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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 王惠鈞(Andrew H.-J. Wang) | |
dc.contributor.author | Kai-Fa Huang | en |
dc.contributor.author | 黃開發 | zh_TW |
dc.date.accessioned | 2021-06-13T06:18:19Z | - |
dc.date.available | 2006-02-07 | |
dc.date.copyright | 2006-02-07 | |
dc.date.issued | 2006 | |
dc.date.submitted | 2006-01-26 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/34613 | - |
dc.description.abstract | 蛋白質氮端由麩酸胺(或麩氨酸)殘基轉變成焦麩氨酸的反應,是體內眾多的賀爾蒙及具生物活性的多胜肽之生合成過程必要的步驟。不正常的焦麩氨酸形成可能與一些病理過程有關,諸如骨質疏鬆症、樣澱粉疾病及風濕性關節炎。這種在蛋白質氮端的環化反應,早期被人們認為是自然發生的;直到麩酸胺環化酵素被發現後,才掀開此種蛋白質氮端後轉譯修飾作用的神秘面紗。在這本博士論文中,我將報告人類麩酸胺環化酵素在大腸桿菌內的表達;結果得到相對地高蛋白質產量及高純度,而且僅需要一個簡單的純化步驟。我們首先證實了一個分子的人類麩酸胺環化酵素含有一分子的鋅離子。我們也發現正常的以及阿茲海默症病人的腦部組織含有豐富的麩酸胺環化酵素。這項發現似乎暗示了體內造成樣澱粉病變的一些多胜肽,其氮端焦麩氨酸的形成是由麩酸胺環化酵素所催化。同時,也更加深了人類麩酸胺環化酵素作為一些樣澱粉疾病之藥物標的蛋白的可能性。接著,我要報告人類麩酸胺環化酵素之高解析度X-光晶體結構;這其中包含了原始結構,受質結合的結構及三種抑制劑結合的結構。我們發現人類麩酸胺環化酵素是一個alpha/beta混合摺疊的蛋白質,而且與雙鋅離子的外切多胜肽水解酵素分享一個演化上高度保留的架構。然而,比起這些多胜肽水解酵素,人類麩酸胺環化酵素的結構含有許多插入及刪除的氨基酸序列,特別是在負責催化的部位。我們也發現人類麩酸胺環化酵素活性部位之結構相對上較為封閉,而且有兩種互相交替的構形,以致於讓我們觀察到兩種受質結合的模式。這現象主要歸因於活性部位的一個色氨酸殘基;其側基正好有兩種幾乎相反方向的構形。鋅離子則位在人類麩酸胺環化酵素的活性部位,與三個高度保留的氨基酸殘基及一個水分子形成配位鍵。我們發現,當抑制劑結合在活性部位時,這個與鋅離子配位的水分子會被抑制劑上的一個氮原子所取代。同時,我也與實驗室一些伙伴進行一系列有系統地人類麩酸胺環化酵素定點突變的實驗,其結果讓我們提出一個合理的麩酸胺環化酵素之催化機制。這些研究成果,讓我們建構出一個穩固的結構基礎,作為未來合理設計人類麩酸胺環化酵素的有效抑制劑之用。 | zh_TW |
dc.description.abstract | N-terminal pyroglutamate (pGlu) formation from its glutaminyl (or glutamyl) precursor is required in the maturation of numerous hormones and bioactive peptides. The aberrant formation of pGlu may be related to several pathological processes, such as osteoporosis, amyloidotic diseases, and rheumatoid arthritis. This N-terminal cyclization reaction, once thought to proceed spontaneously, was found to be catalyzed by the enzyme glutaminyl cyclase (QC). In this dissertation, the expression of functional human QC in Escherichia coli system to a relatively high level and to near homogeneity using a convenient purification procedure is present. We demonstrated, for the first time, that human QC contains one zinc ion per protein molecule. The enzyme was shown to be abundant in the brain tissues of normal adults and some patients with Alzheimer’s disease. This finding suggests that QC is responsible for the formation of N-terminal pGlu on several amyloid-related peptides, strengthening the possibility that human QC can be a drug target for treatment of several amyloidotic disorders. Furthermore, the first high-resolution crystal structures of human QC in free form and bound to a substrate and three imidazole-derived inhibitors are reported. The structure reveals an alpha/beta scaffold akin to that of two-zinc exopeptidases but with several insertions and deletions, particularly in the active-site region. The relatively closed active site of human QC displays alternate conformations primarily due to the different indole orientations of Trp207, resulting in two substrate (glutamine t-butyl ester)-binding modes. The single zinc ion in the active site is coordinated to three conserved residues and one water molecule, which is replaced by an imidazole nitrogen upon binding of the inhibitors. Together with structural and kinetic analyses of several active-site-mutant enzymes, a catalysis mechanism of the formation of protein N-terminal pGlu is proposed. These results provide a structural basis for the rational design of potent inhibitors of human QC. | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T06:18:19Z (GMT). No. of bitstreams: 1 ntu-95-D89242005-1.pdf: 7188115 bytes, checksum: c4b492b21875846b3e3a6e7bd7ae1d0a (MD5) Previous issue date: 2006 | en |
dc.description.tableofcontents | Content
