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Université Du Québec UNIVERSITÉ DU QUÉBEC THÈSE PRÉSENTÉE À L'UNIVERSITÉ DU QUÉBEC À TROIS-RIVIÈRES COMME EXIGENCE PARTIELLE DU DOCTORAT EN BIOLOGIE CELLULAIRE ET MOLÉCULAIRE PAR APARNA SINGH DISCOVERY OF NOVEL GENES AND ENZYMES INVOLVED IN AMARYLLIDACEAE ALKALOID BIOSYNTHESIS USING INTEGRATED MET ABOLOMICS AND TRANSCRIPTOMICS IN NARCISSUS PSEUDONARCISSUS 'KING ALFRED' JUIN 2018 Université du Québec à Trois-Rivières Service de la bibliothèque Avertissement L’auteur de ce mémoire ou de cette thèse a autorisé l’Université du Québec à Trois-Rivières à diffuser, à des fins non lucratives, une copie de son mémoire ou de sa thèse. Cette diffusion n’entraîne pas une renonciation de la part de l’auteur à ses droits de propriété intellectuelle, incluant le droit d’auteur, sur ce mémoire ou cette thèse. Notamment, la reproduction ou la publication de la totalité ou d’une partie importante de ce mémoire ou de cette thèse requiert son autorisation. UNIVERSITÉ DU QUÉBEC À TROIS-RIVIÈRES Cette thèse a été dirigée par: Isabel Desgagné-Penix, Ph. D. Université du Québec à Trois-Rivières Directrice de recherche Institution à laquelle se rattache l' évaluateur Jury d'évaluation de la thèse: Isabel Desgagné-Penix, Ph. D. Université du Québec à Trois-Rivières Prénom et nom, grade Institution à laquelle se rattache l' évaluateur Hugo Germain, Ph. D. Université du Québec à Trois-Rivières Prénom et nom, grade Institution à laquelle se rattache l' évaluateur Céline Van Themsche, Ph. D. Université du Québec à Trois-Rivières Prénom et nom, grade Institution à laquelle se rattache l' évaluateur Charles Goulet, Ph. D. Université Laval Prénom et nom, grade Institution à laquelle se rattache l' évaluateur Thèse soutenue le 28 mai 2018 To my parents and husband who were my strength in this journey IV ACKNOWLEDGEMENTS l am thankful to my research supervisor Isabel Desgagné-Penix for considering me in her laboratory and acquainted me enthusiastically to the field of plant specialized metabolism. She has been an inspiration as a researcher and mentor throughout my Ph.D. She always supported me with her guidance for a successful implementation of the research project. Working in her laboratory has helped me tremendously in developing scientific skills and knowledge. l am also equally thankful to Professor Hugo Germain (Université du Québec à Trois­ Rivières) for his unconditional support, guidance, and manuscript reviewing. His weIl­ established lab has provided me with instruments and reagents, as per the requirement of the project. l am also grateful to Professor Gervais Berubé (Université du Québec à Trois­ Rivières) for standard synthesis and manuscript writing. l would like to acknowledge Professor Céline Van Themsche (Université du Québec à Trois-Rivières) for sharing instruments. Special thanks to Ariane Garand and Marie-Ange Massicotte for working on experiments related to my project. l am also thankful to Vincent Ouellette for synthesizing required chemical standards. l would like to thank Tarun Hotchandani for manuscript revIewmg. l would like to express my gratitude to aIl my labmates, Nicolas Dufour, Tarun Hotchandani, Andrew Diamond, Narimene Fradj, Bulbul Ahmed, Saifur Rahman, Annabelle St-Pierre, Dorian Blondeau, Genevieve Laperriere, Claire Letanneur, Sarah Piette, Joelle Rancourt, Mélodie B. Plourde, Teura Barff, Hur Madina, and Karen Cristine Gonçalves dos Santos for their encouragement and good memories we created in this course of time. v RÉSUMÉ EN FRANÇAIS Au cours des 50 dernières années, des études sur les métabolites secondaires ont été rapportées pour leur rôle majeur dans l'acclimatation de l'environnement végétal. Ils représentent également des molécules d'importance pharmaceutique. Les alcaloïdes sont des métabolites produits par différentes familles de plantes. Les plantes de la famille des Amaryllidaceae produisent des alcaloïdes des Amaryllidaceae (AA) impliqués dans la défense et le développement végétal. Ils possèdent un grand nombre de propriétés bioactives qui en font une cible intéressante pour le développement de médicaments. Les exemples d'AA comprennent la lycorine anti-mitotique, la galanthamine inhibant l'acétylcholinestérase et la crinine cytotoxique. Tous les AA partagent un précurseur intermédiaire commun dans leur voie de biosynthèse, nommé la norbelladine. Comme d'autres métabolites végétaux, les AA sont également produits en très faibles quantités dans les plantes, ce qui les rend inaccessibles pour des applications pharmaceutiques. Selon les études, la galanthamine, qui est extraite de diverses plantes d'Amaryllidaceae, contribue à seulement 0,2% du poids sec d'une plante. Jusqu'à présent, seule la galanthamine est utilisée commercialement pour le traitement de la maladie d'Alzheimer. Son extraction à partir