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Evolution of Nonribosomal Peptide Synthetase Proteins Involved in Secondary Metabolism in Fungi

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Evolution of Nonribosomal Peptide Synthetase Proteins Involved in Secondary Metabolism in Fungi EVOLUTION OF NONRIBOSOMAL PEPTIDE SYNTHETASE PROTEINS INVOLVED IN SECONDARY METABOLISM IN FUNGI A Dissertation Presented to the Faculty of the Graduate School of Cornell University In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy by Kathryn E. Bushley August 2009 © 2009 Kathryn E. Bushley EVOLUTION OF NONRIBOSOMAL PEPTIDE SYNTHETASE PROTEINS INVOLVED IN SECONDARY METABOLISM IN FUNGI Kathryn E. Bushley, Ph. D. Cornell University 2009 Nonribosomal peptide synthetases (NRPSs) are multimodular enzymes which biosynthesize peptides (NRPs) independently of ribosomes. Three core domains (adenylation (A), thiolation (T), condensation (C)) comprise a functional module for NRP biosynthesis. Although NRPSs produce a diversity of bioactive compounds, little is known about the evolutionary relationships of genes encoding NRPSs and the mechanisms by which they evolve. The objectives of this research were to perform phylogenomic analyses to identify major NRPS subclasses and determine evolutionary relationships and to elucidate fine-scale evolutionary mechanisms giving rise to the diverse NRPS domain structures in fungi. Chapter 2 is a published manuscript on ferrichrome synthetases tracking the evolution of domain architectures of these relatively conserved enzymes across fungi. Results supported the hypothesis that ferrichrome synthetases evolved by tandem duplication of complete modules (A-T-C) (single or double units) and loss of single A domains or complete A-T-C modules. A mechanism for evolution of iterative biosynthesis is proposed. Protein modeling of the A domain substrate binding pockets refined characterization of key residues involved in substrate specificity, by identifying novel sites. Chapter 3 reports a fungal kingdom-wide phylogenomic study of NRPSs, with the objective of identifying subclasses. Nine were identified which fell into two major groups. One consisted of primarily mono/bi-modular NRPSs with conserved domain architectures which group with bacterial NRPSs and whose products are associated with conserved metabolic roles. The other consisted of primarily multimodular and exclusively fungal NRPSs with variable domain architectures whose products perform niche-specific functions. All groups of NRPSs were much more common in Euascomycetes than in any other fungal taxonomic group. Although NRPSs are discontinuously distributed across fungal taxa, little evidence was found for horizontal gene transfer from bacteria to fungi. Overall, this study showed that both tandem duplication and loss, as well as recombination and rearrangement, of modular units (either complete A-T-C modules or single A domains) are mechanisms by which NRPSs and their chemical products evolve. Phylogenomic analysis identified subgroups of NRPSs possibly reflecting common function and suggested an older evolutionary origin of several mono/bimodular groups while multimodular fungal NRPSs are more recently derived and highly expanded in Euascomycetes. BIOGRAPHICAL SKETCH Kathryn Bushley was born in Seattle, Washington on August 25, 1968. She attended Oberlin College and obtained a B.A. degree with a double major in Biology and Anthropology in 1991. After working and dancing for several years in the Seattle area and deciding not to pursue a professional career in dance, she returned to graduate school for a Master’s in Environmental Management at Duke University. It was during her master’s degree at Duke where she first fell in love with fungi while working on a masters thesis investigating turnover of mycorrhizal fungal root systems and taking a mycology course with Dr. Rytas Vilgalys. After completing her master’s degree in 1997, she worked for her advisor, Dr. Janet MacFall, for several years at the Duke Medical Center investigating how mycorrhizal fungi bind aluminum in soil using innovative techniques of magnetic resonance imaging to noninvasively measure changes in root volume. She entered the PhD program in Plant Pathology at Cornell University in fall of 2001 to study mycology and joined the Turgeon lab in 2002. iii I would like to dedicate this work to my great grandmother Lillian Vogle whose adventurous spirit inspires me to explore the boundaries of the unknown and go where no woman has gone before iv ACKNOWLEDGMENTS Many people have contributed in both large and small ways to the fruition of this work. I am grateful first and foremost for being blessed with exceptional parents whose love and support sustain me in all my endeavors. I would like to thank my committee members, B. Gillian Turgeon, Jeff Doyle, and Donna Gibson for their support, enthusiasm, and patience throughout the PhD