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Terpene and Isoprenoid Biosynthesis in Cannabis Sativa

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Terpene and Isoprenoid Biosynthesis in Cannabis Sativa TERPENE AND ISOPRENOID BIOSYNTHESIS IN CANNABIS SATIVA by Judith Booth B.Sc., The University of King’s College, 2012 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in The Faculty of Graduate and Postdoctoral Studies (Genome Science and Technology) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) September 2020 © Judith Booth, 2020 The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Terpene and Isoprenoid Biosynthesis in Cannabis sativa submitted by Judith Booth in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Genome Science and Technology Examining Committee: Dr. Joerg Bohlmann, Professor, Michael Smith Laboratories, UBC Supervisor Dr. Anne Lacey Samuels, Professor, Botany, UBC Supervisory Committee Member Dr. Murray Isman, Professor Emeritus, Land and Food Systems, UBC University Examiner Dr. Corey Nislow, Professor, Biochemistry and Molecular Biology, UBC University Examiner Additional Supervisory Committee Members: Dr. Jonathan Page, Adjunct Professor, Botany, UBC Supervisory Committee Member Dr. Reinhard Jetter, Professor, Professor, Botany, UBC Supervisory Committee Member ii Abstract Cannabis sativa (cannabis, marijuana, hemp) is a plant species grown widely for its psychoactive and medicinal properties. Cannabis products were made illegal in most of the world in the early 1900s, but regulations have recently been relaxed or lifted in some jurisdictions, notably Canada and parts of the United States. Cannabis is usually grown for the resin produced in trichomes on the flowers of female plants. The major components of that resin are isoprenoids: cannabinoids, monoterpenes, and sesquiterpenes. Terpene profiles in cannabis flowers can vary widely between cultivars. My research addresses the genomic underpinnings and biochemical mechanisms of terpene and cannabinoid biosynthesis in cannabis, and patterns of terpene accumulation between organs, developmental stages, and cultivars. Using metabolite profiling, I demonstrated that terpenes accumulate in floral trichomes over the course of development, and that terpene profiles in trichomes differ based on tissue and developmental stage. In this thesis, I describe the terpene profiles of seven cannabis cultivars. I identified and characterized 29 terpene synthase (TPS) genes and their encoded enzymes and describe the relationship between TPS expression and metabolite profiles. I describe trichome-specific transcriptomes for five cultivars and identify highly expressed genes common to cannabis trichomes. I also identified and describe an aromatic prenyltransferase responsible for biosynthesis of cannabigerolic acid, the branch-point intermediate in cannabinoid biosynthesis. Collectively, this thesis comprises a broad and detailed characterization of specialized isoprenoid biosynthesis in cannabis. The results provide new insights into mechanisms of terpene and cannabinoid biosynthesis, and the roles of different enzymes in determining the metabolite complement of cannabis trichomes. iii Lay Summary Cannabis sativa, commonly known as cannabis, marijuana, or hemp, is a plant species grown around the globe. The most valuable component of cannabis is its resin, which is produced on female flowers. The most abundant components of the cannabis resin are two related types of molecules: terpenes and cannabinoids. Cannabinoids have medicinal and psychoactive properties, while terpenes are responsible for the distinctive aromas of cannabis. Cannabis produces hundreds of different terpenes, and different types of cannabis contain different terpenes. My research focuses on enzymes that produce terpenes and cannabinoids, with a special focus on the terpene synthases. This thesis describes the discovery and characterization of 29 different terpene synthases and a cannabinoid synthase. I also describe the variety of terpenes found in cannabis, their distribution within the plant, and how they change as the plant develops. iv Preface Chapter 1: Literature review and overall thesis introduction - Enzymes and systems of isoprenoid biosynthesis Portions of chapter 1 have been published. Sections 1.2, 1.3, 1.4, and 1.5, Figures 1.1 and 1.2, and Table 1.1 were published: Booth, J. K., & Bohlmann, J. (2019). Terpenes in Cannabis sativa – From plant genome to humans. Plant Science. The chapter was conceived and designed by Judith Booth and Dr. Jӧrg Bohlmann and written by Judith Booth. The manuscript was reviewed and revised by Dr. Jӧrg Bohlmann. Chapter 2: Terpene synthases from Cannabis sativa A version of Chapter 2 has been published: Booth, J. K., Page, J. E., & Bohlmann, J. (2017). Terpene synthases