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Domain Dynamics and Control of Electron Flux of NADPH Cytochrome P450 Oxidoreductase

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Domain Dynamics and Control of Electron Flux of NADPH Cytochrome P450 Oxidoreductase Universidade Nova de Lisboa Instituto de Higiene e Medicina Tropical Domain dynamics and control of electron flux of NADPH cytochrome P450 oxidoreductase Diana Isabel Viana da Fonseca Campelo Delgado DISSERTAÇÃO PARA A OBTENÇÃO DO GRAU DE DOUTOR NO RAMO DE CIÊNCIAS BIOMÉDICAS, ESPECIALIDADE DE GENÉTICA MAIO 2019 Universidade Nova de Lisboa Instituto de Higiene e Medicina Tropical Domain dynamics and control of electron flux of NADPH cytochrome P450 oxidoreductase Autor: Diana Isabel Viana da Fonseca Campelo Delgado Orientador: Michel Kranendonk Co-orientador: Celso Cunha Dissertação apresentada para cumprimento dos requisitos necessários à obtenção do grau de Doutor no Ramo de Ciências Biomédicas, especialidade de Genética Apoio financeiro da Fundação para a Ciência e a Tecnologia (projecto FCT-ANR/BEX- BCM/0002/2013). Dedico este trabalho aos que me são mais queridos, Ao meu marido, aos meus pais, aos meus irmãos e sobrinhos. AGRADECIMENTOS Gostaria de expressar o meu agradecimento e gratidão a todos os que apoiaram e contribuíram para a realização deste longo trabalho. Ao Doutor Michel Kranendonk, agradeço a oportunidade de realizar este estudo sob a sua orientação e todos os ensinamentos ao longo destes anos. Ao Professor Celso Cunha, por ter aceite orientar este trabalho a partir do Instituto de Higiene e Medicina Tropical. Quero agradecer a todos os meus colegas de laboratório que me acompanharam ao longo do doutoramento. Francisco Esteves, Susana Silva, Bruno Gomes, Bernardo Palma, Célia Martins, Cláudio Pinheiro, Rita Jerónimo, Rita Lourenço, Marisa Cardoso, D. Lucrécia. Agradeço o apoio e convívio amigo, que tornaram todas as horas de trabalho mais fáceis. A todos os colegas e colaboradores do ToxOmics. Prof. Sebastião Rodrigues, Prof. Joaquim Calado, Prof. Aldina Brás, Dr. Helena Borba, Isabel Borba. Agradeço todos os contributos e colaboração para este trabalho. Em especial, ao Professor José Rueff, pelos conselhos sábios e discussões científicas profícuas. Aos nossos colaboradores de Toulouse. Gilles Truan, Philippe Urban, Thomas Lautier, Robert Quast. Obrigada pelas discussões científicas e por confiarem no meu trabalho. Aos colegas de doutoramento, Ana Armada, Luísa Ganço e Tiago Vaz. Obrigada pela amizade e companheirismo. Tornaram aquele duro ano lectivo mais fácil de suportar. Aos meus amigos de sempre, que acompanharam este processo à distância, sempre motivantes, alegres e confiantes. Em especial às amigas de longa data Filipa e Sara, já vão vinte anos a crescer juntas! Aos colegas de faculdade que se tornaram amigos de uma década Joana Pereira, Inês Figueira, Inês Nunes, André, Joaquim, Andreia. À malta dos Olivais, os amigos em Jesus, sempre barulhentos e alegres, a minha alegria! Sou muito grata pela vossa presença na minha vida. À malta dos escuteiros da Portela. Em especial à fantástica patrulha Tigre. Seremos amigos para a vida toda. Cresci muito convosco, dentro e fora do escutismo. Obrigada pelo vosso testemunho, são exemplos para mim! Um agradecimento especial à minha família. Em particular à minha mãe, por todo o amor, apoio, paciência, esforço e dedicação. Aos meus irmãos pelos anos de convivência e aprendizagem juntos e pelo apoio incondicional e incentivo alegre. E aos meus sobrinhos. Como é bom ver-vos crescer! Espero ser sempre um bom exemplo para vocês! Ao meu marido João. Pelo amor, genuíno, discreto, sem floreados. Não sei pôr em palavras o quanto significas para mim e o quão essencial te tornaste. Foste e serás sempre a minha âncora. Acreditaste mais em mim, neste meu trabalho e no que sou capaz do que eu própria. No meio de todo este trabalho, concretizámos um sonho belo juntos. Somos uma família! Obrigada, meu amor. TABLE OF CONTENTS TABLE OF CONTENTS LIST OF PUBLICATIONS AND COMMUNICATIONS ......................................... xi RESUMO .................................................................................................................... xv ABSTRACT .............................................................................................................. xvii LIST OF FIGURES ................................................................................................... xix LIST OF TABLES ...................................................................................................... xx LIST OF ABBREVIATIONS AND ACRONYMS .................................................. xxi 1. INTRODUCTION .................................................................................................... 1 1.1 Biotransformation .............................................................................................. 