Current Perspectives on Biotechnological Cannabinoid Production in Plants

Julia Schachtsiek; Heribert Warzecha; Oliver Kayser; Felix Stehle

doi:10.1055/s-0043-125087

Planta Medica, Table of Contents

Planta Med 2018; 84(04): 214-220
DOI: 10.1055/s-0043-125087

Perspectives

Georg Thieme Verlag KG Stuttgart · New York

Current Perspectives on Biotechnological Cannabinoid Production in Plants

Julia Schachtsiek

¹Laboratory of Technical Biochemistry, Department of Biochemical and Chemical Engineering, TU Dortmund University, Dortmund, Germany

,

Heribert Warzecha

²Plant Biotechnology and Metabolic Engineering, Technische Universität Darmstadt, Darmstadt, Germany

,

Oliver Kayser

¹Laboratory of Technical Biochemistry, Department of Biochemical and Chemical Engineering, TU Dortmund University, Dortmund, Germany

,

Felix Stehle

¹Laboratory of Technical Biochemistry, Department of Biochemical and Chemical Engineering, TU Dortmund University, Dortmund, Germany

› Author Affiliations

Abstract

The plant Cannabis sativa contains a number of psychoactive chemical compounds, the cannabinoids, which possess a significant pharmaceutical potential. Recently, the usage of Cannabis for medicinal purposes was legalized in many countries. Thus, the study on the influence of different cannabinoids in combination with other Cannabis-derived compounds with respect to the treatment of various diseases becomes increasingly important. Besides the production of distinct cannabinoids in a heterologous host, like tobacco or yeast, transgenic Cannabis plants would be a suitable alternative to modify and therefore optimize the cannabinoid profile. This perspective highlights the current efforts on Cannabis cell culture systems, in vitro propagation, and transformation of the plant and reveals the resulting opportunities concerning biotechnological production of cannabinoids. Furthermore, alternative platform organisms for the heterologous production of cannabinoids, like tobacco, are considered and evaluated.

Key words

Cannabis sativa - Cannabaceae - synthetic biology - metabolic engineering - biotechnology - cell culture - tobacco

