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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林俊宏(Chun-Hung Lin) | |
| dc.contributor.author | Wen-Hung Hsu | en |
| dc.contributor.author | 許文鴻 | zh_TW |
| dc.date.accessioned | 2021-06-15T01:28:49Z | - |
| dc.date.available | 2014-07-24 | |
| dc.date.copyright | 2009-07-24 | |
| dc.date.issued | 2009 | |
| dc.date.submitted | 2009-07-21 | |
| dc.identifier.citation | 1. Tabor, C. W.; Tabor, H., Polyamines. Annu Rev Biochem 1984, 53, 749-90.
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N., Leishmania trypanothione synthetase-amidase structure reveals a basis for regulation of conflicting synthetic and hydrolytic activities. J Biol Chem 2008, 283, 17672-80. 58. Vivares, D.; Arnoux, P.; Pignol, D., A papain-like enzyme at work: native and acyl-enzyme intermediate structures in phytochelatin synthesis. Proc Natl Acad Sci U S A 2005, 102, 18848-53. 59. Aravind, L.; Anantharaman, V.; Iyer, L. M., Evolutionary connections between bacterial and eukaryotic signaling systems: a genomic perspective. Curr Opin Microbiol 2003, 6, 490-7. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/42918 | - |
| dc.description.abstract | 穀胱甘肽/精胺質 (glutathionylspermidine, Gsp) 是由一分子穀胱甘肽 (glutathione) 及一分子精胺質 (spermidine) 所組成之生物分子；主要存在於大腸桿菌等少數細菌及單細胞原(protozoa) 中。而Gsp synthetase/amidase (GspSA) 為一負責催化大腸桿菌中Gsp的合成 (同時消耗一分子ATP) 及水解互相拮抗的雙功能酵素；兩個酵素活性分別位於整個蛋白質兩端各自獨立摺疊的活性區塊 (activity domain)。先前的研究也證實大腸桿菌中Gsp amidase屬於半胱胺酸水解酶 (cysteine protease)，以第59號半胱胺酸為催化親核基 (catalytic nucleophile)。
根據文獻報導，GspSA 在大腸桿菌氧化還原調控中扮演著重要的角色；GspSA兩個相拮抗之酵素活性，因應氧化壓力的不同而有所改變。藉由活性探針來觀察大腸桿菌中Gsp amidase的存在 (定性) 及含量 (定量)，將有助於我們探討 GspSA調控兩個相反酵素活性的特殊機制。 本論文藉由蛋白質晶體結構與酵素反應機制，設計並合成了數個 Gsp amidase 的活性探針 (Activity-Based Probes; 簡稱 ABPs)。在 ABPs 的設計上以γ-Glu-Ala-Gly代替穀胱甘肽的三胜肽 (γ-Glu-Cys-Gly) 作為酵素專一性辨識區；並選擇活化酮基 (activated ketone) 當成特定反應基團，使ABPs可以與 Gsp amidase 中參與催化的半胱胺酸 (Cys59) 形成共價鍵鍵結。並進一步地經由ABPs上的標籤基團 (tag)，可以觀察此酵素的存在 (定性) 及含量 (定量)。在合成 ABPs 的過程中，我們改良了傳統合成策略，由二醇類的化合物作為起始物，合成活化酮基類的活性探針，藉此簡化合成的步驟並提高安全性。最後經由電腦模擬與酵素活性的分析，決定最佳的活性探針，並且成功的利用此活性探針在菌體中標示到 GspS。未來期望可藉由此活性探針進一步去探討 Gsp amidase 在生物體內活性的調控 並協助發展出強效活性的酵素抑制劑來治療原蟲疾病的藥物。 | zh_TW |
| dc.description.abstract | Glutathionylspermidine (Gsp), an amide-bond conjugate of glutathione and spermidine, is mainly found in some protozoal parasites and E. coli. Glutathionylspermidine sythetase/amidase is a bifunctional enzyme with separate activity domains to catalyze both the synthesis and hydrolysis of Gsp.
Recently we discovered that Gsp synthetase/amidase plays an important role in redox regulation in E. coli. The amidase activity changes depending on the condition of various oxidative stress. In order to qualitatively and quantitatively monitor the amidase activity level in vivo, it is necessary to design and synthesize specific activity-based probes (ABPs) to investigate how Gsp amidase is involved in redox regulation and how the synthetase and amidase communicate with each other in the oxidative defense. Based on the catalytic mechanism and X-ray structural information of Gsp amidase, the | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T01:28:49Z (GMT). No. of bitstreams: 1 ntu-98-R96b46034-1.pdf: 8702091 bytes, checksum: 359e189dfcb0c4b79851d5a490ec4bd3 (MD5) Previous issue date: 2009 | en |
| dc.description.tableofcontents | 目錄 (I)
縮寫表 (III) 中文摘要 (V) 英文摘要 (VI) 圖目錄 (VIII) 表格目錄 (XI) 流程圖目錄 (XII) 第一章緒論 (1) 1.1大腸桿菌中穀胱甘肽/精胺質合成及水解酵素的簡介 (1) 1.2 Gsp amidase結構及催化機制之探討 (5) 1.3活性探針 (activity-based probes) 之簡介 (9) 1.3.1基因體學及蛋白質體學之發展 (9) 1.3.2活性探針 (Activity-based probes) 之應用 (9) 1.3.3活性探針之基本架構 (11) 1.3.4活性探針之應用及突破 (16) 1.4 研究動機 (18) 第二章 結果與討論 (20) 2.1 Gsp amidase活性探針之設計 (20) 2.2受質類似物及活性探針之合成 (28) 2.2.1 Gsp amidase受質類似物6與12之合成策略 (28) 2.2.2化合物6之合成路徑 (29) 2.2.3化合物12之合成路徑 (30) 2.2.4活性碳針GAP-1之逆合成分析 (31) 2.2.5活性探針GAP-1之合成路徑及改良 (32) 2.2.6活性探針GAP-2及GAP-3之合成方法 (38) 2.2.7標籤分子之合成路徑 (39) 2.2.8活性探針GAP-4之合成方法 (40) 2.3 Gsp amidase與活性探針的生物活性測試 (41) 2.3.1活性探針的酵素動力學分析及其結果討論 (41) 2.3.2 MALDI-TOF串連質譜實驗 (MS-MS) 實驗結果與討論(42) 2.3.3西方墨點標示實驗結果與討論 (43) 2.4 結論與未來展望 (45) 2.4.1 結論 (45) 2.4.2 未來展望 (46) 第三章 實驗部分 (50) 3.1 General method (50) 3.2 Synthetic Procedures and Spectral Data (51) 第四章 補充資料 (88) 第五章 參考文獻 (91) 附錄 (A1) NMR光譜圖 (A1) | |
| dc.language.iso | zh-TW | |
| dc.title | 穀胱甘肽/精胺質水解酵素活性探針之設計與開發 | zh_TW |
| dc.title | Activity-based Probes for Gsp Amidase :
Structure-guided Design, Synthesis and Evaluation. | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 97-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 吳世雄(Shih-Hsiung Wu),羅禮強(Lee-Chiang Lo),陳佩燁(Rita P.-Y. Chen) | |
| dc.subject.keyword | 穀胱甘肽,/精胺質,水解酵素,活性探針, | zh_TW |
| dc.subject.keyword | glutathionylspermidine,protease,activity-based probes, | en |
| dc.relation.page | 101 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2009-07-22 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科學研究所 | zh_TW |
| 顯示於系所單位： | 生化科學研究所 | |
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