process. I am also grateful to Oberlin College, my undergraduate institution, for teaching me to think critically and independently. Thanks to Miguel Carvahlo, Jean Bonasera, and fellow labmembers Shunwen Lu and Patrik Inderbitzin, for providing training and mentoring in molecular biology and phylogenetic techniques during the early stages of my PhD. Special thanks to Genevieve DeClerck and Paul Stodghill for their patience in initiating me into the art of computer programming and for troubleshooting more than one incomprehensible error message. I am also especially grateful to Daniel Ripoll, who performed protein structural modelling of NRPS AMP domains and contributed significantly to insights into substrate specificity of fungal ferrichrome siderophore synthetases discussed in Chapter 2 as well as other staff members of the Cornell Computation Biology Service Unit, Conrad Schoch, Adam Siepel, and Dave Schneider for providing both advice and resources for computational and phylogenetic analyses. I would also like to thank others who have provided advice along the way (Scott Kroken , Henk DeBakker, Kevin Nixon, and Ning Zhang) and the Plant Pathology administrative staff, especially Carol Fisher, for superb administrative support and assistance in formatting the thesis. v TABLE OF CONTENTS Biographical Sketch iii Dedication iv Acknowledgements v List of Tables xi List of Figures xiii List of Appendices xiv 1. Chapter 1: General Introduction 1 1.1 Modular Proteins in Secondary Metabolism 1 1.2 NRPS Biosynthesis 4 1.2.1 Adenylation (A) Domain 6 1.2.2 Thiolation (T) Domain 8 1.2.3 Condensation (C) Domain 9 1.2.4 Termination Domains 10 1.2.5 Decorating Domains 12 1.3 Evolutionary Origins of NRPS and PKS Synthetases 13 1.3.1 Relationship Between NRPSs, PKSs and Primary 13 Metabolism 1.3.2 Discovery of NRPSs and Related AMP Adenylating 14 Enzymes 1.4 Mechanisms of Evolution of Modular Proteins 16 1.4.1 Models of Gene Family Evolution 16 1.4.2 Evolution of Repeated Units in Proteins 17 1.5 Fungal NRPS: Evolution and Functional Groups 20 vi 1.5.1 Mechanisms Leading to the Discontinuous Distribution 20 of Secondary Metabolite Genes in Fungi: Gene Clusters, Horizontal Gene Transfer, and Duplication and Differential Loss (DDL) 1.5.2 Known Functional Classes of Fungal NRPSs 25 1.5.2.1 Conserved Homologs of ChNPS6, ChNPS4, ChNPS10, and ChNPS12 26 1.5.2.2 Siderophore Synthetases 29 1.5.2.3 ACV Synthetases 29 1.5.2.4 Cyclosporin Synthetases 30 1.5.2.5 Cyclic Depsipeptide Synthetases: 32 Enniatin and Related Compounds 1.5.2.6 Ergot Alkaloid Synthetases 33 1.5.2.7 Peramine Synthetase 37 1.5.2.8 Peptaibols 37 1.5.2.9 Diketopiperazines and ETP toxins 38 1.5.2.10 Dothideomycete Host-Selective Toxins 41 1.5.2.11 Fungal PKS:NRPS Hybrids 43 1.5.2.12 NRPS:PKS Hybrids 46 1.6 Objectives 46 References – Chapter 1 47 2. Chapter 2: Module Evolution and Substrate Specificity of Fungal Nonribosomal Peptide Synthetases Involved in Siderophore Biosynthesis. Published manuscript. 87 2.1 Abstract 87 vii 2.2 Background 88 2.3 Materials and Methods 92 2.3.1 Genomes Surveyed for Ferrichrome-Associated Nonribosomal Peptide Synthetases 92 2.3.2 Annotation of Candidate Ferrichrome Synthetases 94 2.3.3 Phylogenetic Analyses 95 2.3.3.1 Complete set of A domains 95 2.3.3.2 Individual Lineage Analysis 96 2.3.4 Substrate Specificity 97 2.3.4.1 Structural Modeling 97 2.3.4.2 Evolutionary Approaches to Identify 99 Specificity Residues 2.4 Results 100 2.4.1 Distribution of Ferrichrome Synthetases in Fungi 100 2.4.2 Domain Architecture of Ferrichrome Synthetases 101 2.4.3 Two Distinct Lineages of Ferrichrome Synthetases 103 2.4.4 Additional Duplications Within the NPS1/SidC Lineage 109 2.4.5 S. pombe sib1 110 2.4.6 Putative Ferrichrome Synthetases in the SidE Clade 110 2.4.7 Individual Lineage Analysis 111 2.4.8 Adenylation Domain Substrate Choice 115 2.4.8.1 Structural Modeling 115 2.4.8.2 Evolutionary Approaches to Identification of Specificity Residues 122 2.5 Discussion 124 2.5.1 Distinct Lineages of Ferrichrome Synthetases 124 viii 2.5.2 Evolution of Domain Architecture 125 2.5.3 Domain Architecture and Mechanism of Biosynthesis 129 2.5.4 Substrate Specificity 131 2.6 Conclusions 133 Appendices – Chapter 2 135 References – Chapter 2 151 3. Chapter 3: Identification, Distribution, and Lineage Specific Expansions of NRPS and NRPS-like Synthetase Subfamilies in Fungi Manuscript submitted 158 3.1 Abstract 158 3.2 Background 159 3.3 Results and Discussion 163 3.3.1 Identification and Domain Structure of Candidate NRPSs 163 3.3.2 Phylogenomic Analysis and Subfamily Identification 164 3.3.3 Relationships Between Fungal and Bacterial NRPSs: Horizontal Transfer or Vertical Transmission and Massive Loss? 172 3.3.4 Distribution of NRPS Subfamilies Across Fungal Taxonomic Groups 174 3.3.5 Lineage Specific Expansions and Contractions 177 3.3.6 Subfamily Distribution 178 3.3.7
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