloganic acid-7-hydroxylase, a step in iridoid and monoterpene indole alkaloid biosynthesis. Plant J 76(5):754–765Google Scholar
  105. 105.
    Saxena B, Subramaniyan M, Malhotra K, Bhavesh NS, Potlakayala SD, Kumar S (2014) Metabolic engineering of chloroplasts for artemisinic acid biosynthesis and impact on plant growth. J Biosci 39(1):33–41Google Scholar
  106. 106.
    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(46):18900–18903Google Scholar
  107. 107.
    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(4):659–678Google Scholar
  108. 108.
    Schoendorf A, Rithner CD, Williams RM, Croteau RB (2001) Molecular cloning of a cytochrome P450 taxane 10β-hydroxylase cDNA from taxus and functional expression in yeast. Proc Natl Acad Sci 98(4):1501–1506Google Scholar
  109. 109.
    Schuler MA, Werck-Reichhart D (2003) Functional genomics of P450s. Annu Rev Plant Biol 54(1):629–667Google Scholar
  110. 110.
    Schuler M, Duan H, Bilgin M, Ali S (2006) Arabidopsis cytochrome P450s through the looking glass: a window on plant biochemistry. Phytochem Rev 5(2–3):205–237Google Scholar
  111. 111.
    Seki H, Ohyama K, Sawai S, Mizutani M, Ohnishi T, Sudo H, Akashi T, Aoki T, Saito K, Muranaka T (2008) Licorice beta-amyrin 11-oxidase, a cytochrome P450 with a key role in the biosynthesis of the triterpene sweetener glycyrrhizin. Proc Natl Acad Sci U S A 105(37):14204–14209Google Scholar
  112. 112.
    Seki H, Sawai S, Ohyama K, Mizutani M, Ohnishi T, Sudo H, Fukushima EO, Akashi T, Aoki T, Saito K, Muranaka T (2011) Triterpene functional genomics in licorice for identification of CYP72A154 involved in the biosynthesis of glycyrrhizin. Plant Cell 23(11):4112–4123Google Scholar
  113. 113.
    Sezutsu H, Le Goff G, Feyereisen R (2013) Origins of P450 diversity. Philos Trans R Soc B: Biol Sci 368(1612):20120428. doi: 10.1098/rstb.2012.0428
  114. 114.
    Sharon-Asa L, Shalit M, Frydman A, Bar E, Holland D, Or E, Lavi U, Lewinsohn E, Eyal Y (2003) Citrus fruit flavor and aroma biosynthesis: isolation, functional characterization, and developmental regulation of Cstps1, a key gene in the production of the sesquiterpene aroma compound valencene. Plant J 36(5):664–674Google Scholar
  115. 115.
    Sintupachee S et al (2014) Plant Sci 229:131–141Google Scholar
  116. 116.
    Sullivan R, Behncke I, Purushotham A (2010) Why do we love medicines so much? An evolutionary perspective on the human love of pills, potions and placebo. EMBO Rep 11(8):572–578Google Scholar
  117. 117.
    Takahashi S, Yeo Y-S, Zhao Y, O’Maille PE, Greenhagen BT, Noel JP, Coates RM, Chappell J (2007) Functional characterization of premnaspirodiene oxygenase, a cytochrome P450 catalyzing regio- and stereo-specific hydroxylations of diverse sesquiterpene substrates. J Biol Chem 282(43):31744–31754Google Scholar
  118. 118.
    Teoh KH, Polichuk DR, Reed DW, Nowak G, Covello PS (2006) Artemisia annua L. (Asteraceae) trichome-specific cDNAs reveal CYP71AV1, a cytochrome P450 with a key role in the biosynthesis of the antimalarial sesquiterpene lactone artemisinin. FEBS Lett 580(5):1411–1416Google Scholar
  119. 119.
    Tian L, Musetti V, Kim J, Magallanes-Lundback M, DellaPenna D (2004) The arabidopsis LUT1 locus encodes a member of the cytochrome P450 family that is required for carotenoid ε-ring hydroxylation activity. Proc Natl Acad Sci 101(1):402–407Google Scholar
  120. 120.
    Ting HM, Wang B, Ryden 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(2):352–366Google Scholar
  121. 121.
