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研究生:邱偉倫
研究生(外文):Wei-Loong Chiu
論文名稱:1.以質譜法分析DNA加成產物、3-硝基酪胺酸與3-溴基酪胺酸2.oxanine對溶菌酶之後轉譯修飾研究
論文名稱(外文):1. Analysis of DNA adducts, 3-nitrotyrosine and 3-bromotyrosine by mass spectrometry.2. Study of post-translational modifications of lysozyme induced by oxanine
指導教授:陳皓君
指導教授(外文):Hauh-Jyun Chen
學位類別:博士
校院名稱:國立中正大學
系所名稱:化學所
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:中文
論文頁數:220
中文關鍵詞:DNA加成產物3-硝基酪胺酸與3-溴基酪胺酸
外文關鍵詞:DNA adducts3-nitrotyrosine and 3-bromotyrosineoxanine
相關次數:
  • 被引用被引用:1
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  • 下載下載:54
  • 收藏至我的研究室書目清單書目收藏:0
第一部分(a) 以質譜法分析人體內的乙烯基DNA加成產物
中文摘要
外來的化學物質或內生的脂質過氧化會引起乙烯基加成產物的生成,而此種類型的DNA加成產物皆為會導致突變發生的前致癌物。組織中的DNA加成產物含量代表生物體之DNA因氧化壓力增加所產生的加成產物含量與體內酵素修復系統所修復後之穩定量,而存在於尿液中的含量則表現出生物體的切除修復能力以及整個生物體DNA遭受破壞的總程度。於過去研究中,已知在組織DNA中乙烯基腺嘌呤與1,N2-乙烯基鳥糞嘌呤會導致基因產生突變,並可被人體內具特異性的DNA醣解酶所修復。在此研究中,我們預期被DNA醣解酶切除後的DNA加成產物將被代謝至尿液中,並成尼Q用同位素稀釋氣相層析負離子化學游離質譜法與液相層析電噴灑游離串聯質譜法偵測並定量了尿液中此二種乙烯基加成產物。更進一步,在經過肌酸酐與體重校正尿液之代謝量後進行統計後,發現此二種DNA乙烯基加成產物之含量與所吸煙行為具有關連性。因此,尿液中乙烯基加成產物之含量或野i以作為一個用來評估氧化壓力傷害的非侵入性生化指標,而利用高特異性與高靈敏度的質譜法亦是一個在定量尿液中DNA加成產物含量時良好的分析方法。除此以外,我們發現在利用質譜法分析DNA中的乙烯基腺嘌呤與乙烯基胞嘧啶時,用來避免腺嘌呤造成質譜干擾的腺嘌呤去胺酶具有醣解乙烯基腺嘌呤去氧核苷,而對乙烯基胞嘧啶去氧核苷無效,且此活性經推測極有可能來自此市售酵素的不純物。我們亦將其酵素之特性應用於定量經氯乙醛處理過之小牛胸腺DNA或人類胎盤DNA上的乙烯基加成產物。在酵素水解得到乙烯基腺嘌呤與乙烯基胞嘧啶去氧核苷後,利用同位素稀釋氣相層析負離子化學游離質譜法與液相層析電噴灑游離串聯質譜法進行分析,在不需進行酸水解之狀況下,即可利用質譜法分析DNA中乙烯基腺嘌呤之含量。


第一部份 (b) 以穩定同位素稀釋液相層析電噴灑游離串聯質譜法同時定量人類尿液中的3-硝基酪胺酸與3-溴基酪胺酸

中文摘要
在生物體被病原體入侵的同時,被活化的嗜菌細胞會釋放如嗜酸性白血球過氧化酵素(eosinophil peroxidase)與骨髓過氧化酵素 (myeloperoxide),催化H2O2與Br-或亞硝酸之反應形成具反應性物種。對入侵病原體所進行的硝化與鹵化反應目前已知為生物體一個重要的防衛機制,但同時也會因為在此過程氧化壓力的增加而對生物體本身造成傷害,並已知與一些疾病具有關連性。過量的反應性物種與蛋白質上的酪基酸進行反應時,會將蛋白質上的酪胺酸轉變為3-硝基酪胺酸 (3-nitrotyrosine)與3-溴基酪胺酸(3bromotyrosine),此一過程所造成的傷害目前被認為與氣喘、發炎與癌症等具有相關性。在此研究中,鑑於液相層析質譜法之高靈敏度與高特異性,本實驗室發展出一套穩定同位素稀釋液相層析串聯質譜法同時對人體尿液蛋白質中的3-硝基酪胺酸與3-溴基酪胺酸定量之分析方法,並希望以尿液蛋白質做為評估體內溴化與硝化程度的非侵入性的生化指標,同時這亦是第一次對尿液蛋白質之溴化程度進行定量之研究。本研究所開發之LC/ESI/MS/MS分析方法對3-硝基酪胺酸與3-溴基酪胺酸之偵測極限各為9.3 pg與5.0 pg,其定量極限為88 pM (20 pg 3NT) and 77 pM (20 pg 3BT)。以LC/ESI/MS/MS分析在人類尿液蛋白質上3NT與3BT所修飾之程度為1.6 到 39 3NT / 105 Tyr 與 0.3到16 3BT / 103 Tyr。但nanoLC/ESI/MS/MS並無偵測到任何free 3NT與3BT存在。經肌酸酐校正過後,我們亦發現人類尿液蛋白質中的3-溴基酪胺酸的修飾程度與尿液中的可丁尼濃度具有正相關性。這是第一次對尿液蛋白質之溴化程度進行定量之研究。