Full Text

References

References
1 Fasinu PS, Phillips S, ElSohly MA, Walker LA. Current status and prospects for cannabidiol preparations as new therapeutic agents. Pharmacotherapy 2016; 36: 781-796
2 Bifulco M, Pisanti S. Medicinal use of cannabis in Europe: the fact that more countries legalize the medicinal use of cannabis should not become an argument for unfettered and uncontrolled use. EMBO Rep 2015; 16: 130-132
3 Ablin J, Ste-Marie PA, Schäfer M, Häuser W, Fitzcharles MA. Medizinischer Gebrauch von Cannabisprodukten: Was können wir von Israel und Kanada lernen?. Schmerz 2016; 30: 3-13
4 Carlini EA. The good and the bad effects of (−) trans-delta-9-tetrahydrocannabinol (Δ⁹-THC) on humans. Toxicon 2004; 44: 461-467
5 Pertwee RG. Cannabinoid pharmacology: the first 66 years. Br J Pharmacol 2006; 147: 163-171
6 Andre CM, Hausman JF, Guerriero G. Cannabis sativa: the plant of the thousand and one molecules. Front Plant Sci 2016; 7: 1-17
7 Zirpel B, Stehle F, Kayser O. Production of Δ⁹-tetrahydrocannabinolic acid from cannabigerolic acid by whole cells of Pichia (Komagataella) pastoris expressing Δ⁹-tetrahydrocannabinolic acid synthase from Cannabis sativa L. Biotechnol Lett 2015; 37: 1869-1875
8 Zirpel B, Degenhardt F, Martin C, Kayser O, Stehle F. Engineering yeasts as platform organisms for cannabinoid biosynthesis. J Biotechnol 2017; 259: 204-212
9 Carvalho Â, Hansen EH, Kayser O, Carlsen S, Stehle F. Designing microorganisms for heterologous biosynthesis of cannabinoids. FEMS Yeast Res 2017;
10 Flores-Sanchez IJ, Peč J, Fei J, Choi YH, Dušek J, Verpoorte R. Elicitation studies in cell suspension cultures of Cannabis sativa L. J Biotechnol 2009; 143: 157-168
11 Pacifico D, Miselli F, Carboni A, Moschella A, Mandolino G. Time course of cannabinoid accumulation and chemotype development during the growth of Cannabis sativa L. Euphytica 2008; 160: 231-240
12 Sirikantaramas S, Taura F, Tanaka Y, Ishikawa Y, Morimoto S, Shoyama Y. Tetrahydrocannabinolic acid synthase, the enzyme controlling marijuana psychoactivity, is secreted into the storage cavity of the glandular trichomes. Plant Cell Physiol 2005; 46: 1578-1582
13 Morimoto S, Tanaka Y, Sasaki K, Tanaka H, Fukamizu T, Shoyama Y, Shoyama Y, Taura F. Identification and characterization of cannabinoids that induce cell death through mitochondrial permeability transition in Cannabis leaf cells. J Biol Chem 2007; 282: 20739-20751
14 Slusarkiewicz-Jarzina A, Ponitka A, Kaczmarek Z. Influence of cultivar, explant source and plant growth regulator on callus induction and plant regeneration of Cannabis sativa L. Acta Biol Cracoviensia Ser Bot 2005; 47: 145-151
15 Feeney M, Punja ZK. Tissue culture and Agrobacterium-mediated transformation of hemp (Cannabis sativa L.). Vitro Cell Dev Biol Plant 2003; 39: 578-585
16 Chandra S, Lata H. Micropropagation of Cannabis sativa L. – an Update. In: Chandra S, Lata H, Mahmoud A ElSohly. eds. Cannabis sativa L. – Botany and Biotechnology. Cham, Switzerland: Springer International Publishing AG; 2017: 285-298
17 Lata H, Chandra S, Techen N, Khan IA, ElSohly MA. In vitro mass propagation of Cannabis sativa L.: a protocol refinement using novel aromatic cytokinin meta-topolin and the assessment of eco-physiological, biochemical and genetic fidelity of micropropagated plants. J Appl Res Med Aromat Plants 2016; 3: 18-26
18 Sirkowski EE. Marked Cannabis for Indicating Medical Marijuana. US Patent 20120311744 A1, 06.12.2012
19 Chaohua C, Gonggu Z, Lining Z, Chunsheng G, Qing T, Jianhua C, Xinbo G, Dingxiang P, Jianguang S. A rapid shoot regeneration protocol from the cotyledons of hemp (Cannabis sativa L.). Ind Crops Prod 2016; 83: 61-65
20 Ghosh A, Igamberdiev AU, Debnath SC. Detection of DNA methylation pattern in thidiazuron-induced blueberry callus using methylation-sensitive amplification polymorphism. Biol Plant 2017; 61: 511-519
21 Kaeppler SM, Kaeppler HF, Rhee Y. Epigenetic aspects of somaclonal variation in plants. Plant Mol Biol 2000; 43: 179-188
22 Park SY, Murthy HN, Chakrabarthy D, Paek KY. Detection of epigenetic variation in tissue-culture-derived plants of Doritaenopsis by methylation-sensitive amplification polymorphism (MSAP) analysis. Vitro Cell Dev Biol Plant 2009; 45: 104-108
23 Wahby I, Caba JM, Ligero F. Agrobacterium infection of hemp (Cannabis sativa L.): establishment of hairy root cultures. J Plant Interact 2013; 8: 312-320
24 Ruffoni B, Pistelli L, Bertoli A, Pistelli L. Plant Cell Cultures: Bioreactors for industrial Production. In: Giardi MT, Rea G, Berra B. eds. Bio-Farms for Nutraceuticals: functional Food and Safety Control by Biosensors. Berlin/Heidelberg: Landes Bioscience and Springer Science + Business Media; 2009: 203-221
25 Vainstein A, Marton I, Zuker A, Danziger M, Tzfir T. Permanent genome modifications in plant cells by transient viral vectors. Acta Hortic 2012; 953: 31-36
