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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 戴桓青(Hwan-Ching Tai) | |
| dc.contributor.author | Che-Fan Huang | en |
| dc.contributor.author | 黃哲凡 | zh_TW |
| dc.date.accessioned | 2021-06-16T08:05:25Z | - |
| dc.date.available | 2014-07-08 | |
| dc.date.copyright | 2014-07-08 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-06-25 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/58068 | - |
| dc.description.abstract | 活性氧化物質造成的蛋白質氧化常與老化及神經退化疾病連結。蛋白質中，能與金屬離子產生螯合作用的組胺酸是常見的氧化受損目標物。2-氧基組胺酸便是近期研究發現組胺酸在金屬催化下氧化的產物，並有潛力作為蛋白質氧化受損之生物標記物。然而，受限於合成方法不足，它的生物物理及生化特性都尚未被透徹地研究了解。我們發展了一個有效的方法，能利用金屬催化氧化反應，在胺基酸單體及胜肽鏈上產生2-氧基組胺酸。在常見的二價銅離子/抗壞血酸鈉/氧氣的金屬催化氧化系統中，我們調整了試劑的比例及反應的緩衝溶液系統，使得反應的產率較文獻報導增加了十倍以上，並且能得到完全氧化的2-氧基組胺酸胜肽鏈，以鑑定其性質。
含有2-氧基組胺酸之胜肽鏈在液相層析串聯式質譜儀的分析中，於碳-18管柱的滯留時間較長；其結構在質譜儀電噴灑游離及串聯式質譜碰撞誘導解離的過程中展現高度的穩定性。因此，針對2-氧基組胺酸做蛋白質體的質譜分析是可行的。我們合成的2-氧基組胺酸胜肽鏈可以作為這類質譜實驗的標準品，也可進一步用作胜肽探針或誘導抗體產生，對此非酵素性後轉譯修飾的研究，有相當的價值。 在這份研究中，我們將含有2-氧基組胺酸之胜肽鏈連接到生物素上，作為研究2-氧基組胺酸交互作用體的探針。生物素能將探針固定在修飾有抗生物素蛋白的固相上，和海拉細胞裂解液作用後，便能得到2-氧基組胺酸的交互作用體並且以質譜鑑定。由於新的證據漸漸顯示氧化受損的蛋白質可能藉由蛋白脢體分解，因此我們將2-氧基組胺酸交互作用體與蛋白脢體交互作用體交叉分析，企圖嘗試了解其中細胞對蛋白質品質調控的機制。 | zh_TW |
| dc.description.abstract | Protein oxidation by reactive oxygen species has been associated with aging and neurodegenerative disorders, and histidine is a major target for oxidation due to its metal chelating property and susceptibility to metal-catalyzed oxidation. 2-oxohistidine, the major product of histidine oxidation, has been recently identified as a stable marker of oxidative damage in biological systems, but its biophysical and biochemical properties are understudied, partly due to difficulties in its chemical synthesis. We developed an efficient method to generate 2-oxohistidine side chain using metal catalyzed oxidation, applicable to both monomers and peptides. By optimizing reagent ratios and pH value in Cu2+/ascorbate/O2 reaction system, we improved the yield more than 10 fold compared to reported conditions, which allowed us to obtain homogeneously modified 2-oxohisidine peptides for further characterization.
