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Metabolomics, Proteomics, and Transcriptomics of Cannabis Sativa L

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Metabolomics, Proteomics, and Transcriptomics of Cannabis sativa L. Trichomes Zur Erlangung des akademischen Grades eines Dr. rer. nat. von der Fakultät Bio- und Chemieingenieurwesen der Technischen Universität Dortmund Dissertation vorgelegt von Nizar Happyana, M.Sc. aus Bandung, Indonesien Tag der mündlichen Prüfung: 18.12.2014 1. Gutachter: Prof. Dr. Oliver Kayser 2. Gutachter: Prof. Dr. Robert Verpoorte Dortmund 2014 ii Acknowledgements Alhamdulillahirabilallamin. Foremost, I would like to express my deepest gratitude to my supervisor, Prof. Oliver Kayser. Dear Oliver, I am grateful to have an opportunity to conduct PhD study in your laboratory. It is a pleasure to work with you. Thank you very much for your guidance, patience, and all supports you have given to me during my PhD. I was very happy when you drove me to Veendam for collecting Cannabis. I also really enjoyed scientific and non-scientific discussion with you. I gratefully acknowledge the Directorate General of Higher Education, Ministry of National Education, Indonesia, for providing me the doctoral scholarship. I am deeply indebted to Tjalling Erkelens and Freerk Bruining from Bedrocan BV for supplying the plant material. Thank you very much for your hospitality when I came to Veendam. It was nice to have discussion with you both. I gratefully acknowledge to Prof. Robert Verpoorte from Leiden University, Prof. Sebastian Engell and Prof. Gabriele Sadowski from TU Dortmund for being my PhD Committee. I am utterly grateful to Prof. Jörn Kalinowski and Oliver Rupp from CEBITEC for helping us in analyzing the cDNA library. I would like to thank Prof. Bernd Schneider and Sara Agnolet from MPI (Chemical Ecology) for cryogenic NMR measurements. Many thanks to Annie Van Dam from Groningen University for the LCMS measurements. I would like to thank Remco Muntendam for fruitful discussions and sharing your research experience with me. I am deeply indebted to Fabian Real for driving me 4 times to Veendam for collecting the plant materials. I would like to thank Prof. Albert Sickmann and Stefan Loroch from ISAS for the collaboration in the proteomic project. I would like to thank Dr. Armin Quentmeier and Dr. Felix Stehle for all suggestions and comments regarding my research. Many thanks to Kristine Blase for the administrative supports. My special thanks to Jörg, Bettina, and Fabian for their helps during my laboratory works. I would like to thank all the current and former members of the Technical Biochemistry Department. Super thanks to Sayed, Marcello, Beer, Anna, and Parijat. Thank you so much for our friendship and for sure I am going to miss you all. Special thanks to Kathleen, Magda, Friederike, Torsten, Rike, Eva, Bastian, Joanna, Katharina, Alena, and the other students for the good atmosphere in our group. Most of all, I would like to thank my beloved family for their unconditional love, pray, and supports throughout my entire life. I have dedicated this thesis to you all. Kanggo Mama, Bapa, A Janjan, Teh Eros, Teh Eneng, A Yanto, Teh Euis, A Heri, Fajar, Risma, Agnes, Oki, Saskia, Marsya, Natya, Keisha, Milan sareng kulawargi sanesna, hatur nuhun pisan kana bantosanna, pidu’ana, dukunganna, sareng nu sanesna. Untuk Mama, Papa, dan Cesar, terima kasih banyak atas do’anya, dukungan moralnya, dan bantuan yang lainnya. Very super special thanks to my dearest wife Prita and my little angel, Tania. Simply, you both make me be a better man. i Table of Contents Acknowledgements ....................................................................................................................... i Table of Contents ......................................................................................................................... ii Abstract .................................................................................................................................. iii Zusammenfassung ........................................................................................................................ iv Chapter 1 Introduction and Scope of the Thesis ......................................................................... 1 Chapter 2 Metabolomics as Bioanalytical Tool for Characterization of Medicinal Plants and their Phytomedical Preparations ........................................................................................ 5 Chapter 3 1H NMR-Based Metabolomics Differentiation and Real Time PCR Analysis of Medicinal Cannabis Organs ....................................................................................................... 31 Chapter 4 Monitoring and Differentiation of Metabolites of Medicinal Cannabis Trichomes during Flowering Period using 1H NMR-based Metabolomics ............................................... 