3 1.2 Cytochrome P450 ............................................................................................... 5 1.2.1 Catalytic Cycle of CYPs ................................................................................ 7 1.2.2 CYP Isoforms used in the studies of this thesis: CYP1A2, 2A6 and 3A4 ... 10 1.3 NADPH dependent P450 oxidoreductase ........................................................ 13 1.3.1 Electron-transfer function ............................................................................ 13 1.3.2 CPR protein conformation ........................................................................... 14 1.3.3 The hinge segment of CPR .......................................................................... 16 1.3.4 CPR genetic variations ................................................................................. 18 1.3.5 Multiple Redox partners .............................................................................. 19 1.3.6 CYP:CPR Interaction ................................................................................... 21 1.4 Heterologous expression of human biotransformation enzymes ..................... 23 1.4.1 Bacterial system used for the functional study of CPR ............................... 24 1.5 Aim and outline of this thesis........................................................................... 26 1.5.1 Aim .............................................................................................................. 26 1.5.2 Outline of this thesis .................................................................................... 27 1.6 REFERENCES ................................................................................................. 28 2. RESULTS ............................................................................................................... 43 vii TABLE OF CONTENTS 2.1 The Hinge Segment of Human CPR in Conformational Switching: The Critical Role of Ionic Strength ................................................................................................. 44 2.1.1 ABSTRACT ................................................................................................. 46 2.1.2 INTRODUCTION ........................................................................................ 47 2.1.3 MATERIALS AND METHODS ................................................................. 50 2.1.4 RESULTS ..................................................................................................... 55 2.1.5 DISCUSSION .............................................................................................. 68 2.1.6 AUTHOR CONTRIBUTIONS .................................................................... 72 2.1.7 FUNDING .................................................................................................... 72 2.1.8 ACKNOWLEDGMENT .............................................................................. 72 2.1.9 SUPPLEMENTARY MATERIAL .............................................................. 73 2.1.10 REFERENCES ............................................................................................. 74 2.2 Probing the Role of the Hinge Segment of Cytochrome P450 Oxidoreductase in the Interaction with Cytochrome P450 ............................................................................. 81 2.2.1 ABSTRACT ................................................................................................. 83 2.2.2 INTRODUCTION ........................................................................................ 84 2.2.3 RESULTS ..................................................................................................... 86 2.2.4 DISCUSSION .............................................................................................. 95 2.2.5 MATERIALS AND METHODS ............................................................... 100 2.2.6 SUPPLEMENTARY MATERIALS .......................................................... 105 2.2.7 AUTHOR CONTRIBUTIONS .................................................................. 106 2.2.8 FUNDING .................................................................................................. 106 2.2.9 CONFLICTS OF INTEREST .................................................................... 106 2.2.10 REFERENCES ........................................................................................... 107 3. DISCUSSION ....................................................................................................... 113 3.1 DISCUSSION AND CONCLUSIONS .......................................................... 115 viii TABLE OF CONTENTS 3.2 REFERENCES ............................................................................................... 121 4. ANNEXES ............................................................................................................ 127 4.1 ANNEX
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