Analysis of 2-oxohistidine-containing model peptides by liquid chromatography-tandem mass spectrometry revealed increased retention time in reverse-phase chromatography and general stability of 2-oxohistidine under electrospray ionization and collision-induced dissociation. Thus, large-scale analysis of 2-oxohistidine-modified proteome should be feasible using shotgun protein mass spectrometry. Peptide probes and antigens containing 2-oxohistidine will be important tools to advance the biochemical and proteomic studies of this non-enzymatic post-translational modification. Furthermore, 2-oxohistidine containing peptides were conjugated with biotin to make probes for interactome analysis. The 2-oxohistidine peptide probe was bound to monomeric avidin agarose and incubated with HeLa cell lysate to capture 2-oxohistidine interactome, which was finally eluted by biotin and identified with LC-MS/MS. Recent evidence has shown that some oxidized proteins are degraded by proteasomes. The interconnection between 2-oxohistidine interactome and proteasome interactomes was studied as an attempt to understand the underlying quality control mechanism. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T08:05:25Z (GMT). No. of bitstreams: 1 ntu-103-R01223108-1.pdf: 3091740 bytes, checksum: 3e55319d082f517d6f24e5ad27f41c89 (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | 口試委員會審定書 #
誌謝 i 中文摘要 ii ABSTRACT iii CONTENTS v LIST OF FIGURES viii LIST OF TABLES x ABBREVIATIONS xi Chapter 1 Introduction 1 1.1 Reactive oxygen species 1 1.2 Protein oxidation 3 1.3 Free radical theory of aging and diseases 8 1.4 Biological functions of histidine 10 1.5 Metal-catalyzed oxidation of histidine 11 1.6 Biological studies of 2-oxohistidine 13 1.7 Protein degradation: the ubiquitin-proteasome system 15 1.8 Interactomic approach of proteomic studies 21 1.9 Specific aim and research strategy 22 Chapter 2 Results and Discussion 24 2.1 Synthesis of N-benzoyl-L-2-oxohistidine 24 2.2 Oxidation of peptide histidine residues 28 2.2.1 Peptide design for direct oxidation 28 2.2.2 Reaction conditions and LC/MS analysis 29 2.2.3 Identification of peptide oxidation site by LC-MS/MS 33 2.3 2-oxohistidine peptide probe interactome 37 2.3.1 Synthesis of peptide probes 37 2.3.2 Affinity purification of peptide probe interactome 38 2.3.3 Analysis of peptide probe interactome 41 2.4 Composition of HeLa cell proteasomes 43 2.4.1 Affinity purification of proteasomes 43 2.4.2 LC-MS/MS identification of proteasomes and their interactome 45 2.5 Interconnection between 2-oxohistidine and proteasomes 51 Chapter 3 Conclusions 54 3.1 Synthetic achievement 54 3.2 Preliminary biological discovery 54 Chapter 4 Experimental section 56 4.1 General Description and Instrumentation 56 4.2 Methods 57 4.2.1 Oxidation of N- benzoyl-L-histidine 57 4.2.2 Synthesis of 2-oxohistidine peptide probes 58 4.2.3 HeLa cell culture 59 4.2.4 Peptide probe pull-down 59 4.2.5 Proteasome purification 60 4.2.6 SDS-PAGE using home-made gradient gel 61 4.2.7 Western transfer and blotting 62 4.2.8 Trypsin digestion 63 4.2.9 LC-MS/MS method for protein identification 64 Chapter 5 References 65 APPENDIX 72 | |
| dc.language.iso | en | |
| dc.subject | 交互作用體 | zh_TW |
| dc.subject | 2-氧基組胺酸 | zh_TW |
| dc.subject | 活性氧化物質 | zh_TW |
| dc.subject | 金屬催化氧化 | zh_TW |
| dc.subject | 蛋白脢體 | zh_TW |
| dc.subject | 2-oxohistidine | en |
| dc.subject | interactome | en |
| dc.subject | proteasome | en |
| dc.subject | metal-catalyzed oxidation | en |
| dc.subject | reactive oxygen species | en |
| dc.title | 合成含有2-氧基組胺酸之多肽鏈並鑑定其交互作用體 | zh_TW |
| dc.title | Synthesis of Peptides Containing 2-Oxohistidine Residues and Identification of their Interactome | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 陳平(Richard P. Cheng),王宗興(Tsung-Shing Wang) | |
| dc.subject.keyword | 2-氧基組胺酸,活性氧化物質,金屬催化氧化,蛋白脢體,交互作用體, | zh_TW |
| dc.subject.keyword | 2-oxohistidine,reactive oxygen species,metal-catalyzed oxidation,proteasome,interactome, | en |
| dc.relation.page | 83 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2014-06-25 | |
| dc.contributor.author-college | 理學院 | zh_TW |
| dc.contributor.author-dept | 化學研究所 | zh_TW |
| 顯示於系所單位： | 化學系 | |
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