Abstract (English)...(i) Abstract (Chinese)...(ii) Abbreviations ...(iii) Chapter 1 Introduction ...(1) 1.1 Numerous bioactive peptides and proteins contain a pyroglutamate residue at their N-terminal position ...(3) 1.2 Glutaminyl cyclase has been identified as catalysis responsible for the post- translational pyroglutamate formation ...(4) 1.3 Genetic mutations in human QC gene (QPCT) are strikingly correlated with osteoporosis susceptibility in adult women ...(8) 1.4 Human QC is a possible biomarker for rheumatoid arthritis ...(10) 1.5 Human QC is a possible drug target for amyloidotic disorders ...(11) 1.6 Recombination and inhibition of human QC ...(13) 1.7 Theoretical model of human QC ...(15) Chapter 2 Materials and Methods ...(18) 2.1 Cloning of QC cDNA and construction of expression vectors ...(19) 2.2 Protein expression and purification ...(20) 2.2.1 Nus protein-fusion human QC ...(20) 2.2.2 Thioredoxin-fusion human QC ...(22) 2.2.3 Se-Met labeled and mutant human QCs ...(22) 2.3 Mass spectrometry analysis ...(23) 2.4 Circular dichroism spectroscopy analysis ...(24) 2.5 Atomic absorption analysis ...(24) 2.6 Chemical synthesis of human QC substrates ...(24) 2.7 QC activity analysis ...(25) 2.7.1 QC and EC activity assays ...(25) 2.7.2 Enzyme kinetic assay ...(25) 2.8 Quick screening for human QC inhibitors ...(26) 2.9 Western immunoblotting analysis ...(26) 2.10 Screening for human QC crystals ...(26) 2.11 Final crystallization conditions, data collection, structure determination and refinement ...(27) 2.11.1 Final crystallization conditions ...(27) 2.11.2 Data collection ...(28) 2.11.3 Structure determination ...(28) 2.11.4 Refinement ...(29) 2.11.5 Graphics and structure deposit in Protein Data Bank ...(29) Chapter 3 Results ...(30) 3.1 Cloning and expression of human QC ...(31) 3.1.1 Cloning of human QC cDNA ...(31) 3.1.2 Expression using the Nus protein-fusion vector ...(31) 3.1.3 Expression using the thioredoxin-fusion vector ...(32) 3.2 QC activity of the recombinant human QC ...(32) 3.2.1 QC activity on physiological substrates ...(32) 3.2.2 Enzyme kinetic assay of QC activity on synthetic substrates ...(33) 3.3 Human QC is a single zinc metalloenzyme ...(34) 3.4 Inhibition of QC activity by imidazole, triazole, and tetrazole derivatives ...(34) 3.5 Screening for human QC crystals and preliminary X-ray crystallographic analysis ...(35) 3.6 Determination of human QC structure ...(35) 3.7 Overall structure of human QC ...(36) 3.8 Structure of human QC active site ...(37) 3.9 Structure of the enzyme-substrate complex ...(38) 3.10 Structure of the enzyme-inhibitor complexes ...(39) 3.11 EC activity of the recombinant human QC ...(40) 3.12 Distribution of human QC in normal and AD’s brain tissues ...(40) Chapter 4 Discussion ...(42) 4.1 Expression and characterization of human QC ...(43) 4.2 Human QC shares a conserved core structure to the exopeptidase family ...(43) 4.3 Comparison of the active site structures of mononuclear human QC and the binuclear exopeptidases ...(44) 4.4 Inhibition of human QC by imidazole derivatives ...(45) 4.5 Proposed substrate-binding and catalysis mechanism of human QC ...(46) 4.6 Human QC is a possible drug target for amyloidotic disorders ...(49) Figures ...(50) Tables ...(89) References ...(98) Appendixes ...(110) Curriculum Vitae ...(114) Published Papers ...(117) | |
dc.language.iso | en | |
dc.title | 蛋白質後轉譯修飾作用之焦麩氨酸形成:人類麩酸胺環化酵素的蛋白質生產、晶體結構、催化機制、抑制及病理生理學之研究 | zh_TW |
dc.title | Post-Translationally Pyroglutamate Formation on Proteins: Studies on protein production, crystal structures, catalysis mechanism, inhibition and pathophysiology of human glutaminyl cyclase | en |
dc.type | Thesis | |
dc.date.schoolyear | 94-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 張固剛(Gu-Gang Chang),蕭傳鐙(Chwan-Deng Hsiao),梁博煌(Po-Huang Liang),陳佩燁(Rita P.-Y. Chen) | |
dc.subject.keyword | 人類麩酸胺環化酵素,焦麩氨酸,後轉譯修飾作用,X─光繞射晶體學,阿茲海默症,鋅離子, | zh_TW |
dc.subject.keyword | human glutaminyl cyclase,pyroglutamate,post-translational modification,X-ray crystallography,zinc ion, | en |
dc.relation.page | 113 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2006-01-27 | |
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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