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The Use of Microbial Genome Mining for in Silico Discovery of Novel Secondary Metabolite Gene Clusters Copyright © Jafar Alawn

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The Use of Microbial Genome Mining for in Silico Discovery of Novel Secondary Metabolite Gene Clusters Copyright © Jafar Alawn THE USE OF MICROBIAL GENOME MINING FOR IN SILICO DISCOVERY OF NOVEL SECONDARY METABOLITE GENE CLUSTERS BY JAFAR ALAWNEH ADISSERTATION SUBMITTED TO RUTGERS-SCHOOL OF HEALTH PROFESSIONS IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN BIOMEDICAL INFORMATICS DEPARTMENT OF HEALTH INFORMATICS SCHOOL OF HEALTH PROFESSIONS RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY APRIL 2019 COPYRIGHT © JAFAR ALAWNEH 2019 I FINAL DISSERTATION DEFENSE APPROVAL FORM THE USE OF MICROBIAL GENOME MINING FOR THE IN SILICO DISCOVERY OF NOVEL ANTICANCER AGENTS AND NOVEL ANTIMICROBIAL COMPOUNDS BY JAFAR ALAWNEH DISSERTATION COMMITTEE: FREDERICK COFFMAN, PhD SHANKAR SRINIVASAN, PhD AMRO HANORA, PhD APPROVED BY THE DISSERTATION COMMITTEE: ______________________________________________ DATE: __________________ ______________________________________________ DATE: __________________ ______________________________________________ DATE: __________________ ______________________________________________ DATE: __________________ II TABLE OF CONTENTS ABSTRACT ...................................................................................................................... VI ACKNOWLEDGMENT.................................................................................................VIII DEDICATION .................................................................................................................. IX LIST OF FIGURE...............................................................................................................X LIST OF TABLES ............................................................................................................ XI CHAPTER 1: INTRODUCTION 1. Medically Relevant SMs ................................................................................................. 2 1.1 Antibacterial drugs .................................................................................................... 2 1.1.1 β-lactams ............................................................................................................. 2 1.1.2 Vancomycin ........................................................................................................ 3 1.1.3 Erythromycin ...................................................................................................... 3 1.1.4 Teicoplanin ......................................................................................................... 4 1.1.5 Tetracyclines ....................................................................................................... 4 1.1.6 Capreomycin ....................................................................................................... 5 1.1.7 Bleomycin ........................................................................................................... 5 1.1.8 Quinoxalines ....................................................................................................... 5 1.2 Antifungal compounds .................................................................................................. 6 1.2.1 Polyene antibiotics ................................................................................................. 6 1.2.2 Cispentacin ............................................................................................................. 6 1.3 Antiparasitic Compounds.............................................................................................. 7 1.3.1 Fumagillin .............................................................................................................. 7 1.3.2 Paromomycin ......................................................................................................... 7 1.4 Antiviral Drugs ............................................................................................................. 7 1.4.1 FK506 ..................................................................................................................... 7 1.4.2 RP 71955 ................................................................................................................ 8 1.5 Drugs acting on the immune system ............................................................................. 8 1.5.1 Rapamycin (Sirolimus) .......................................................................................... 8 III 1.5.2 Cyclosporin A ........................................................................................................ 8 1.6 Microbial SMs with Cytotoxic activity......................................................................... 9 1.6.1 Enediynes ............................................................................................................... 9 1.6.2 Actinomycins ......................................................................................................... 9 1.6.3 Anthracyclines ...................................................................................................... 10 1.6.4 Rapamycin ............................................................................................................ 10 1.6.5 Geldanamycin....................................................................................................... 11 1.6.6 Histone deacetylase inhibitors .............................................................................. 11 1.6.7 Bryostatins ............................................................................................................ 11 1.2 Genome mining for the discovery of novel secondary metabolites ............................ 14 1.2.1 Classical methods of genome mining................................................................... 15 1.2.2 Phylogeny-based genome mining ........................................................................ 16 1.2.3 Resistance and target based genome mining ........................................................ 16 1.2.4 Regulator-based genome mining .......................................................................... 17 1.2.5 Comparative genome mining ............................................................................... 17 1.3 Discovery of microbial SMs by genome mining ........................................................ 18 1.4 Statement of the problem ............................................................................................ 22 CHAPTER II: LITERATURE REVIEW 2. Nonribosomal peptides (NRPs) and polyketides (PKs) ................................................ 31 2.1 Historical View ....................................................................................................... 32 2.2 Natural Functions of SMs ....................................................................................... 33 2.3 Natural Functions of SMs in Fungi ......................................................................... 34 2.3 Natural Functions of SMs in Bacteria ..................................................................... 36 2.4 Characteristics of NRPSs and PKSs........................................................................ 38 2.4.1 Characteristics of Bacterial and Fungal PKSs...................................................... 39 2.4.2 Characteristics of Bacterial and Fungal NRPSs ................................................... 40 2.5 Biosynthesis Strategies of NRPs and PKs .................................................................. 40 2.5.1 Priming ................................................................................................................. 42 2.5.2 Initiation ............................................................................................................... 43 2.5.3 Elongation ............................................................................................................ 44 2.5.4 Termination .......................................................................................................... 44 2.6 Other Biosynthesis Strategies of NRPs....................................................................... 45 2.6.1 Heterocyclization ................................................................................................. 45 2.6.2 Epimerization and Amino Acid Racemization..................................................... 45 IV 2.6.3 Methylations ......................................................................................................... 46 2.6.4 Oxidation .............................................................................................................. 46 2.6.5 Reduction ............................................................................................................. 47 2.7 Regulation of NRPS Genes ......................................................................................... 47 2.8 Structure of NRPs ....................................................................................................... 49 2.8.1 Adenylation (A) domain....................................................................................... 49 2.8.3 Condensation (C) domain..................................................................................... 51 2.8.4 Thioesterase (TE) domain .................................................................................... 51 2.9 Production of novel NRPS through reconstruction and engineering .......................... 52 CHAPTER III : METHODS 3.1 Genes of S. sorangium’s Epothilone Gene Cluster ..................................................... 55 3.2 Finding EpoA-F Homologs (the EAFHs) ..................................................................
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