from Cannabis sativa. PLOS ONE, 12(3), e0173911. The chapter was conceived and designed by Judith Booth, Dr. Jӧrg Bohlmann, and Dr. Jonathan Page. Experiments and data analysis were performed by Judith Booth. The manuscript was written by Judith Booth, and reviewed and revised by Dr. Jӧrg Bohlmann with input from Dr. Jonathan Page. Chapter 3: Terpene synthases and terpene variation in Cannabis sativa A version of Chapter 3 has been accepted to the journal Plant Physiology with the following author list: Judith K Booth, Macaire MS Yuen, Sharon Jancsik, Lufiana L Madilao, Jonathan E. Page, and Jörg Bohlmann. The chapter was conceived and designed by Judith Booth and Dr. Jӧrg Bohlmann, with input from Dr. Jonathan Page. Experiments were designed and performed by Judith Booth. Macaire Yuen performed transcriptome assembly and assisted with transcriptome data analysis and statistics. Sharon Jancsik assisted with all aspects of data generation and bench work. Lufiana Madilao assisted with GC/MS experiments and data analysis. The manuscript was written by Judith Booth, and reviewed and revised by Dr. Jӧrg Bohlmann. Chapter 5: Synthetic Biology of Cannabinoids and Cannabinoid Glycosides in Nicotiana benthamiana and Saccharomyces cerevisiae A version of Chapter 6 has been accepted to the Journal of Natural Products with the following author list: Thies Gülck, Judith K. Booth, Ângela Carvalho, Christoph Crocoll, Mohammed Saddik Motawie, Birger Lindberg Møller, Jörg Bohlmann, Nethaji J. Gallage. This part of the thesis was a collaborative work: Judith Booth performed experimental design, construct design and cloning in tobacco, phylogenetic analysis, pathway expression in tobacco, subcellular localization of GFP- fusion proteins in tobacco, shotgun proteomics, LC-MS sample preparation, LC-MS data analysis. Thies Gülck performed experimental design, construct design and cloning for tobacco and yeast experiments, pathway expression in tobacco, transcriptomics interpretation, pathway expression in yeast and cannabinoid glycosylation in yeast in vivo, LC-MS sample preparation, LC-MS data analysis, manuscript writing. Ângela Carvalho performed construct design and cloning for tobacco v expression and UGT screening, UGT-screening in vitro. Christoph Crocoll performed LC-MS Q- TOF and tQuad performance and analysis, writing of the LC-MS method description. Mohammed Saddik Motawie performed chemical synthesis of OA-glucoside, writing of the method description of the chemical synthesis and reaction schemes. Jörg Bohlmann provided mentoring and discussion throughout the work and contribution to finalization of the manuscript. Birger Lindberg Møller provided mentoring and discussion throughout the work and contribution to finalization of the manuscript. Nethaji J. Gallage was responsible for experimental design, mentoring and discussion throughout the work and contribution to finalization of the manuscript. Appendix: Cannabis glandular trichomes alter morphology and metabolite content during gland maturation The data in this appendix is drawn from: Livingston, S. J., Quilichini, T. D., Booth, J. K., Wong, D. C. J., Rensing, K. H., Laflamme‐Yonkman, J., Castellarin, S. D., Bohlmann, J., Page, J. E., & Samuels, A. L. (2020). Cannabis glandular trichomes alter morphology and metabolite content during flower maturation. The Plant Journal, 101(1), 37–56. The appendix represents the portions performed by Judith Booth. vi Table of Contents Abstract ........................................................................................................................................... iii Lay Summary ................................................................................................................................. iv Preface .............................................................................................................................................. v Table of Contents .......................................................................................................................... vii List of Tables ................................................................................................................................ xiii List of Figures ................................................................................................................................ xv List of Abbreviations ................................................................................................................. xviii Acknowledgements ...................................................................................................................... xxi Dedication ...................................................................................................................................
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