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研究生： 林樹熙
Lin, Shu-Hsi
論文名稱： 真菌類聚酮合成酵素和基因強健性之演化研究
Evolutionary Studies of Fungal Polyketide Synthases and Genetic Robustness
指導教授： 呂平江
Lyu, Ping-Chiang
唐傳義
Tang, Chuan-Yi
口試委員: 有田正規
莊永仁
陳倩琪
Masanori Arita
Chen, Chien-Chi
學位類別： 博士
Doctor
系所名稱： 生命科學暨醫學院 - 生物資訊與結構生物研究所
Institute of Bioinformatics and Structural Biology
論文出版年： 2013
畢業學年度： 101
語文別： 英文
論文頁數： 136
中文關鍵詞： 二次代謝產物 、基因調控網路 、演化 、生物強健性 、聚酮
外文關鍵詞： Secondary metabolite, Genetic regulation network, Evolution, Biological robustness, Polykeitde
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    • 聚酮化合物是由聚酮合成酵素(polyketide synthease, PKS)透過逐步縮合反應催化產生的結構多樣之自然產物，主要被發現在微生物和植物中產生，並且廣泛運用在醫藥和農業上。聚酮合成酵素的基因會群集在一起形成基因簇，而且此類基因簇蘊含了與聚酮生物合成路徑與調控機制相關的龐大訊息。隨著基因體計畫的快速成長，聚酮合成酵素基因數據大量地增加，也因此促進了新生物活性化合物的開發和探討聚酮合成路徑之特性的研究。
    本論文研究著重於從演化的觀點來探討真菌第一型聚酮合成酵素基因、其合成酵素和相對應的代謝物結構關係。我們收集真菌的此類基因和相關產物資料，建立一個維基介面資料庫，其包含超過400個以上的聚酮合成酵素基因，並且針對8株基因定序完成的麴黴屬物種(Aspergillus)，進行真菌迭代式第一型聚酮合成酵素基因的系统發育基因組學分析。由高保留度的聚酮合成酵素結構域建立的家族系譜顯示出清楚的系統發育分類關係，包含了三群較大的非還原聚酮合成酵素，兩群分別與細菌聚酮合成酵素和雜合型聚酮合成酵素/非核醣體胜肽合成酵素 [PKS/ NRPS)(nonribosomal peptide synthase)] 形成嵌套混合群 (nested clades)的部分還原聚酮合成酵素和超過十群較小的還原聚酮合成酵素。除此之外，我們發現雜合型非核醣體胜肽合成酵素/聚酮合成酵素的分支呈現為複系群(polyphyly)，此現象可能與這兩種合成酵素如何結合的機制相關。總和來說，麴黴屬的第一型聚酮合成酵素基因呈現了高比率的基因重製和趨異。
    除此之外，為了表達真菌聚酮合成酵素基因，設計出更具效率且容易進行基因操作的異源表達宿主，我們探討分析酵母菌的基因強健機制。特別是，著重於轉錄修復在基因強健性中扮演的腳色，並利用酵母菌中非同源性合成致死 (synthetic-lethal)基因對的多種數據進行評估。我們認為非同源性基因造成的功能性緩衝有三個特徵: 有(i)合成致死交互作用， (ii) 高比例的共同交互作用搭檔，和(iii)共同調控的程度。結果也顯示轉錄重整程序(transcriptional reprogramming)對於非同源基因間功能性修復機制僅佔有很小的比例。
    綜合上面所述，此論文的研究分析促進我們對真菌聚酮合成酵素演化系統發育關係和功能修復機制的了解。維基介面的聚酮化合物資料庫將進一步整合各種聚酮化合物的數據，並預期將促進新生物活性產物的鑑定與應用。

