Advertisement

Cannabinoids: Biosynthesis and Biotechnological Applications

  • Supaart Sirikantaramas
  • Futoshi Taura
Chapter

Abstract

Cannabinoids are unique terpenophenolic metabolites found only in Cannabis sativa. The biosynthetic mechanism of these compounds had long been ambiguous since conventional biogenetic studies using radiolabelled precursors did not provide definitive results. On the other hand, various enzymological, molecular biological, and omics-based studies conducted over the past two decades have identified the majority of the enzymes and genes involved in the cannabinoid pathway, opening the way to the biotechnological production of pharmacologically active cannabinoids. This chapter describes the history of the biosynthetic studies, in particular those focused on the biosynthetic enzymes, and recent topics linked to cannabinoid-related biotechnology.

Keywords

Hairy Root Hairy Root Culture Glandular Trichome Flavin Adenine Dinucleotide Secretory Cavity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

We would like to thank all the collaborators who contributed to our studies on cannabinoid biosynthesis. Research in the corresponding author’s laboratory was partially supported by grants from the Chulalongkorn Academic Advancement into Its 2nd Century Project (to SS) and Thailand Research Fund RG578008 (to SS).

References

  1. Abe I, Oguro S, Utsumi Y, Sano Y, Noguchi H (2005) Engineered biosynthesis of plant polyketides: chain length control in an octaketide-producing plant type III polyketide synthase. J Am Chem Soc 127:12709–12716CrossRefPubMedGoogle Scholar
  2. Abe I, Morita H (2010) Structure and function of the chalcone synthase superfamily of plant type III polyketide synthases. Nat Prod Rep 27:809–838CrossRefPubMedGoogle Scholar
  3. Akhtar MT, Mustafa NR, Verpoorte R (2015) Hydroxylation and glycosylation of Δ9-tetrahydrocannabinol by Catharanthus roseus cell suspension culture. Biocatal Biotransform. 33:279–286Google Scholar
  4. Alaoui MA, Ibrahimi A, Semlali O, Tarhda Z, Marouane M, Najwa A, Soulaymani A, Fahime EE (2014) Affinity comparison of different THCA synthase to CBGA using modeling computational approaches. Bioinformation 10:33–38CrossRefPubMedPubMedCentralGoogle Scholar
  5. Andre CM, Hausman J-F, Guerriero G (2016) Cannabis sativa: the plant of the thousand and one molecules. Front Plant Sci 7:19CrossRefPubMedPubMedCentralGoogle Scholar
  6. Appendino G, Gibbons S, Giana A, Pagani A, Grassi G, Stavri M, Smith E, Rahman MM (2008) Antibacterial cannabinoids from cannabis sativa: a structure-activity study. J Nat Prod 71:1427–1430CrossRefPubMedGoogle Scholar
  7. Austin MB, Noel JP (2003) The chalcone synthase superfamily of type III polyketide synthases. Nat Prod Rep 20:79–110CrossRefPubMedGoogle Scholar
  8. Baker D, Pryce G, Giovannoni G, Thompson AJ (2003) The therapeutic potential of cannabis. Lancet Neurol 2:291–298CrossRefPubMedGoogle Scholar
  9. Beaudry CM, Malerich JP, Trauner D (2005) Biosynthetic and biomimetic electrocyclizations. Chem Rev 105:4757–4778CrossRefPubMedGoogle Scholar
  10. Bielecka M, Kaminski F, Adams I, Poulson H, Sloan R, Li Y, Larson TR, Winzer T, Graham IA (2014) Targeted mutation of ∆12 and ∆15 desaturase genes in hemp produce major alterations in seed fatty acid composition including a high oleic hemp oil. Plant Biotechnol J 12:613–623CrossRefPubMedGoogle Scholar
  11. Cai Z, Kastell A, Knorr D, Smetanska I (2012) Exudation: an expanding technique for continuous production and release of secondary metabolites from plant cell suspension and hairy root cultures. Plant Cell Rep 31:461–477CrossRefPubMedGoogle Scholar
