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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 詹迺立(Nei-Li Chan) | |
| dc.contributor.author | Min-Hao Wu | en |
| dc.contributor.author | 吳旻昊 | zh_TW |
| dc.date.accessioned | 2022-11-24T03:06:28Z | - |
| dc.date.available | 2022-02-15 | |
| dc.date.available | 2022-11-24T03:06:28Z | - |
| dc.date.copyright | 2022-02-15 | |
| dc.date.issued | 2022 | |
| dc.date.submitted | 2022-02-11 | |
| dc.identifier.citation | Abad, A., Lopez-Perez, J.L., del Olmo, E., Garcia-Fernandez, L.F., Francesch, A., Trigili, C., Barasoain, I., Andreu, J.M., Diaz, J.F., and San Feliciano, A. (2012) Synthesis and antimitotic and tubulin interaction profiles of novel pinacol derivatives of podophyllotoxins. J. Med. Chem. 55, 6724–6737. Afonine, P.V., Grosse-Kunstleve, R.W., Echols, N., Headd, J.J., Moriarty, N.W., Mustyakimov, M., Terwilliger, T.C., Urzhumtsev, A., Zwart, P.H., and Adams, P.D. (2012) Towards automated crystallographic structure refinement with phenix.refine. Acta Crystallogr. D Biol. Crystallogr. 68, 352–367. Aik, W., McDonough, M.A., Thalhammer, A., Chowdhury, R., and Schofield, C.J. (2012) Role of the jelly-roll fold in substrate binding by 2-oxoglutarate oxygenases. Curr. Opin. Struct. Biol. 22, 691–700. Aik, W.S., Chowdhury, R., Clifton, I.J., Hopkinson, R.J., Leissing, T., McDonough, M.A., Nowak, R., Schofield, C.J., and Walport, L.J. (2015). 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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/80428 | - |
| dc.description.abstract | 鬼臼毒素是(podophyllotoxin)一種醫學上重要的芳基四氫萘木脂素，可作為臨床使用的抗腫瘤藥物依託泊苷(etoposide)和替尼泊苷(teniposide)的前驅物。由於對鬼臼毒素的需求持續增長，結合化學與酵素(chemoenzymatic)的合成方法被認為比純化學合成的方式來得更加有效，且能克服鬼臼毒素生成上所遇到的立體化學問題。其中，去氧鬼臼毒素合成酶(deoxypodophyllotoxin synthase)的酵素活性對發展化學酵素合成法相當關鍵。去氧鬼臼毒素合酶能催化亞太因(yatein)的碳6 (C6)及碳7′ (C7′)之間形成碳–碳單鍵，進而生成擁有四環核心的去氧鬼臼毒素(deoxypodophyllotoxin)。此酵素為非血基質鐵及2-側氧戊二酸依賴型加氧酶(non-heme iron- and 2-oxoglutarate-dependent oxygenase)超家族(superfamily)中的一員，該家族成員共通的特徵包括：由雙層β-螺旋(double-stranded β-helix)所構成的催化核心結構，內含一個以二組胺酸一羧酸模體(2-His-1-carboxylate motif)與鐵離子配位所形成的活性中心。先前探討催化機制的研究指出，去氧鬼臼毒素合酶所催化的環化作用(cyclization)可能是經由一個苯甲基自由基(benzylic radical)或是碳陽離子(carbocation)所介導的途徑去完成的。然而，依舊缺乏去氧鬼臼毒素合酶在蛋白結構上的相關資訊。此外，近期的研究指出兩種亞太因的鏡像異構物(enantiomer)皆可做為去氧鬼臼毒素合酶的受質，但羥基化副產物生成與否則截然不同，引發受質立體化學結構如何影響催化途徑的疑問。這些研究也揭露了去氧鬼臼毒素合酶可以主導產物中新生成之掌性中心(chiral center)的立體化學結構。為了闡釋去氧鬼臼毒素合酶催化環化反應中的結構基礎，我們針對去氧鬼臼毒素合酶與鐵離子和消旋亞太因(racemic yatein)複合體進行晶體結構解析。有趣的是，亞太因的鏡像異構物因為與去氧鬼臼毒素合酶結合，而呈現U字型的構形，使其碳7′靠近催化中心的鐵離子，讓氫原子的轉移(hydrogen atom transfer)得以發生。此外，活性中心的空間障礙規範了產物去氧鬼臼毒素在碳7′位置的掌性。我們的實驗結果為去氧鬼臼毒素合酶所催化的合環反應提供了重要的結構觀點，並為去氧鬼臼毒素合酶於化學酵素合成法的應用奠基。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-24T03:06:28Z (GMT). No. of bitstreams: 1 U0001-1102202215104300.pdf: 6922286 bytes, checksum: dce99142d222e23081716f7f7f45c83a (MD5) Previous issue date: 2022 | en |