de matériel végétal est un processus coûteux. De plus, la structure complexe des AA est difficile à synthétiser chimiquement. Par conséquent, la découverte de nouveaux gènes codant pour des enzymes biosynthétiques est nécessaire afin de faciliter le développement de méthodes de production biotechnologiques alternatives. Comme les Amaryllidaceae sont des plantes non modèles, nous avons appliqué la biologie des systèmes pour atteindre nos objectifs de recherche. Parmi ceux-ci nous avons utilisé deux outils 'O'miques (métabolomique et transcriptomique) dans cette recherche. Les deux objectifs de ce projet étaient, en premier lieu, d'étudier les gènes et les précurseurs de la biosynthèse des AA par une étude comparative métabolomique et transcriptomique de Narcissus pseudonarcissus 'King Alfred'. Le deuxième objectif a impliqué le clonage et la caractérisation d'une norbelladine synthase (NpNBS), un nouveau gène catalysant la première étape dans la biosynthèse des AA. À partir de la première étude, nous avons obtenu un profil de métabolites par analyse UPLC-QTOF-MS qui présentait un grand nombre d'AA synthétisés dans différents tissus végétaux, principalement dans les feuilles et les bulbes. Les trois catégories d'AA ont été détectées dans différents tissus. Les AA de la catégorie para-ortho' (c'est-à-dire de type galanthamine) et ortho-para' (c'est-à-dire de type lycorine) étaient abondants dans les tissus souterrains alors que l'inverse était observé dans les feuilles. En outre, l'assemblage et l'annotation du transcriptome de novo ont donné Il 708 transcrits annotés. L'annotation du transcriptome a révélé la présence de tous les gènes de biosynthèse des AA proposés, qui soutenaient leur implication dans la VI biosynthèse des AA susmentionnés dans les tissus de N pseudonarcissus King Alfred. Nous avons également constaté que les gènes les plus exprimés appartenaient à des processus tels que le métabolisme, la survie et la défense. Notamment, NpNBS a été détecté parmi les gènes les plus exprimés. Nous avons identifié avec succès la séquence complète du gène NpNBS à partir du transciptome annoté de Narcissus pseudonarcissus 'King Alfred', qui a été plus tard cloné, exprimé et caratériser par un dosage enzymatique. Nous avons trouvé que NpNBS était responsable de la formation de la norbelladine. En outre, phylogénétiquement, elle est liée à une norcoclaurine synthase de Papaver somniferum (PsNCS) et est une protéine de la famille des Bet vl/PR-l O. NpNBS catalyse la première étape engagée dans la voie de biosynthèse des AA et fournit une structure de base commune à divers AA. Ainsi, nous avons pu caractériser un nouveau gène de la voie des AA et contribuer à la découverte de la voie de biosynthèse des AA en construisant une banque de données pour la caractérisation d'autres gènes inconnus dans l'avenir. Mots-clés: Alcaloïdes des Amaryllidaceae, norbelladine, norcraugsodine, transcriptome, séquençage de nouvelle génération, biosynthèse, métabolisme spécialisé, métabolite secondaire, norbelladine synthase, pathogenesis-related class-l 0 (PR-l 0). ABSTRACT Over the last 50 years, studies on specialized metabolites have increased for their medicinal properties and major roles in acclimatization of the plant to their environment. They are natural molecules of immense pharmaceutical importance. Alkaloids comprise one of the categories of specialized metabolites that are produced by different plant families. The plants of Amaryllidaceae family produces large number of AmaryIlidaceae alkaloids (AAs) thought to be involved in their defense and development. Their enormous bioactive properties make them an interesting target for drug development. Few examples include an anti-mitotic alkaloid-lycorine, an acety1cholinesterase inhibiting alkaloid­ galanthamine, and the cytotoxic alkaloid-crinine. AlI AAs share a common intermediate precursor in their biosynthesis pathway, norbeIladine. Like other plant metabolites, AAs are produced in very low quantities in plants which makes them inaccessible for pharmaceutical applications. According to the data, galanthamine extraction from various Amaryllidaceae plants contributes to only 0.2% dry weight of a plant. Until now, only galanthamine is used commerciaIly for the treatment of Alzheimer's disease. Its extraction completely relies on natural sources, which makes it an expensive process. Moreover, the complex structure of AAs is difficult to reproduce chemicaIly. Therefore, a betler understanding of their biosynthesis is necessary for their large-scale production through metabolic engineering. As Amaryllidaceae are non-model plants, we applied systems biology to accomplish our research goals. Among several OMICS tools, we utilized metabolomics and transcriptomics in this study. The two objectives
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