  12. Cascini F (2011) Investigations into the hypothesis of transgenic cannabis. J Forensic Sci 57:718–721CrossRefPubMedGoogle Scholar
  13. Chaohua C, Gonggu Z, Lining Z, Chunsheng G, Qing T, Jianhua C, Xinbo G, Dingxiang P, Jianguang S (2016) A rapid shoot regeneration protocol from the cotyledons of hemp (Cannabis sativa L.). Ind Crop Prod 83:61–65CrossRefGoogle Scholar
  14. Crombie L, Rossiter JT, Van Bruggen N, Whiting DA (1992) Deguelin cyclase, a prenyl to chromen transforming enzyme from Tephrosia vogellii. Phytochemistry 31:451–461CrossRefGoogle Scholar
  15. Croteau R (1987) Biosynthesis and catabolism of monoterpenoids. Chem Rev 87:929–954CrossRefGoogle Scholar
  16. Daniel B, Pavkov-Keller T, Steiner B, Dordic A, Gutmann A, Nidetzky B, Sensen CW, van der Graaff E, Wallner S, Gruber K, Macheroux P (2015) Oxidation of monolignols by members of the berberine bridge enzyme family suggests a role in cell wall metabolism. J Biol Chem 290:18770–18781CrossRefPubMedPubMedCentralGoogle Scholar
  17. de Meijer EPM, Bagatta M, Carboni A, Crucitti P, Moliterni VMC, Ranallib P, Mandolino G (2003) The inheritance of chemical phenotype in Cannabis sativa L. Genetics 163:335–346PubMedPubMedCentralGoogle Scholar
  18. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949CrossRefPubMedGoogle Scholar
  19. Dewick PM (2002) Aromatic polyketides. In: Medicinal natural products. a biosynthetic approach, Ed2. Wiley, Sussex, UK, pp 60–92Google Scholar
  20. de Zeeuw RA, Wijsbek J, Breimer DD, Vree TB, van Ginneken CA, van Rossum JM (1972) Cannabinoids with a propyl side chain in Cannabis. Occurrence chromatographic behavior. Science 175:778–779CrossRefPubMedGoogle Scholar
  21. Di Sansebastiano GP, Rizzello F, Durante M, Caretto S, Nisi R, De Paolis A (2015) Subcellular compartmentalization in protoplasts from Artemisia annua cell cultures: engineering attempts using a modified SNARE protein. J Biotechnol 202:146–152CrossRefPubMedGoogle Scholar
  22. Dijkman WP, de Gonzalo G, Mattevi A, Fraaije MW (2013) Flavoprotein oxidases: classification and applications. Appl Microbiol Biotechnol 97:5177–5188CrossRefPubMedGoogle Scholar
  23. Dittrich H, Kutchan TM (1991) Molecular cloning, expression, and induction of berberine bridge enzyme, an enzyme essential to the formation of benzophenanthridine alkaloids in the response of plants to pathogenic attack. Proc Natl Acad Sci U S A 88:9969–9973CrossRefPubMedPubMedCentralGoogle Scholar
  24. Eisenreich W, Schwarz M, Cartayrade A, Arigoni D, Zenk MH, Bacher A (1998) The deoxyxylulose phosphate pathway of terpenoid biosynthesis in plants and microorganisms. Chem Biol 5:R221–233CrossRefPubMedGoogle Scholar
  25. ElSohly MA, Slade D (2005) Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci 78:539–548CrossRefPubMedGoogle Scholar
  26. Fairbairn JW (1972) The trichomes and glands of Cannabis sativa L. Bull Narc 23:29–33Google Scholar
  27. Farag S, Kayser O (2015) Cannabinoids production by hairy root cultures of Cannabis sativa L. Am J Plant Sci 6:1874–1884Google Scholar
  28. Feeney M, Punja ZK (2003) Tissue culture and Agrobacterium-mediated transformation of hemp (Cannabis sativa L.). In Vitro Cell Dev Biol Plant 39:578–585CrossRefGoogle Scholar
  29. Fellermeier M, Zenk MH (1998) Prenylation of olivetolate by a hemp transferase yields cannabigerolic acid, the precursor of tetrahydrocannabinol. FEBS Lett 427:283–285CrossRefPubMedGoogle Scholar
  30. Fellermeier M, Eisenreich W, Bacher A, Zenk MH (2001) Biosynthesis of cannabinoids. Incorporation experiments with 13C-labeled glucoses. Eur J Biochem 268:1596–1604CrossRefPubMedGoogle Scholar
