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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 梁博煌 | zh_TW |
| dc.contributor.advisor | Po-Huang Liang | en |
| dc.contributor.author | 劉嘉晉 | zh_TW |
| dc.contributor.author | Jia-Jin Liu | en |
| dc.date.accessioned | 2025-07-30T16:16:25Z | - |
| dc.date.available | 2025-07-31 | - |
| dc.date.copyright | 2025-07-30 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-07-25 | - |
| dc.identifier.citation | Chapter I:
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Synthesis, Biological Evaluation and 3D-QSAR Studies of 3-Keto Salicylic Acid Chalcones and Related Amides as Novel HIV-1 Integrase Inhibitors. Bioorg. Med. Chem. 2011, 19 (6), 2030–2045, DOI: 10.1016/j.bmc.2011.01.047 59. Sivakumar, P. M.; Prabhakar, P. K.; Doble, M. Synthesis, Antioxidant Evaluation, and Quantitative Structure-Activity Relationship Studies of Chalcones. Med. Chem. Res. 2011, 20 (4), 482–492, DOI: 10.1007/s00044-010-9342-1 60. Sashidhara, K. V.; Avula, S. R.; Mishra, V.; Palnati, G. R.; Singh, L. R.; Singh, N.; Chhonker, Y. S.; Swami, P.; Bhatta, R. S.; Palit, G. Identification of Quinoline-Chalcone Hybrids as Potential Antiulcer Agents. Eur. J. Med. Chem. 2015, 89, 638–653, DOI: 10.1016/j.ejmech.2014.10.068 | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/98190 | - |
| dc.description.abstract | Chapter I:
真核生物的去氫多萜二磷酸合成酶（Dehydrodolichyl diphosphate synthases, DHDDSs）是一類順式異戊二烯轉移酶（cis-prenyltransferases, cis-PTs），負責合成多萜類（dolichols）的前驅物，從而調控蛋白質醣基化。這些酶需要合作夥伴，例如酵母中的Nus1和動物中的NgBR，它們是缺乏催化結構域的 cis-PT 同源蛋白，但能夠增強 DHDDS 活性。與動物不同，植物擁有多種cis-PTs，這些蛋白可以配對或單獨行動，生成具有不同鏈長的產物，但其生理功能尚不清楚。我們選擇研究台灣牛樟（Cinnamomum kanehirae），基因組分析顯示該物種含有兩個DHDDS類蛋白與三個NgBR類蛋白。我們發現，一個DHDDS類蛋白作為同源二聚體的cis-PT，可生成中鏈長的C55產物，而另一個則與兩個NgBR類蛋白中的任何一個形成二聚體複合物，以產生更長鏈的產物。此外，這些複合物在較高溫度下能補充酵母rer2缺失菌株的生長缺陷。基於聚異戊二烯醇和多萜類的生物合成功能以及序列特徵，我們比較來自多個物種的cis-PTs同源蛋白，並揭示植物的cis-PTs可能的演化路徑。 Chapter II: 具有降解纖維素與半纖維素活性的多功能且耐高溫之酵素，對於將植物性生物質轉化為生物燃料的過程具有重要應用價值。過去的研究中，我們已鑑定來自Clostridium thermocellum的雙功能纖維素酶/木聚糖酶Cel5E（CtCel5E）以及來自Thermotoga maritima的雙功能纖維素酶/甘露聚糖酶Cel5A（TmCel5A）。儘管這兩種酶在胺基酸序列與三維結構上高度保守，卻展現出明顯不同的半纖維素受質特異性。在本研究中，我們進一步分析另一種GH5家族的酶CtCel5T，其被註釋為三功能纖維素酶/木聚糖酶/甘露聚糖酶。透過結構比較並結合點突變實驗，我們鑑定出CtCel5T的Met277及Glu360分別佔據與TmCel5A的His205和Trp210相似的空間位置，並對辨識半纖維素受質發揮關鍵作用。因此，透過親緣關係樹與多重胺基酸序列比對，可以鑑定具結構功能一致性的纖維素酶/半纖維素酶或預測未知酵素之功能。本研究深化了對多功能纖維素酶/半纖維素酶受質特異性機制的理解，並為其在工業應用中的蛋白質工程設計提供了理論支持。 Chapter III: 2019年新型冠狀病毒肺炎 （COVID-19）於 2019 年 12 月首次被確認，隨後演變為全球大流行，已導致超過 700 萬人死亡，致死率約為 1%。我們報導並鑑定了兩類化合物，1-（4-（芳乙基羰基）苯基）-4-羧基-2-吡咯烷酮和四氫吡嗪[2 ，1-a：5,4-a']二異喹啉，作為嚴重急性呼吸綜合症冠狀病毒2型 （SARS-CoV-2）的抑制劑，該病毒是COVID-19的病原體。我參與的研究包含提供電腦模擬和藥物動力學預測技術，以合理化該系列中最有效的抑製劑與其目標蛋白之結合模式，並評估其作為藥物之特徵。此外，具抗生素耐藥性之細菌的出現，如抗甲氧苯青黴素金黃色葡萄球菌 （MRSA），主要歸因於長期濫用和過度依賴抗生素，已成為當代醫療保健的一個關鍵挑戰。我們設計、合成和評估了一類 MRSA抑製劑。作為初步研究，我分析了這類MRSA抑製劑針對潛在的目標蛋白，催化十一異戊基二烯焦磷酸（UPP）生成以作為細胞壁肽聚糖生合成之脂質載體前驅物的十一異戊基二烯焦磷酸合成酶 （UPPS）之抑制效果，並利用電腦模擬合理化最佳抑制劑的結合模式，以及對查耳酮衍生物進行針對UPPS的電腦輔助藥物篩選，為開發潛在抗菌劑提供新的見解。 | zh_TW |
| dc.description.abstract | Chapter I:
Eukaryotic dehydrodolichyl diphosphate synthases (DHDDSs) are cis-prenyltransferases (cis-PTs) that synthesize dolichol precursors essential for protein glycosylation. These enzymes require non-catalytic partners, such as Nus1 in yeast and NgBR in animals, which are cis-PT homologues devoid of the catalytic domain but enhancing DHDDS activity. In contrast to animals, plants possess multiple cis-PT homologues that can function independently or in pairs to produce products of varying chain lengths, with their physiological roles remaining largely unexplored. In this study, we investigated cis-PTs from Cinnamomum kanehirae, a tree identified through genomic analysis to express