原核生物特殊巨大基因和核苷酸醣焦磷酸化酶的分子演化分析及細菌尿嘧啶雙磷酸葡萄糖焦磷酸化酶抑制劑的搜尋

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研究生：	郭敏潔 Kuo, Min-Chieh
論文名稱：	原核生物特殊巨大基因和核苷酸醣焦磷酸化酶的分子演化分析及細菌尿嘧啶雙磷酸葡萄糖焦磷酸化酶抑制劑的搜尋 Molecular Evolution of Exceptionally Large Genes and Nucleotide-Sugar Pyrophosphorylases in Prokaryotes, and Identification of Potential Inhibitors of UDP-Glucose Pyrophosphorylase
指導教授：	張晃猷 Chang, Hwan-You
口試委員:	林志侯 Lin, Thy-Hou 彭慧玲 Peng, Hwei-Ling 蕭乃文 Hsiao, Nai-Wan 陳盈璁 Chen, Ying-Tsong
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 分子醫學研究所 Institute of Molecular Medicine
論文出版年：	2012
畢業學年度：	100
語文別：	英文
論文頁數：	111
中文關鍵詞：	特殊巨大基因、核苷酸醣焦磷酸化酶、分子演化、尿嘧啶雙磷酸葡萄糖焦磷酸化酶、抑制劑
外文關鍵詞：	exceptionially large-sized genes (ELSGs), nucleotide-sugar pyrophosphorylase (NDP-sugar PPase), molecular evolution, UDP-glucose pyrophosphorylse (UGPase), inhibitor
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本論文分為三章，第一章和第二章與分子演化相關，第三章主要為電腦輔助藥物設計。
第一章，探討原核生物特殊巨大基因的生成及演化過程。細菌基因平均大小為1 kb左右，但創傷弧菌大於13 kb的基因有3個，而介於8至13 kb之間的基因卻不存在。進一步調查46種細菌和11種古生菌，在將近17萬個基因中，找到大於5 kb的基因有312個(佔0.19%)，大於10 kb的基因有42個(佔0.03%)。由同源分析的結果顯示，除了非核醣體胜肽合成酵素外，很多超大基因可能是膜蛋白。利用點矩陣圖分析這些超大基因產物序列顯示，大部分超大基因產生的主要機制為蛋白質功能區間的多重複製。也有經由不同基因間的重組(13個)、基因融合(1個)、和經由水平基因轉移(2個)而使基因增大。由此可知，超大基因是經由不同的演化過程而產生的。
第二章，探討原核生物中核苷酸醣焦磷酸化酶/磷酸化酶的演化。這類酵素在生物體中提供核苷酸醣於複合多醣類合成。我們收集KEGG資料庫中所有細菌、古生菌、和6種真核生物的核苷酸醣焦磷酸化酶/磷酸化酶序列，共計2千5百多筆，並篩選出86個具代表性的基因。演化分析和蛋白質功能區的分析結果顯示，GDP-甘露糖焦磷酸化酶有最分岐的蛋白質序列，可能最接近核苷酸醣焦磷酸化酶/磷酸化酶的共同祖先。本研究也提出不同核苷酸醣焦磷酸化酶/磷酸化酶的演化模型，並說明其功能區間保留、失去、或得到的過程。
第三章，探討細菌尿嘧啶雙磷酸葡萄糖焦磷酸化酶的抑制劑篩選。由於原核和真核生物的尿嘧啶雙磷酸葡萄糖焦磷酸化酶的蛋白質序列不相似，可能具有不同的催化機制，適合當作藥物篩選結合標的。本研究利用模擬細菌尿嘧啶雙磷酸葡萄糖焦磷酸化酶分子結構，對不同的化合物資料庫進行抑菌藥物的篩選。在ZINC化合物資料庫，找到了22個尿嘧啶雙磷酸葡萄糖的結構類似物；在NCI化合物資料庫，找到了另外97個化合物，而其中的5個化合物也可被第2種藥物篩選程式挑選出來。這27個化合物可以當作有潛力的抑菌候選藥物，來進行後續的藥物試驗研究。
本論文說明了細菌特殊巨大基因的形成，也利用酵素核心功能區間對核苷酸醣焦磷酸化酶進行分類及說明其演化過程，並找到了有潛力的抑菌候選化合物。下一步，希望能取得或合成這些候選化合物，或者再針對已核准藥物的資料庫進行篩選(老藥新用)，進行後續的微生物抑制試驗，以提供未來新抑菌藥物的研究與開發。