26 Staniek A, Bouwmeester H, Fraser PD, Kayser O, Martens S, Tissier A, van der Krol S, Wessjohann L, Warzecha H. Natural products – modifying metabolite pathways in plants. Biotechnol J 2013; 8: 1159-1171
27 Jube S, Borthakur D. Expression of bacterial genes in transgenic tobacco: methods, applications and future prospects. Electron J Biotechnol 2007; 10: 452-467
28 Jiang Z, Kempinski C, Bush CJ, Nybo SE, Chappell J. Engineering triterpene and methylated triterpene production in plants provides biochemical and physiological insights into terpene metabolism. Plant Physiol 2015; 170: 702-716
29 Rontein D, Onillon S, Herbette G, Lesot A, Werck-Reichhart D, Sallaud C, Tissier A. CYP725A4 from yew catalyzes complex structural rearrangement of taxa-4(5), 11(12)-diene into the cyclic ether 5(12)-oxa-3(11)-cyclotaxane. J Biol Chem 2008; 283: 6067-6075
30 Eisenreich W, Bacher A, Arigoni D, Rohdich F. Biosynthesis of isoprenoids via the non-mevalonate pathway. Cell Mol Life Sci 2004; 61: 1401-1426
31 Tissier A. Trichome specific Expression: Promoters and their Applications. In: Çiftçi YÖ. ed. Transgenic Plants – Advances and Limitations. Rijeka, Croatia: InTechOpen; 2012: 353-378
32 Brückner K, Tissier A. High-level diterpene production by transient expression in Nicotiana benthamiana . Plant Methods 2013; 9: 46
33 Kumar S, Hahn FM, Baidoo E, Kahlon TS, Wood DF, McMahan CM, Cornish K, Keasling JD, Daniell H, Whalen MC. Remodeling the isoprenoid pathway in tobacco by expressing the cytoplasmic mevalonate pathway in chloroplasts. Metab Eng 2012; 14: 19-28
34 Malhotra K, Subramaniyan M, Rawat K, Kalamuddin M, Qureshi MI, Malhotra P, Mohmmed A, Cornish K, Daniell H, Kumar S. Compartmentalized metabolic engineering for artemisinin biosynthesis and effective malaria treatment by oral delivery of plant cells. Mol Plant 2016; 9: 1464-1477
35 Bick JA, Lange BM. Metabolic cross talk between cytosolic and plastidial pathways of isoprenoid biosynthesis: unidirectional transport of intermediates across the chloroplast envelope membrane. Arch Biochem Biophys 2003; 415: 146-154
36 Clark TJ, Bunch JE. Determination of volatile acids in tobacco, tea, and coffee using derivatization – purge and trap gas chromatography – selected ion monitoring mass spectrometry. J Chromatogr Sci 1997; 35: 206-208
37 Cheon Y, Kim JS, Park JB, Heo P, Lim JH, Jung GY, Seo JH, Park JH, Koo HM, Cho KM, Park JB, Ha SJ, Kweon DH. A biosynthetic pathway for hexanoic acid production in Kluyveromyces marxianus . J Biotechnol 2014; 182 – 183: 30-36
38 Hitchman T. Hexanoate synthase, a specialized type I fatty acid synthase in aflatoxin B₁ biosynthesis. Bioorg Chem 2001; 29: 293-307
39 Page JE, Boubakir Z. Aromatic Prenyltransferase from Cannabis . US Patent 8884100 B2, 11.11.2014
40 Sirikantaramas S, Morimoto S, Shoyama Y, Ishikawa Y, Wada Y, Shoyama Y, Taura F. The gene controlling marijuana psychoactivity: molecular cloning and heterologous expression of Delta1-tetrahydrocannabinolic acid synthase from Cannabis sativa L. J Biol Chem 2004; 279: 39767-39774
41 Nonaka S, Arai C, Takayama M, Matsukura C, Ezura H. Efficient increase of γ-aminobutyric acid (GABA) content in tomato fruits by targeted mutagenesis. Sci Rep 2017; 7: 7057
42 Spyropoulou EA, Haring MA, Schuurink RC. Expression of terpenoids 1, a glandular trichome-specific transcription factor from tomato that activates the terpene synthase 5 promoter. Plant Mol Biol 2014; 84: 345-357
43 Toyota M, Shimamura T, Ishii H, Renner M, Braggins J, Asakawa Y. New bibenzyl cannabinoid from the New Zealand liverwort Radula marginata . Chem Pharm Bull (Tokyo) 2002; 50: 1390-1392
44 Gertsch J, Pertwee RG, Di Marzo V. Phytocannabinoids beyond the Cannabis plant – do they exist?. Br J Pharmacol 2010; 160: 523-529
45 Türk H, Yilmaz M, Tay T, Türk AÖ, Kivanç M. Antimicrobial activity of extracts of chemical races of the lichen Pseudevernia furfuracea and their physodic acid, chloroatranorin, atranorin, and olivetoric acid constituents. Z Naturforsch C – Sect C J Biosci 2006; 61: 499-507
46 Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol 2011; 163: 1344-1364
47 McPartland JM, Russo EB. Cannabis and cannabis extracts: greater than the sum of their parts?. J Cannabis Ther 2001; 1: 103-132
48 Nelson BK, Cai X, Nebenführ A. A multicolored set of in vivo organelle markers for co-localization studies in Arabidopsis and other plants. Plant J 2007; 51: 1126-1136
49 Lata H, Chandra S, Khan I, ElSohly MA. Thidiazuron-induced high-frequency direct shoot organogenesis of Cannabis sativa L. Vitro Cell Dev Biol Plant 2009; 45: 12-19
50 Lata H, Chandra S, Khan IA, ElSohly MA. High frequency plant regeneration from leaf derived callus of high Δ⁹-tetrahydrocannabinol yielding Cannabis sativa L. Planta Med 2010; 76: 1629-1633
51 Mackinnon L, Mcdougall G, Aziz N, Millam S. Progress towards Transformation of fibre Hemp. Scottish Crop Research Institute Annual Report 2000/2001. Invergowrie, Dundee: Scottish Crop Research Institute; 2000: 84-86

Supplementary Material

Supporting Information