two DHDDS-like and three NgBR-like proteins. One DHDDS-like protein functioned as a homodimeric cis-PT, producing medium-chain C55 products, whereas the other formed heterodimeric complexes with either of two NgBR homologues to synthesize longer-chain products. Both complexes effectively complemented the growth defect of a yeast rer2 deletion strain at elevated temperatures. By examining the roles of these cis-PTs in polyprenol and dolichol biosynthesis and comparing their sequence motifs across species, we inferred the potential evolutionary paths for these cis-PTs. Chapter II: Multifunctional and heat-resistant enzymes with both cellulose and hemicellulose degrading activities are particularly useful to convert plant biomass into biofuel. In the past, we have characterized the bifunctional cellulase/xylanase Cel5E from Clostridium thermocellum (CtCel5E) and the bifunctional cellulase/mannanase Cel5A from Thermotoga maritima (TmCel5A). Despite highly conserved amino acid sequences and structures, they exhibit distinct hemicellulase substrate specificities. In the current study, we further characterized another GH5 enzyme, CtCel5T, annotated as a trifunctional cellulase/xylanase/mannanase. Through structural comparison coupled with site-directed mutagenesis, we identified Glu360 in loop 8 and Met277 in loop 6 of CtCel5T occupying the overlapped spatial positions with that of Trp210 and His205 in loop 6 of TmCel5A, respectively, play critical roles in substrate recognition. Therefore, phylogenetic tree analysis and multiple sequence alignment are useful to find characterized cellulases/hemicellulases with functions consistent with the structural features or uncharacterized enzymes for predicting their functions. This study thus enhances our understanding on the mechanisms for substrate specificities and engineering of multifunctional cellulases/hemicellulases for industrial applications. Chapter III: The coronavirus disease 2019 (COVID-19), initially identified in December 2019, has evolved into a global pandemic, resulting in over 7 million deaths with approximately 1% mortality rate. We identified and characterized two classes of compounds, 1-(4-(arylethylenylcarbonyl)phenyl)-4-carboxy-2-pyrrolidinones and tetrahydropyrazino[2,1-a:5,4-a']diisoquinolines, as inhibitors against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19. I have engaged in the studies for providing computer modeling and pharmacokinetic prediction technology to rationalize the binding mechanisms and assess the drug-likeness properties of the most potent candidates within these series. Furthermore, the emergence of antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), largely attributed to the prolonged misuse and excessive reliance on antibiotics, has become a critical challenge in contemporary healthcare. We designed, synthesized, and evaluated a class of MRSA inhibitors. As a preliminary study, I assayed the inhibitory activities of the active compounds against the possible target, undecaprenyl diphosphate synthase (UPPS) that catalyzes C55 UPP as a lipid carrier for biosynthesis of the cell wall peptidoglycan, and rationalize the binding mode using computer modeling. Moreover, virtual screening of chalcone derivatives against UPPSs provides valuable insights into developing potential anti-bacterial agents. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2025-07-30T16:16:25Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2025-07-30T16:16:25Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | CONTENTS I