  31. Flores-Sanchez IJ, Verpoorte R (2008) Secondary metabolism in cannabis. Phytochem Rev 7:615–639CrossRefGoogle Scholar
  32. Flores-Sanchez IJ, Peč J, Fei J, Choi YH, Dušek J, Verpoorte R (2009) Elicitation studies in cell suspension cultures of Cannabis sativa L. J Biotechnol 143:157–168CrossRefPubMedGoogle Scholar
  33. Gagne SJ, Stout JM, Liu E, Boubakir Z, Clark SM, Page JE (2012) Identification of olivetolic acid cyclase from Cannabis sativa reveals a unique catalytic route to plant polyketides. Proc Natl Acad Sci U S A 109:12811–12816CrossRefPubMedPubMedCentralGoogle Scholar
  34. Galanie S, Thodey K, Trenchard IJ, Interrante MF, Smolke CD (2015) Complete biosymnthesis of opioids in yeast. Science 349:1095–1100CrossRefPubMedPubMedCentralGoogle Scholar
  35. Gaoni Y, Mechoulam R (1964) Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem Soc 86:1946–1647Google Scholar
  36. Giacoppo S, Mandolino G, Galuppo M, Bramanti P, Mazzon E (2014) Cannabinoids: new promising agents in the treatment of neurological diseases. Molecules 19:18781–18816CrossRefPubMedGoogle Scholar
  37. Guzman M (2003) Cannabinoids: potential anticancer agents. Nat Rev Cancer 3:745–755CrossRefPubMedGoogle Scholar
  38. Hirai MY, Sugiyama K, Sawada Y, Tohge T, Obayashi T, Suzuki A, Araki R, Sakurai N, Suzuki H, Aoki K, Goda H, Nishizawa OI, Shibata D, Saito K (2007) Omics-based identification of Arabidopsis Myb transcription factors regulating aliphatic glucosinolate biosynthesis. Proc Natl Acad Sci U S A 104:6478–6483CrossRefPubMedPubMedCentralGoogle Scholar
  39. Hampson AJ, Grimaldi M, Axelrod J, Wink D (1998) Cannabidiol and (–) Δ9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A 95:8268–8273CrossRefPubMedPubMedCentralGoogle Scholar
  40. Hatoum NS, Davis WM, Elsohly MA, Turner CE (1981) Cannabichromene and delta 9-tetrahydrocannabinol: interactions relative to lethality, hypothermia and hexobarbital hypnosis. Gen Pharmacol 12:357–362CrossRefPubMedGoogle Scholar
  41. Kajima M, Piraux M (1982) The biogenesis of cannabinoids in Cannabis sativa. Phytochemistry 21:67–69CrossRefGoogle Scholar
  42. Kim ES, Mahlberg PG (1997) Immunochemical localization of tetrahydrocannabinol (THC) in cryofixed glandular trichomes of Cannabis (Cannabaceae). Am J Bot 84:336–342CrossRefPubMedGoogle Scholar
  43. Kimura M, Okamoto K (1970) Distribution of tetrahydrocannabinolic acid in fresh wild cannabis. Experientia 26:819–820CrossRefPubMedGoogle Scholar
  44. Kushima H, Shoyama Y, Nishioka I (1980) Cannabis XII: variations of cannabinoid contents in several strains of Cannabis sativa L. with leaf-age, season and sex. Chem Pharm Bull 28:594–598CrossRefGoogle Scholar
  45. Kutchan TM, Dittrich H (1995) Characterization and mechanism of the berberine bridge enzyme, a covalently flavinylated oxidase of benzophenanthridine alkaloid biosynthesis in plants. J Biol Chem 270:24475–24481CrossRefPubMedGoogle Scholar
  46. Lange K, Schmid A, Julsing MK (2015) ∆9-tetrahydrocannabinolic acid synthase production in Pichia pastoris enables chemical synthesis of cannbinoids. J Biotechnol 211:68–76CrossRefPubMedGoogle Scholar
  47. Lastres-Becker I, Molina-Holgado F, Ramos JA, Mechoulam R, Fernandez-Ruiz J (2005) Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson’s disease. Neurobiol Dis 19:96–107CrossRefPubMedGoogle Scholar
  48. Leferinka NGH, Heutsb DPHM, Fraaijeb MW, van Berkela WJH (2008) The growing VAO flavoprotein family. Arch Biochem Biophys 474:292–301CrossRefGoogle Scholar
  49. Lindberg P, Park S, Melis A (2010) Engineering a platform for photosynthetic isoprene production in cyanobacteria, using Synechocystis as the model organism. Metab Eng 12:70–79CrossRefPubMedGoogle Scholar