    Tsuruta H, Paddon CJ, Eng D, Lenihan JR, Horning T, Anthony LC, Regentin R, Keasling JD, Renninger NS, Newman JD (2009) High-level production of amorpha-4,11-diene, a precursor of the antimalarial agent artemisinin, in Escherichia coli. PLoS ONE 4(2):e4489Google Scholar
  122. 122.
    van Beilen JB, Holtackers R, Lüscher D, Bauer U, Witholt B, Duetz WA (2005) Biocatalytic production of perillyl alcohol from limonene by using a novel Mycobacterium sp. Cytochrome P450 alkane hydroxylase expressed in Pseudomonas putida. Appl Environ Microbiol 71(4):1737–1744Google Scholar
  123. 123.
    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(12):e14222Google Scholar
  124. 124.
    Wang Q, Hillwig ML, Wu Y, Peters RJ (2012) CYP701A8: a rice ent-kaurene oxidase paralog diverted to more specialized diterpenoid metabolism. Plant Physiol 158(3):1418–1425Google Scholar
  125. 125.
    Wriessnegger T, Augustin P, Engleder M, Leitner E, Müller M, Kaluzna I, Schürmann M, Mink D, Zellnig G, Schwab H, Pichler H (2014) Production of the sesquiterpenoid (+)-nootkatone by metabolic engineering of Pichia pastoris. Metab Eng 24:18–29Google Scholar
  126. 126.
    Wu S, Jiang Z, Kempinski C, Eric Nybo S, Husodo S, Williams R, Chappell J (2012) Engineering triterpene metabolism in tobacco. Planta 236(3):867–877Google Scholar
  127. 127.
    Wurtzel ET, Quinlan R (2013) Cells and methods for producing lutein. WO2013119552 A2, PCT/US2013/024746. Aug 15, 2013 Google Scholar
  128. 128.
    Yokoshima S, Tokuyama H, Fukuyama T (2010) Total synthesis of (+)-vinblastine: control of the stereochemistry at C18′. Chem Rec 10(2):101–118Google Scholar
  129. 129.
    Yu F, Okamoto S, Harada H, Yamasaki K, Misawa N, Utsumi R (2011) Zingiber zerumbet CYP71BA1 catalyzes the conversion of α-humulene to 8-hydroxy-α-humulene in zerumbone biosynthesis. Cell Mol Life Sci 68(6):1033–1040Google Scholar
  130. 130.
    Yun C-H, Kim K-H, Kim D-H, Jung H-C, Pan J-G (2007) The bacterial P450 BM3: a prototype for a biocatalyst with human P450 activities. Trends Biotechnol 25(7):289–298Google Scholar
  131. 131.
    Zerbe P, Chiang A, Yuen M, Hamberger B, Hamberger B, Draper JA, Britton R, Bohlmann J (2012) Bifunctional cis-abienol synthase from Abies balsamea discovered by transcriptome sequencing and its implications for diterpenoid fragrance production. J Biol Chem 287(15):12121–12131Google Scholar
  132. 132.
    Zerbe P, Hamberger B, Yuen MMS, 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(2):1073–1091Google Scholar
  133. 133.
    Zhan X, Han LA, Zhang Y-H, Chen D-F, Simonsen HT (2014) Metabolic engineering of the moss Physcomitrella patens to produce the sesquiterpenoids patchoulol and α/β-santalene. Front Plant Sci 5:636. doi:  10.3389/fpls.2014.00636 eCollection 2014
  134. 134.
    Zi J et al (2013) Org Biomol Chem 11:7650–7652Google Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Irini Pateraki
    • 1
    • 2
    • 3
  • Allison Maree Heskes
    • 1
    • 2
    • 3
  • Björn Hamberger
    • 2
    • 3
    • 4
  1. 1.Department of Plant and Environmental Sciences, Faculty of ScienceUniversity of CopenhagenCopenhagenDenmark
  2. 2.Center for Synthetic Biology bioSYNergyCopenhagenDenmark
  3. 3.Copenhagen Plant Sciences CentreUniversity of CopenhagenCopenhagenDenmark
  4. 4.Plant Biochemistry Laboratory, Department of Plant and Environmental SciencesUniversity of CopenhagenCopenhagenDenmark

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