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Asteraceae) Family University of Calgary PRISM: University of Calgary's Digital Repository Graduate Studies The Vault: Electronic Theses and Dissertations 2013-05-06 Biochemical and evolutionary studies of sesquiterpene lactone metabolism in the sunflower (Asteraceae) family Nguyen, Trinh Don Nguyen, T. D. (2013). Biochemical and evolutionary studies of sesquiterpene lactone metabolism in the sunflower (Asteraceae) family (Unpublished doctoral thesis). University of Calgary, Calgary, AB. doi:10.11575/PRISM/25121 http://hdl.handle.net/11023/702 doctoral thesis University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. Downloaded from PRISM: https://prism.ucalgary.ca UNIVERSITY OF CALGARY Biochemical and evolutionary studies of sesquiterpene lactone metabolism in the sunflower (Asteraceae) family by Trinh Don Nguyen A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF BIOLOGICAL SCIENCES CALGARY, ALBERTA APRIL, 2013 © Trinh Don Nguyen 2013 Abstract Plants have evolved the capacity to synthesize a myriad of specialized metabolites which enhance their fitness in specific living conditions. These compounds are also widely utilized for human purposes. Elucidating the enzymes in plant specialized metabolism has been one of the main forces driving plant biochemistry. The more intriguing question, however, is how these enzymes evolved to acquire their existent functions. The Asteraceae, the largest flowering plant family, is well-known for its enormously diverse and lineage-characteristic contents of sesquiterpene lactones (STLs). Thousands of compounds in this subclass of specialized metabolites have been studied extensively for their structures and valuable bioactivities. However, the details of their metabolism are poorly understood. Studying STLs in the Asteraceae thus improves our knowledge of the biosynthesis of these compounds. Furthermore, the tight links between STLs and the Asteraceae family provide an excellent model to explore enzyme adaptive evolution. My thesis aims to advance our understanding of STL metabolism by focusing on elucidating the enzyme that is responsible for the oxidation of sesquiterpene to sesquiterpene carboxylic acid in the general STL biosynthetic route of the Asteraceae. In lettuce, two cytochrome P450- dependent monooxygenase (P450) isoforms responsible for oxidizing the three consecutive oxidations of germacrene A to germacrene A carboxylic acid in the biosynthesis of costunolide were characterized. This was achieved using a combination of genomic and biochemical approaches, and the aid of a metabolically-engineered yeast system. Furthermore, this germacrene A oxidase (GAO) activity was demonstrated to be highly conserved throughout the Asteraceae, even in the phylogenetically basal subfamily Barnadesioideae, which split from the rest of the family at least 50 million years go. Previous studies have characterized an Artemisia annua-specific sesquiterpene oxidase, amorphadiene oxidase (AMO), which is considered to have diverged from an ancestral GAO. The substrate specificity/promiscuity of AMO and GAOs towards each other’s natural substrates and seven other non-natural substrates was investigated to test the general hypothesis of enzyme evolution from ancestral promiscuity. The results from these combinatorial biochemistry studies and phylogenetic relations of AMO and GAOs provided deep insights into the evolution of these P450s in the context of the chemical diversity of the Asteraceae. ii Acknowledgements This work would never be possible without the kind supports of many people. First of all, I would like to express my gratitude to my supervisor, Dr. Dae-Kyun Ro, for introducing me to the exciting world of the sunflower family and terpenoids, and for mentoring and inspiring me throughout the years. I would like to thank Dr. Chendanda C. Chinnappa and Mrs. Janaki Chinnappa for encouraging me to get my education at the University of Calgary and making me feel like home in Canada. I want to thank my two Supervisory Committee members, Dr. Sui- Lam Wong and Dr. Gregory Moorhead, and Dr. Edward C. Yeung for continuously giving me helpful advice during my study. I would like to thank all current and former members of the Ro Lab, including Gillian MacNevin, Dr. Nobuhiro Ikezawa, Dr. Jens Göpfert, Vince Yang Qu, Dr. Hue T. Tran, Dr. Romit Chakrabarty, Dr. Benjamin Pickel, Kiva Ferraro, Tegan Haslam, Dr. Jorge Bariuso, Rod Mitchell, Mohamed Attia, Bryan Pyle, Merisa Tran, and Elysabeth Reavell- Roy for their help and friendliness. My research would have been very difficult without the kind help of many colleagues, particularly Dr. David Dietrich (University of Alberta), Chi Nguyen (University of California, Irvine), the late Dr. Dean McIntyre (University of Calgary), and Dr. Ping Zhang (University of Calgary). I also want to acknowledge Dr. John Vederas (University of Alberta), Dr. Sheryl S.C. Tsai (University of California, Irvine, USA), Dr. Isabelle Barrette-Ng (University of Calgary), and my colleagues from the University of Calgary’s Department of Biological Sciences, particularly the Facchini Laboratory and the Zaremberg Laboratory, for their supports. My study was financially supported in part by the University of Calgary’s Department of Biological Sciences, and the Bettina Bahlsen Memorial Graduate Scholarship. I want to thank all my friends in Calgary, especially anh Hoàng – Huyền, cô Kim – chú Dzũng, anh Thắng – chị Trang, and many Canadians who did not even let me know their names for their helps in times of need. I appreciate Dr. Dương Tấn Nhựt (Tây Nguyên Institute for Scientific Research, Viet Nam) and the Biotechnology Center of Hô Chi Minh City (Viet Nam) for supporting my intention to study in Canada. I am truly grateful to my grandparents, my parents and parents-in-law, my brothers and sister, cô Hiền – chú Tý, cô Kiều Anh – chú Chí, and chị Tuyết Phương for all their love, support, and encouragement. And to my wife, Thuỷ, I am forever indebted for your love, sacrifice, and friendship. iii Dedication , for always believing in me. iv Table of Contents Abstract .......................................................................................................................................... ii Acknowledgements ........................................................................................................................ iii Dedication ...................................................................................................................................... iv Table of Contents .............................................................................................................................v List of Tables ................................................................................................................................. ix List of Figures ..................................................................................................................................x List of Abbreviations .................................................................................................................... xii Published Materials ...................................................................................................................... xiv Chapter 1: General introduction ..................................................................................................1 1.1. Secondary or specialized metabolism in plants ......................................................................1 1.2. Terpenoid biosynthesis ...........................................................................................................5 1.2.1. Structures and functions of terpenoids ..............................................................................5 1.2.2. Biogenesis and cellular compartmentalization of the central precursors ..........................9 1.2.3. Biogenesis of terpenoid structural diversity by TPSs and modifying enzymes ..............12 1.2.4. Cytochrome P450-dependent monooxygenases .............................................................15 1.3. STLs in the Asteraceae family..............................................................................................17 1.3.1. Structures and functions of STLs ....................................................................................17 1.3.2. Occurrence of STLs in the Asteraceae family ................................................................19 1.3.3. Biosynthesis of STLs ......................................................................................................21 1.4. Approaches to understanding the biochemistry of plant specialized metabolism ................23 1.4.1. Traditional biochemical approaches ...............................................................................23 1.4.2. Genomics-based approaches ...........................................................................................24 1.4.3. Metabolic engineering and synthetic biology in studying specialized metabolism ........25 1.5. Adaptive enzyme evolution ..................................................................................................27 1.5.1. Enzyme evolution in the context
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