  50. Liu J, Osbourn A, Ma P (2015) MYB transcription factors as regulators of phenylpropanoid metabolism in plants. Mol Plant 8:689–708CrossRefPubMedGoogle Scholar
  51. Ma X, Panjikar S, Koepke J, Loris E, Stöckigt J (2006) The structure of Rauvolfia serpentina strictosidine synthase is a novel six-bladed beta-propeller fold in plant protein. Plant Cell 18:907–920CrossRefPubMedPubMedCentralGoogle Scholar
  52. Marks MD, Tian L, Wenger JP, Omburo SN, Soto-Fuentes W, He J, Gang DR, Weiblen GD, Dixon RA (2009) Identification of candidate genes affecting ∆9-tetrahydrocannbinol biosynthesis in Cannabis sativa. J Exp Bot 13:3715–3726CrossRefGoogle Scholar
  53. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564CrossRefPubMedGoogle Scholar
  54. Mechoulam R (1970) Marihuana chemistry. Science 168:1159–1166CrossRefPubMedGoogle Scholar
  55. Mechoulam R, Benshabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR, Pertwee RG, Griffin G, Bayewitch M, Barg J, Vogel Z (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90CrossRefPubMedGoogle Scholar
  56. Mechoulam R (2000) Looking back at Cannabis research. Curr Pharm Des 6:1313–1322CrossRefPubMedGoogle Scholar
  57. Mora-Pale M, Sanchez-Rodriguez SP, Linhardt RJ, Dordick JS, Koffas MAG (2014) Biochemical strategies for enhancing the in vivo production of natural products with pharmaceutical potential. Curr Opin Biotechnol 25:86–94CrossRefPubMedGoogle Scholar
  58. Morimoto S, Komatsu K, Taura F, Shoyama Y (1997) Enzymological evidence for cannabichromenic acid biosynthesis. J Nat Prod 60:854–857CrossRefGoogle Scholar
  59. Morimoto S, Komatsu K, Taura F, Shoyama Y (1998) Purification and characterization of cannabichromenic acid synthase from Cannabis sativa. Phytochemistry 49:1525–1529CrossRefPubMedGoogle Scholar
  60. Morimoto S, Tanaka Y, Sasaki K, Tanaka H, Fukamizu T, Shoyama Y, Shoyama Y, Taura F (2007) Identification and characterization of cannabinoids that induce cell death through mitochondrial permeability transition in Cannabis leaf cells. J Biol Chem 282:20739–20751CrossRefPubMedGoogle Scholar
  61. Munakata R, Inoue T, Koeduka T, Karamat F, Olry A, Sugiyama A, Takanashi K, Dugrand A, Froelicher Y, Tanaka R, Uto Y, Hori H, Azuma J, Hehn A, Bourgaud F, Yazaki K (2014) Molecular cloning and characterization of a geranyl diphosphate-specific aromatic prenyltransferase from lemon. Plant Physiol 166:80–90CrossRefPubMedPubMedCentralGoogle Scholar
  62. Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65CrossRefPubMedGoogle Scholar
  63. 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 496:528–532CrossRefPubMedGoogle Scholar
  64. Page JE, Boubakir Z (2011) Aromatic prenyltransferase from Cannabis. Patent WO 2011(017798):A1Google Scholar
  65. Peč J, Flores-Sanchez IJ, Choi YH, Verpoorte R (2010) Metabolic analysis of elicited cell suspension cultures of Cannabis sativa L. by 1H-NMR spectroscopy. Biotechnol Lett 32:935–941CrossRefPubMedGoogle Scholar
  66. Pollastro F, Taglialatela-Scafati O, Allarà M, Muñoz E, Di Marzo V, de Petrocellis L, Appendino G (2011) Bioactive prenylogous cannabinoid from fiber hemp (Cannabis sativa). J Nat Prod 74:2019–2022CrossRefPubMedGoogle Scholar
  67. Rodríguez-Concepción M, Boronat A (2015) Breaking new ground in the regulation of the early steps of plant isoprenoid biosynthesis. Curr Opin Plant Biol 25:17–22CrossRefPubMedGoogle Scholar
  68. Runguphan W, O’Conner SE (2009) Metabolic reprogramming of periwinkle plant culture. Nat Chem Biol 5:151–153CrossRefPubMedPubMedCentralGoogle Scholar
  69. Saito K, Sudo H, Yamazaki M, Koseki-Nakamura M, Kitajima M, Takayama H, Aimi N (2001) Feasible production of camptothecin by hairy root culture of Ophiorriza pumila. Plant Cell Rep 20:267–271CrossRefGoogle Scholar