55 Chapter 5 Proteomic Profiling of Medicinal Cannabis Trichomes ................................................ 99 Chapter 6 Transcriptome Analysis of Medicinal Cannabis Trichomes: Assembly, Annotation, and Elucidation of Biosynthetic Pathway of Secondary Metabolites ............................... 137 Chapter 7 Analysis of cannabinoids in laser-microdissected trichomes of medicinal Cannabis sativa using LCMS and cryogenic NMR ..................................................................... 159 Chapter 8 General Discussion ................................................................................................. 181 References ............................................................................................................................... 193 Curriculum Vitae ....................................................................................................................... 206 Publications .............................................................................................................................. 207 Summary ............................................................................................................................... 209 Rangkuman ............................................................................................................................... 211 ii Abstract Cannabis sativa L. trichomes are the main site for synthesizing and storing cannabinoids and other secondary metabolites on this plant. Metabolomics, proteomics, and transcriptomics were applied in this research as analytical approaches in order to study secondary metabolites, proteins, and genes that are synthesized in the trichomes. The function of specific trichomes and their individual parts in the cannabinoid biosynthesis was investigated as well. 1H NMR- based metabolomics has been successfully applied for monitoring the production of metabolites, especially cannabinoids in the Cannabis trichomes during the last weeks of flowering period. Proteomics analysis of the Cannabis trichomes revealed that many enzymes corresponding in the biosynthesis of secondary metabolites, including cannabinoids, flavonoids, and terpenoids were successfully recorded. This finding supported the function of Cannabis trichomes as the main site of secondary metabolite production. Although there is no flavonoid reported from the trichomes, however the identification of enzymes related to its biosynthesis indicated that this compound might be present in this organ. Interestingly, identification of enzymes involved in the biosynthesis of cannabinoids, terpenoids, and flavonoids in the proteomic work has been also confirmed by the detection of their putative transcripts in the cDNA library of Cannabis trichomes. Analysis of cannabinoids in the laser- microdissected trichomes of Cannabis showed that these compounds were detected not only in the head of capitate-stalked trichomes but also in its stem part. This finding suggest that cannabinoid biosynthesis is not only limited to the expected head cells, but also the stems of Cannabis capitate-stalked trichomes might play a role in the cannabinoids biosynthesis. iii Zusammenfassung Cannabis sativa L. Trichome sind der hauptsächliche Ort der Cannabinoid-Biosynthese. Im Rahmen dieser Arbeiten wurden Techniken angewandt und verbessert, um das Metabolom, Transkriptom und Proteom der biosynthetisierenden Zellen der sezernierenden Trichome zu erforschen. Die Biosyntheleistung der drei Trichomtypen wurde mit Hilfe von LC-MS, Laser Dissection Mikroskopie und 1H-NMR Metabolomics untersucht, um die Biosynthese über 8 Wochen qualitativ und quantitativ zu erfassen. Weitere Analysen des Proteom zeigten auf, das Genexpression und Funktion biosynthetischer Proteine für Cannabinoide, Flavonoide und Terpene des ätherischen Öls ist stark abhängig von Alter und Blütenbildung ist. Analyse und Annotierung der Gene ist durch die eigens erstellte cDNA Bank ermöglicht worden. Die Ergebnisse zeigen, das eine Biosynthese in den sezernierenden Kopfzellen sehr stark aber auch in den Stielzellen zu finden ist. Auf Grund der Proteomuntersuchungen im ätherischen Öl ist eine Biotransformation im nicht wässrigen Milieu ausgeschlossen worden. Mit Hilfe von 1H-NMR Metabolomics und statistischer PCA-Analyse konnten Strategien entwickelt warden, um Zuchtlinien von Cannabis sativa zu identifizieren und auf Basis des metabolomischen Profil voneinander zu unterscheiden iv Chapter 1 Introduction and scope of the thesis Nizar Happyana 1 ---------------------------------------------------------------- Chapter 1 --------------------------------------------------------------- Since ancient time, human beings could not be separated from medicinal plants to fulfill their basic health needs. One of medicinal
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