| dc.description.tableofcontents | 口試委員會審定書 I 謝辭 II 摘要 III Abstract V Contents VII List of Figures IX List of Tables XI 1. Introduction 1 1.1 Podophyllotoxin 2 1.2 Iron(II)- and 2-oxoglutarate-dependent oxygenases 6 1.3 Deoxypodophyllotoxin synthase 12 1.4 Specific aims of this study 14 2. Materials and Methods 16 2.1 Construction of plasmid for expression of DPS 17 2.2 Protein expression 17 2.3 Protein purification 18 2.4 Crystallization 19 2.5 Data collection and structure determination 20 2.6 Molecular docking 22 3. Results 24 3.1 Structure determination of DPS complexes 25 3.2 The overall structure of DPS 27 3.3 The active site of DPS 29 3.4 The substrate binding site of DPS 31 3.5 Substrate selectivity 34 3.6 The orientation of the ferryl intermediate 36 3.7 Effect of substrate C7–OH modification on cyclization 39 4. Discussion 42 5. Conclusion 49 6. Figures 51 7. Tables 81 8. References 85 9. Appendix 95 | |
| dc.language.iso | en | |
| dc.subject | 二價鐵及2-側氧戊二酸依賴型加氧酶 | zh_TW |
| dc.subject | 去氧鬼臼毒素合酶 | zh_TW |
| dc.subject | 環化作用 | zh_TW |
| dc.subject | deoxypodophyllotoxin synthase | en |
| dc.subject | cyclization | en |
| dc.subject | Fe(II)- and 2-oxoglutarate-dependent oxygenase | en |
| dc.title | 探討去氧鬼臼毒素合酶催化立體專一性環化反應之結構機轉 | zh_TW |
| dc.title | Structural Insights into the Stereospecific Cyclization Reaction Catalyzed by Deoxypodophyllotoxin Synthase | en |
| dc.date.schoolyear | 110-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.author-orcid | 0000-0002-9696-2890 | |
| dc.contributor.advisor-orcid | 詹迺立(0000-0003-0139-6513) | |
| dc.contributor.oralexamcommittee | 徐駿森(Yi-Ting Chen),簡敦誠(Jr-Yan Wang),李宗璘(Rachel J. Huang),林曉青(Yu-Chin Hsu) | |
| dc.subject.keyword | 去氧鬼臼毒素合酶,二價鐵及2-側氧戊二酸依賴型加氧酶,環化作用, | zh_TW |
| dc.subject.keyword | deoxypodophyllotoxin synthase,Fe(II)- and 2-oxoglutarate-dependent oxygenase,cyclization, | en |
| dc.relation.page | 95 | |
| dc.identifier.doi | 10.6342/NTU202200567 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2022-02-11 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
| 顯示於系所單位： | 生物化學暨分子生物學科研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| U0001-1102202215104300.pdf 授權僅限NTU校內IP使用（校園外請利用VPN校外連線服務） | 6.76 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。