致謝 VIII Chapter I: Complexation and evolution of cis-prenyltransferases in Cinnamomum kanehirae deduced from kinetic and functional characterizations IX 中文摘要 IX ABSTRACT X ABBREVIATIONS XI LIST OF TABLES XIII LIST OF FIGURES XIV 1. INTRODUCTION 1 1.1 Cis-Prenyltransferases 1 1.2 The structures of cis-PTs 2 1.3 Specific aim of this study 3 2. MATERIALS AND METHODS 4 2.1 Materials 4 2.2 Expression and purification of the recombinant RWR89 5 2.3 Expression and purification of the recombinant RWR78, sRWR71, sRWR93, RWR78/sRWR71, RWR78/sRWR93 and RWR89 using yeast 6 2.4 Size-exclusion chromatography analysis 7 2.5 Cis-PTs activity assay 8 2.6 Yeast complementary assay 8 2.7 Polyisoprenoids extraction from yeast rer2Δ strain 9 2.8 HPLC product analysis 10 2.9 Protein multiple sequence alignment, phylogenetic analysis, and motif elicitation of cis-PTs 10 2.10 Homology Modeling of homodimeric RWR89, DHDDS, RWR78 and heteromeric RWR78/RWR71 and RWR78/RWR93 11 2.11 RNA-seq analysis of five C. kanehirae cis-PTs 11 3. RESULTS 12 3.1 Multiple sequence alignment of cis-PT homologues 12 3.2 Expression, purification, and characterization of recombinant RWR89 13 3.3 Expression, purification, and characterization of recombinant RWR78, sRWR71, sRWR93 and their heteromeric complexes 15 3.4 Functional analysis of two complexes in rer2-deletion (rer2Δ) S. cerevisiae 18 3.5 Homology modeling of RWR89 19 3.6 Homology modeling of RWR78/RWR71 and RWR78/RWR93 heterodimeric complexes 20 3.7 Possible evolutionary paths for C. kanehirae cis-PTs and homologues 24 4. DISCUSSION 28 TABLE 33 FIGURES 34 SUPPLEMENTARY INFORMATION 48 REFERENCES 60 Chapter II: Identification of a structural mechanism for substrates discrimination and prediction of multifunctional GH5 cellulases/hemicellulases XVI 中文摘要 XVI ABSTRACT XVII ABBREVIATIONS XVIII LIST OF TABLES XIX LIST OF FIGURES XX 1. INTRODUCTION 69 1.1 Sustainable energy production from agriculture biomass 69 1.2 Composition of agriculture biomass 70 1.3 Clostridium thermocellum cellulosome for plant biomass degradation 71 1.4 Substrate specificities of CtCel5E, CtCel5T and TmCel5A 71 1.5 Specific aim of this study 72 2. MATERIALS AND METHODS 73 2.1 Materials 73 2.2 Construction of expression plasmids 74 2.3 Expression and purification of recombinant proteins 74 2.4 Enzyme activity assays 76 2.5 End-product analysis 77 2.6 Multiple sequence alignment and phylogenetic tree analysis 78 3. RESULTS 78 3.1 Structural and sequence comparison of CtCel5T, CtCel5E and TmCel5A 78 3.2 Expression, purification, and characterization of CtCel5T 80 3.3 Functional characterization of the crucial residues in CtCel5T by site-directed mutagenesis 81 3.4 Pivotal roles of Met277 and Glu360 in CtCel5T on substrate discrimination 83 3.5 Phylogenetic tree analysis of GH5 families and prediction of substrate binding modes of hemicellulases with substrate preference to xylan or mannan 86 3.6 Confirmation of the prediction of MtGlu5 as a multifunctional cellulase/mannanase 90 4. DISCUSSION 91 TABLES 96 FIGURES 101 SUPPLEMENTARY INFORMATION 111 REFERENCES 116 Chapter III: Other studies for identification of inhibitors as potent antiviral or antibacterial agents XXI 中文摘要 XXI ABSTRACT XXII ABBREVIATIONS XXIV LIST OF TABLES XXVI LIST OF FIGURES XXVII 1. INTRODUCTION 128 1.1 Entry of SARS-CoV-2 into host cells 128 1.2 Discovery of 1-(4-(arylethylenylcarbonyl)phenyl)-4-carboxy-2-pyrrolidinones as SARS-CoV-2 entry inhibitors 129 1.3 Discovery of tetrahydropyrazino[2,1-a:5,4-a']diisoquinolines as SARS-CoV-2 inhibitors 130 1.4 Threats of multiple drug-resistant pathogens 130 1.5 Role of UPPS for bacterial cell wall biosynthesis 131 1.6 Specific aims of this study 132 2. MATERIALS AND METHODS 