This thesis consists of 3 chapters. The first 2 chapters describe the molecular evolution of prokaryotic exceptionally large-sized genes (ELSGs) and nucleotide-sugar pyrophosphorylases/phosphorylases (NDP-sugar PPases/Pases). The third chapter describes a computer-aided drug design for searching bacterial UDP-glucose pyrophosphorylase (UGPase) inhibitors.
In chapter 1, we have noted that, in contrast to the average gene size of approximately 1 kb in bacteria, 3 genes > 13 kb were present in Vibrio vulnificus. The finding prompted us to investigate the prevalence, possible function, and origin of ELSGs (>10 kb) in prokaryotes. Forty-two ELSGs (0.03%) were identified after searching more than 170,000 genes in 46 bacterial and 11 archaeal species. Homology analysis of these ELSGs indicated that, in addition to encoding non-ribosomal peptide synthetic enzymes, many ELSGs likely encode membrane-anchored proteins. Dot-matrix plot analysis of these ELSGs indicated that domain-duplication contributed significantly to size expansion. Other size expansion mechanisms were direct gene fusion, recombination of different genes, and horizontal gene transfer. In summary, ELSGs are commonly present in prokaryotes, and the evolutionary processes that have contributed to the formation of ELSGs are relatively heterogeneous.
NDP-sugar PPases/Pases play a central role in providing sugar donor for the formation of glycoconjugates. Despite each of the enzymes has unique substrate specificity, they share homologous protein sequences and are therefore difficult to annotate. Chapter 2 describes our effort to better categorize these enzymes. More than 2,500 NDP-sugar PPases/Pases sequences were collected from the KEGG in this study and 86 representative sequences were selected. Phylogenetic and domain analyses revealed that members of GDP-Man PPase had the most diverse protein sequences implying that this enzyme is evolutionally closer to the common ancestor of the NDP-sugar PPases/Pases than other members of the family. Most NDP-sugar PPases/Pases were apparently derived by gene duplication although horizontal gene transfer, as in the case of eukaryotic UDP-Glc PPase, also contributed to the gene diversification. An evolutionary model for this group of enzymes was established by combining phylogenetic analysis and domain profiling. The core domains of each of the enzymes, trend of domain gain and loss, and evolutionary transition were demonstrated. These non-redundant 86 representative sequences may be used as the reference sequences for NDP-sugar PPases/Pases categorization.
The low levels of sequence homology between prokaryotic and eukaryotic UGPase makes the enzyme a good target for antimicrobial drug development. Chapter 3 describes 22 UDP-Glc analogs and 97 candidate compounds, respectively selected from the ZINC and NCI compound databases using the protein docking program, LigandFit, that have potential to inhibit the bacterial UGPase activity. Five of the 97 candidate compounds were also identified by another docking program, Libdock. These 27 compounds represent potential bacterial UGPase inhibitors.
The research interpreted the evolution of prokaryotic ELSGs, the categorization and evolutionary history of NDP-sugar PPases/Pases, and obtained the potential bacterial UGPases candidate inhibitors. The next step, we hope to obtain or synthesis these candidate compounds, or to screen the approved drugs in drug product database (new uses for old drugs) to perform the antimicrobial assay for the research and development of novel antimicrobial agents.