  70. Sirikantaramas S, Morimoto S, Shoyama Y, Ishikawa Y, Wada Y, Shoyama Y, Taura F (2004) The gene controlling marijuana psychoactivity: molecular cloning and heterologous expression of ∆1-tetrahydrocannabinolic acid synthase from Cannabis sativa L. J Biol Chem 279:39767–39774CrossRefPubMedGoogle Scholar
  71. Sirikantaramas S, Taura F, Tanaka Y, Ishikawa Y, Morimoto S, Shoyama Y (2005) Tetrahydrocannabinolic acid synthase, the enzyme controlling marijuana psychoactivity, is secreted into the storage cavity of the glandular trichomes. Plant Cell Physiol 46:1578–1582CrossRefPubMedGoogle Scholar
  72. Sirikantaramas S, Yamazaki M, Saito K (2008) Mechanisms of resistance to self-produced toxic secondary metabolites in plants. Phytochem Rev 7:467–477CrossRefGoogle Scholar
  73. Sirikantaramas S, Yamazaki M, Saito K (2014) How plants avoid the toxicity of self-produced defense bioactive compounds. In: Osbourn A, Goss, RJ, Carter GT (eds) Natural products: discourse, diversity, and design. Wiley, pp 69–82Google Scholar
  74. Shoyama Y, Yagi M, Nishioka I, Yamauchi T (1975) Biosynthesis of cannabinoid acids. Phytochemistry 14:2189–2192CrossRefGoogle Scholar
  75. Shoyama Y, Takeuchi A, Taura F, Tamada T, Adachi M, Kuroki R, Shoyama Y, Morimoto S (2005) Crystallization of ∆1-tetrahydrocannabinolic acid (THCA) synthase from Cannabis sativa. Acta Cryst F61:799–801Google Scholar
  76. Shoyama Y, Tamada T, Kurihara K, Takeuchi A, Taura F, Arai S, Blaber M, Shoyama Y, Morimoto S, Kuroki R (2012) Structur and function of ∆1-tetrahydrocannabinolic acid (THCA) synthase, the enzyme controlling the psychoactivity of Cannabis sativa. J Mol Biol 423:96–105CrossRefPubMedGoogle Scholar
  77. Springob K, Samappito S, Jindaprasert A, Schmidt J, Page JE, de-Eknamkul W, Kutchan TM (2007) A polyketide synthase of Plumbago indica that catalyzes the formation of hexaketide pyrones. FEBS J 274:406–417Google Scholar
  78. Stout JM, Boubakir Z, Ambrose SJ, Purves RW, Page JE (2012) The hexanoyl-CoA precursor for cannabinoid biosynthesis is formed by an acyl-activating enzyme in Cannabis sativa trichomes. Plant J 71:353–365PubMedGoogle Scholar
  79. Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, Yamashita A, Waku K (1995) 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 215:89–97CrossRefPubMedGoogle Scholar
  80. Syed YY, McKeage K, Scott LJ (2014) Delta-9-Tetrahydrocannabinol/Cannabidiol (Sativex®): a review of its use in patients with moderate to severe spasticity due to multiple sclerosis. Drugs 74:563–578CrossRefPubMedGoogle Scholar
  81. Tantong S, Incharoensakdi A, Sirikantaramas S, Lindblad P (2016) Potential of Synechocystis PCC 6803 as a novel cyanobacterial chassis for heterologous expression of enzymes in the trans-resveratrol biosynthetic pathway. Protein Express Purif 121:163–168CrossRefGoogle Scholar
  82. Taura F, Morimoto S, Shoyama Y, Mechoulam R (1995) First direct evidence for the mechanism of Δ1-tetrahydrocannabinolic acid biosynthesis. J Am Chem Soc 117:9766–9767CrossRefGoogle Scholar
  83. Taura F, Morimoto S, Shoyama Y (1996) Purification and characterization of cannabidiolic-acid synthase from Cannabis sativa L. Biochemical analysis of a novel enzyme that catalyzes the oxidocyclization of cannabigerolic acid to cannabidiolic acid. J Biol Chem 271:17411–17416CrossRefPubMedGoogle Scholar
  84. Taura F, Dono E, Sirikantaramas S, Yoshimura K, Shoyama Y, Morimoto S (2007a) Production of ∆1-tetrahydrocannabinolic acid by the biosynthetic enzyme secreted from transgenic Pichia pastoris. Biochem Biophys Res Commun 361:675–680CrossRefPubMedGoogle Scholar