    Polyketide synthases (PKS) catalyze stepwise condensation reactions of small carboxylic acid units to form structurally diverse natural products. The products, mainly found from microorganisms and plant, possess a wide range of important agriculture and pharmaceutical applications. PKS-encoding genes, located closely as a cluster, have been mined for immense information about polyketide biosynthesis and its regulation mechanisms. With the endeavor on genome projects, the increased availability of PKS gene data has enabled to discover new bioactive compound and to explore polyketide biosynthetic manner.
    The focus of the present thesis was the exploration the interrelationships between the fungal type I PKS genes, proteins and the corresponding metabolite structures from evolutionary perspectives. We created a wiki-based database to accommodate our publicly accessible and manually curated PKS gene data. With more than 400 PKS gene data in the database, we conducted a phylogenomic approach to investigate the distribution of iterative PKS genes from eight sequenced Aspergilli and other fungi. Their genealogy by the conserved ketosynthase (KS) domain unveiled the clear phylogenetic classification within three large groups of non-reducing PKS, two partial-reducing PKS groups nested with bacterial PKSs and PKS-nonribosomal peptide synthase (NRPS) respectively, and more than 10 small groups of reducing PKSs.
    In addition, polyphyly of PKS-NRPS hybrid genes raised questions regarding the recruitment of the elegant conjugation machinery. Overall, high rates of gene duplication and divergence for type I PKSs were frequent.
    In order to design a more efficient and easier genetically manipulated heterologous system for the expression of fungal PKS genes, we addressed the genetic robustness mechanism in yeast. Especially, we focused on the exploration on the role of transcriptional compensation in genetic robustness. A set of non-homologous synthetic-lethal gene pairs was assessed with various type data in yeast. We considered the functional buffering of non-homologous genes can be characterized by three features: (i) synthetic-lethal interaction, (ii) the ratio of shared common interacting partners, and (iii) the degree of co-regulation. The results also suggested that transcriptional reprogramming may plays a limited role in functional compensation among non-homologous genes.
    As stated above, our assessment aids in understanding the phylogenetic relationship of fungal PKSs and the mechanism of functional compensation in yeast. The PKS wiki-database will further integrate various types of polyketide information and facilitate the identification and the application of new bioactive products.

    中文摘要 i ABSTRACT iii ACKNOWLEDGEMENT v TABLE OF CONTENT vii LIST OF FIGURES x LIST OF TABLES xi LIST OF ABBREVIATIONS xii PUBLICATIONS xiv CHAPTER 1. Introduction 15 1.1 General Introduction 16 1.2 Natural Products as Drugs 17 1.3 A Historic Perspective on Polyketides Research 22 1.3.1 The early age of polyketide research 23 1.3.2 Isotopic-labelling applications on polyketide 23 1.3.3 The genetic approach on polyketide synthase studies 25 1.4 Genomics and Secondary Metabolism 28 1.4.1 Fungal genome mining for new natural products and biosynthetic pathways 28 1.4.2 Genomics-based methods for the discovery of new natural products 29 1.5 Objectives of the Thesis 31 CHAPTER 2. Phylogenomic and Domain Analysis of Iterative Polyketide Synthases in Aspergillus Species 32 2.1 Introduction 33 2.1.1 The paradigms of polyketide synthase studies 33 2.1.2 Fungal type I polyketide synthases 36 2.1.3 Dual and hybrid synthases systems 41 2.1.4 Genome mining of polyketide synthases in Aspergillus species 43 2.1.5 Evolution of polyketide synthases 46 2.1.5.1 Phylogenomics analysis in secondary metabolites 46 2.1.5.2 Keto-synthase domain phylogeny 46 2.2 Materials and Methods 50 2.2.1 PKS genes and genome databases 50 2.2.2 Assignment of catalytic domains and PKS types 51 2.2.3 Domain genealogy construction 53 2.2.4 Database construction 53 2.3 Results and Discussion 54 2.3.1 Distribution of PKS-related genes 54 2.3.2 Domain compositions 56 2.3.3 Phylogenomic analysis of KS domains 58 2.3.5 Orthologous genes 63 2.3.6 Web-based database system 67 2.4 Conclusion 68 CHAPTER 3. Feature Identification of Compensatory Gene Pairs without Sequence Homology in Yeast 70 3.1 Introduction 71 3.1.1 Transcriptional regulation of secondary metabolism gene clusters 71 3.2.1.1 Pathway-specific regulators 72 3.2.1.2 Global regulatory proteins 73 3.1.2 Yeast as a robust heterologous host for secondary metabolite production 74 3.1.3 Genetic network robustness 76 3.2 Materials and Methods 79 3.2.1 Dataset of synthetic lethal genes and mRNA expression data 79 3.2.2 Calculation of sequence similarity and assignment of functional modules 79 3.2.3 Biological network construction 80 3.2.4 Promoter regulatory elements analyses 80 3.2.5 MES and PCoR analyses 81 3.2.6 Functional relatedness analyses 81 3.3 Results and Discussion 83 3.3.1 Sequence similarity and functional module analysis 83 3.3.2 Gene expression analyses 83 3.3.3 Network-based modeling 85 3.3.4 Motif-sharing analysis of non-homologous SSL pairs 87 3.3.5 Identification of functionally compensatory genes 89 3.4 Conclusions 91 CHAPTER 4. Conclusions and Future Perspectives 93 4.1 Polyketide Synthase Diversity and Evolution of Secondary Metabolite Gene Clusters in Fungi 94 4.2 Database of Polyketide and Polyketide Synthase 96 4.3 Evolution and Genetic Robustness 97 REFERENCES 100 Appendix A. Phylogenetic relationship of iPKS in Aspergillus species 124 Appendix B. A list of candidates of compensatory gene 132

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