Background and Significance    01
Part-I: Molecular Evolution    02
Chapter 1    Evolution of exceptionally large-sized genes in prokaryotes    03
    1.1. Abstract            04
    1.2. Introduction        05
    1.3. Material and Methods    06
        1.3.1.    Data source    06
        1.3.2.    Identification of repeat units and identity    07
        1.3.3.    Identification of orthologous groups and ELSGs features    08
        1.3.4.    GC content, codon usage, cladogram, and similarity of ELSGs    08
        1.3.5.    Gene expression profiles    09
    1.4. Results and Discussion    10
        1.4.1.    Gene size distribution in Vibrio vulnificus    10
        1.4.2.    Distribution of prokaryotic gene sizes    11
        1.4.3.    Evolutionary relationship among ELSGs and functional inferring    13
        1.4.4.    Expression profiles of ELSGs    14
        1.4.5.    Codon usage in the ELSGs    15
        1.4.6.    Possible origins of the ELSGs    16
        1.4.7.    Identification of domain multiplication events in ELSGs    17
        1.4.8.    Direct evidence of domain multiplication in ELSG formation    19
        1.4.9.    Evidence of recombination events in ELSGs    20
        1.4.10.    Direct evidence of gene fusion in ELSGs    20
    1.5. Tables            22
        Table 1.1    The presence of large-sized genes in prokaryotes and S. cerevisiae.     22
        Table 1.2    Percentage of ELSGs in analyzed taxa.    24
        Table 1.3    The size and putative function of the 46 ELSGs.    25
        Table 1.4
    GC content and Nc values of the selected genomes and ELSGs.    26
        Table 1.5    The characteristics of repetitive sequence in ELSGs.     27
        Table 1.6    The singleton and multi-domain proteins in analyzed prokaryotes.    28
    1.6. Figures            29
        Fig. 1.1    Gene size distribution of V. vulnificus YJ016.    29
        Fig. 1.2    Gene size distribution of 57 prokaryotic species.    30
        Fig. 1.3    Evolutionary relationship of ELSGs.    31
        Fig. 1.4    Identification of repeat sequences in ELSGs.    32
        Fig. 1.5    Mechanisms of ELSG formation.    34
Chapter 2    Evolution and categorization of nucleotide-sugar pyrophosphorylases in prokaryotes    35
    2.1. Abstract            36
    2.2. Introduction        37
    2.3. Materials and Methods    38
        2.3.1.    Data collection of NDP-sugar PPases/Pases    38
        2.3.2.    Phylogenetic analysis    39
        2.3.3.    Protein structures, identification of functional domains and motifs    39
        2.3.4.    Domain-based phylogenetic analysis    40
    2.4. Results            40
        2.4.1.    Protein diversities of NDP-sugar PPases/Pases    40
        2.4.2.    Evolutionary relationship of NDP-sugar PPases/Pases    42 
        2.4.3.    Domain pattern and categorization of NDP-sugar PPases/Pases    44 
        2.4.4.    Core domains and evolutionary history of NDP-sugar PPases/Pases    47 
    2.5. Discussion            49 
    2.6. Tables            53 
        Table 2.1    Initially extracted and representative gene numbers of NDP-sugar PPases/Pases in 6 eukaryotes and all prokaryotes.    53 
        Table 2.2
    List of questionable grouped genes from phylogenetic analysis.    54 
        Table 2.3    Domain index.    55 
    2.7. Figures            57 
        Fig. 2.1
    The flow chart of data collection, selection, and analysis in this study.    57 
        Fig. 2.2    The evolutionary relationship estimation of NDP-sugar PPases/Pases.    58 
                
        Fig. 2.3    Domain pattern of 86 representative sequences.    63 
        Fig. 2.4    Domain cluster of NDP-sugar PPases/Pases.    64 
        Fig. 2.5    A proposed evolution history of NDP-sugar PPases/Pases.    67 
    2.8. Supporting Information    73 
        Table S2.1    Gene information of 86 representative sequences.    73 
Part-II:    75 
Chapter 3
    Identification of potential inhibitors of bacterial UDP-glucose pyrophosphorylases by computer-aided drug design    75 
    3.1. Abstract            76 
    3.2. Introduction        78 
    3.3. Materials and Methods    79 
        3.3.1.    Homology modeling and verification    79 
        3.3.2.    Protein docking and scoring    80 
        3.3.3.    Reagents, proteins, and experimental validation of UGPases    81 
        3.3.4.    Protein structures of UGPases    82 
        3.3.5.    Compound databases and compounds for protein docking    82 
        3.3.6.    Protein-ligand interaction    83 
    3.4. Results    83 
        3.4.1.    Homology modeling and structure verification    83 
        3.4.2.    Docking by NDP-sugars and experimental validation    85 
        3.4.3.    Protein identities and RMSD values of known UGPase structures    86 
        3.4.4.    Docking by UDP-Glc analogs and NCI compounds, and the potential inhibitors    86 
        3.4.5.    Protein-compound interactions    87 
    3.5. Discussion            89 
    3.6. Conclusion            90 
    3.7. Tables            92 
        Table 3.1    The results of protein docking and activity assay of UGPase of K. pneumoniae.    92 
        Table 3.2    Twenty-two common candidates were UDP-Glc analogs screened from ZINC compound database.    93 
        Table 3.3    Top ten, 55th, and 82th of the 97 common candidates were screened from NCI compound database.    94 
    3.8. Figures            95 
        Fig. 3.1
    Comparison of K. pneumoniae Gal, GalF, and E. coli GalU (2E3D).    95
        Fig. 3.2    Evaluation of the K. pneumoniae UGPase molecular model.    96 
        Fig. 3.3
    GalU of K. pneumoniae was docked by 9 naturally occurring NDP-sugars.    97 
        Fig. 3.4
    Chemical structures of 3 natural substrates used in the protein docking and validation experiments.    98
        Fig. 3.5
    Comparison of different UGPases with known molecular structures.    99
        Fig. 3.6
    Structures of the potential bacterial UGPases inhibitors in this study.    101 
        Fig. 3.7    Protein diagram of UGPase-ligand interaction.    102 
    3.9. Supporting Information    104 
        Table S3.1    Ninety-seven common candidates were screened from NCI compound database.    104 
References            106 
                                

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