133 2.1 Molecular docking for 1-(4-(3-(1H-indol-4-yl)acryloyl)phenyl)-4-carboxy-2-pyrrolidinone (2f) and a tetrahydropyrazino[2,1-a:5,4-a']diisoquinoline (50) 133 2.2 Drug-likeness analysis 134 2.3 Expression and purification of recombinant EcUPPS and SaUPPS 135 2.4 Inhibition Assay against EcUPPS and SaUPPS 136 2.5 Molecular docking of the UPPS inhibitors 137 2.6 Virtual screening of chalcones against UPPSs 138 2.7 Pharmacophore anchors generation 138 3. RESULTS 139 3.1 Binding modes of 2f with TMPRSS2, Furin, and RBD 139 3.2 Drug-likeness analysis of 2f as judged from Lipinski rule of five and ADMET properties 141 3.3 Binding Mode of the tetrahydropyrazino[2,1-a:5,4-a']diisoquinoline Inhibitor 50 with RBD 142 3.4 Drug-likeness analysis of compound 50 as judged from Lipinski rule of five and ADMET properties 143 3.5 Evaluations of the inhibitors against UPPSs 145 3.6 Drug-Likeness of 87 and 94 as Judged from Lipinski Rule of Five and ADMET Properties 147 3.7 Virtual screening of chalcone-like compounds against EcUPPS and SaUPPS 149 4. DISCUSSION 153 TABLES 157 FIGURES 172 REFERENCES 187 APPENDIX 201 LIST OF PUBLICATIONS 201 STATEMENT OF ORIGINALITY 202 | - |
| dc.language.iso | en | - |
| dc.subject | NgBR | zh_TW |
| dc.subject | 生物燃料 | zh_TW |
| dc.subject | 纖維素酶 | zh_TW |
| dc.subject | 半纖維素酶 | zh_TW |
| dc.subject | 受質特異性 | zh_TW |
| dc.subject | 點突變 | zh_TW |
| dc.subject | 蛋白質醣基化 | zh_TW |
| dc.subject | 順式異戊二烯轉移酶 | zh_TW |
| dc.subject | 抗生素 | zh_TW |
| dc.subject | 耐藥性 | zh_TW |
| dc.subject | MRSA | zh_TW |
| dc.subject | 查爾酮 | zh_TW |
| dc.subject | 多萜 | zh_TW |
| dc.subject | 新型冠狀病毒肺炎 | zh_TW |
| dc.subject | DHDDS | zh_TW |
| dc.subject | COVID-19 | en |
| dc.subject | cis-prenyltransferase | en |
| dc.subject | dolichol | en |
| dc.subject | protein glycosylation | en |
| dc.subject | DHDDS | en |
| dc.subject | NgBR | en |
| dc.subject | biofuel | en |
| dc.subject | cellulase | en |
| dc.subject | hemicellulase | en |
| dc.subject | substrate specificity | en |
| dc.subject | site-directed mutagenesis | en |
| dc.subject | antibiotics | en |
| dc.subject | drug resistance | en |
| dc.subject | MRSA | en |
| dc.subject | chalcone | en |
| dc.title | 精準結構功能分析應用：臺灣牛樟樹順式異戊二烯轉移酶的演化、多功能纖維素酶/半纖維素酶改造、以及抗病毒/抗菌抑制劑篩選設計 | zh_TW |
| dc.title | Applications of Precise Structure-Function Analyses: Evolution of cis-Prenyltransferases from Taiwan Stout Camphor Tree (Cinnamomum kanehirae), Engineering of Multifunctional Cellulases/Hemicellulases, and Antiviral/Antibacterial Inhibitors Screening and Design | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 113-2 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.oralexamcommittee | 楊啟伸;何孟樵;林曉青;郭致榮 | zh_TW |
| dc.contributor.oralexamcommittee | Chii-Shen Yang;Meng-Chiao Ho;Hsiao-Ching Lin;Chih-Jung Kuo | en |
| dc.subject.keyword | 順式異戊二烯轉移酶,多萜,蛋白質醣基化,DHDDS,NgBR,生物燃料,纖維素酶,半纖維素酶,受質特異性,點突變,新型冠狀病毒肺炎,抗生素,耐藥性,MRSA,查爾酮, | zh_TW |
| dc.subject.keyword | cis-prenyltransferase,dolichol,protein glycosylation,DHDDS,NgBR,biofuel,cellulase,hemicellulase,substrate specificity,site-directed mutagenesis,COVID-19,antibiotics,drug resistance,MRSA,chalcone, | en |
| dc.relation.page | 254 | - |
| dc.identifier.doi | 10.6342/NTU202502385 | - |
| dc.rights.note | 同意授權(全球公開) | - |
| dc.date.accepted | 2025-07-29 | - |
| dc.contributor.author-college | 生命科學院 | - |
| dc.contributor.author-dept | 生化科學研究所 | - |
| dc.date.embargo-lift | 2025-07-31 | - |
| Appears in Collections: | 生化科學研究所 | |
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| ntu-113-2.pdf | 38.01 MB | Adobe PDF | View/Open |
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