  85. Taura F, Sirikantaramas S, Shoyama Y, Yoshikai K, Shoyama Y, Morimoto S (2007b) Cannabidiolic-acid synthase, the chemotype-determining enzyme in the fiber-type Cannabis sativa. FEBS Lett 581:2929–2934CrossRefPubMedGoogle Scholar
  86. Taura F, Sirikantaramas S, Shoyama Y, Shoyama Y, Morimoto S (2009a) Phytocannabinoids in Cannabis sativa: Recent studies on biosynthetic enzymes. In: Lambert DM (ed) Cannabinoids in nature and medicine. Wiley-VHCA AG, pp 51–65Google Scholar
  87. Taura F, Tanaka S, Taguchi C, Fukamizu T, Tanaka H, Shoyama Y, Morimoto S (2009b) Characterization of olivetol synthase, a polyketide synthase putatively involved in cannabinoid biosynthetic pathway. FEBS Lett 583:2061–2066CrossRefPubMedGoogle Scholar
  88. Thomas A, Stevenson LA, Wease KN, Price MR, Baillie G, Ross RA, Pertwee RG (2005) Evidence that the plant cannabinoid Delta9-tetrahydrocannabivarin is a cannabinoid CB1 and CB2 receptor antagonist. Br J Pharmacol 146:917–926CrossRefPubMedPubMedCentralGoogle Scholar
  89. Turner CE, Elsohly MA (1981) Biological activity of cannabichromene, its homologs and isomers. J Clin Pharmacol 21:283S–291SCrossRefPubMedGoogle Scholar
  90. van Bakel H, Stout JM, Cote AG, Tallon CM, Sharpe AG, Hughes TR, Page JE (2011) The draft genome and transcriptome of Cannabis sativa. Genome Biol 12:R102CrossRefPubMedPubMedCentralGoogle Scholar
  91. Wahby I, Caba JM, Ligero F (2013) Agrobacterium infection of hemp (Cannabis sativa L.): establishment of hairy root cultures. J Plant Interact 8:312–320CrossRefGoogle Scholar
  92. Weiblen GD, Wenger JP, Craft KJ, ElSohly MA, Medmedic Z, Treiber EL, Marks MD (2015) Gene duplication and divergence affecting drug content in Cannabis sativa. New Phytol 208:1241–1250CrossRefPubMedGoogle Scholar
  93. Welle R, Grisebach H (1988) Induction of phytoalexin synthesis in soybean: enzymatic cyclization of prenylated pterocarpans to glyceollin isomers. Arch Biochem Biophys 263:191–198CrossRefPubMedGoogle Scholar
  94. Winkler A, Lyskowski A, Riedl S, Puhl M, Kutchan TM, Macheroux P, Gruber K (2008) A concerted mechanism for berberine bridge enzyme. Nat Chem Biol 4:739–741CrossRefPubMedGoogle Scholar
  95. Yamauchi T, Shoyama Y, Aramaki H, Azuma T, Nishioka I (1967) Tetrahydrocannabinolic acid, a genuine substance of tetrahydrocannabinol. Chem Pharm Bull 15:1075–1076CrossRefPubMedGoogle Scholar
  96. Yang X, Matsui T, Kodama T, Mori T, Zhou X, Taura F, Noguchi H, Abe I, Morita H (2016) Structural basis for olivetolic acid formation by a polyketide cyclase from Cannabis sativa. FEBS J 283:1088–1106CrossRefPubMedGoogle Scholar
  97. Yazaki K, Sasaki K, Tsurumaru Y (2009) Prenylation of aromatic compounds, a key diversification of plant secondary metabolites. Phytochemistry 70:1739–1745CrossRefPubMedGoogle Scholar
  98. Yotoriyama M, Ito I, Takashima D, Shoyama Y, Nishioka I (1980) Plant breeding of Cannabis. Determination of cannabinoids by high-pressure liquid chromatography. Yakugaku Zasshi 100:611–614CrossRefPubMedGoogle Scholar
  99. Zirpel B, Stehle F, Kayser O (2015) Production of ∆9-tetrahydrocannabinolic acid from cannabigerolic acid by whole cells of Pichia (Komagataella) pastoris expression ∆9-tetrahydrocannabinolic acid synthase from Cannabis sativa L. Biotechnol Lett 37:1869–1875CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Biochemistry, Faculty of ScienceChulalongkorn UniversityPathum WanThailand
  2. 2.Omic Sciences and Bioinformatics CenterChulalongkorn UniversityPathum WanThailand
  3. 3.Laboratory of Medicinal Bio-Resources, Graduate School of Medicine and Pharmaceutical Sciences for ResearchUniversity of ToyamaSugitani, ToyamaJapan

Personalised recommendations