第二部份 oxanine對溶菌酶之後轉譯修飾研究

中文摘要
反應性含氮物種已知與釵h發炎和癌症具有關連性,Oxanine即是一種因為一氧化氮與亞硝酸等反應性含氮物種攻擊鳥糞嘌呤造成DNA損害的產物。根據過去利用電泳法進行的研究顯示,oxanine 會造成DNA與蛋白質進行反應並進而形成DNA-蛋白質交聯產物 (DNA-protein cross-links, DPCs)。雖然過去曾報導過2’-deoxyoxanosine會與甘氨酸N端的氨基進行反應,但實際上因oxanine造成的DNA-蛋白質交聯產物結構從未被真正確認過。在這個研究中,我們選擇了溶菌酶作為一個蛋白質模型進行DNA-蛋白質交聯產物的研究,並利用高效能液相層析串聯質譜法鑑定在溶菌酶中經過dOxo-DNA反應後的胺基酸殘基位置。我們的研究結果顯示在溶菌酶上的Lys-13、 Lys-97、 Lys-116、 Ser-85 與Ser-86在與2''-deoxy-oxanosine反應後會被修飾,並且發現主要被修飾上蛋白質的為失去去氧核醣的oxanine而非2’-deoxyoxanosine。另外,在dOxo-DNA與溶菌酶的反應中我們發現僅有Lys-116、Ser-85 和Ser-86三個胺基酸殘基會被oxanine修飾,根據溶菌酶胺基酸側鏈暴露於溶劑中的面積與二級結構,目前我們推測dOxo-DNA與溶菌酶的交聯反應與被修飾的胺基酸是否處於蛋白質表面有相當大的關連性。由於DNA-蛋白質交聯產物的修復機制仍未被廣泛的進行研究。未來應將研究重點置於鑑定生物體內的DNA-蛋白質交聯產物結構與其在生理上重要的意義。
1(a). Analysis of 1,N 6-ethenoadenine and 1,N2-ethenoguanine in human body by mass spectrometry
Abstract
Etheno DNA adducts are promutagenic DNA lesions derived from exogenous as well as endogenous sources. The levels of etheno adducts in tissue DNA are elevated in cancer prone tissues, and the urinary excretion of etheno adducts is associated with oxidative stress. 1,N 6-ethenoadenine and 1,N2-ethenoguanine are promutagenic lesion detected in tissue DNA. it has been shown that these adducts can be repaired by human DNA glycosylases, and they are expected to be excreted in urine. In this study, we have developed for the accurate quantifi-cation of eAde and 1,N 2-eGua in human urine samples by the highly sensitive and specific stable isotope dilution gas chromatography/negative ion chemical ionization/mass spectrometric assay (GC/NICI/MS) and liquid chromatography-electrospray ionization/ tandem mass spectrometry. (LC-ESI/MS/MS). After adjusting for creatinine levels and body weight, statistically significant associations were observed between urinary levels of these two adducts and cigarette smoking. Three highly specific and sensitive assays based on mass spectrometry should be valuable in measuring urinary etheno adducts as a potential noninvasive biomarker for oxidative DNA damage.During analysis of eAde and/or eCyt in DNA by GC/MS or LC/MS, adenosine deaminase is used to convert adenine or deoxyadenosine to the deaminated analog. It is due to the fact that abundant unmodified adenine or deoxy-adenosine could interfere with analysis of the trace amount of etheno adducts and that adenine and deoxyadenosine have the same mass as those of eCyt and its dexoyribonucleoside, respectively. We herein report identification of a glycosylase activity for eAde, but not eCyt, as a contaminant in a commercialized adenosine deaminase preparation. Enzyme hydrolysis of chloroacetaldehyde treated calf thymus DNA and human placental DNA followed by adenosine deaminase treatment yielded ede determined by isotope dilution GC/NICI/MS and LC/ESI/MS/MS.

1(b). Simultaneous quantification of 3-nitrotyrosine and 3-bromotyrosine in human urine by stable isotope dilution liquid chromatography/ electrospray ionization-tandem mass spectrometry

Abstract
Upon stimulation by invasion of pathogens, reactive species are generated by activated phagocytes, which can damage normal tissue and contribute to inflammatory injury. Myeloperoxidase and eosinophil peroxidase are abundant leukocyte proteins which catalyze oxidation of nitrite and Br- by H2O2 to produce nitrating and brominating agents. Halogenation and nitration of biomolecules have been proposed as key mechanisms of host defense. Reactive oxidants also have the potential to damage host tissue, and they have been implicated in disease. In this study, an assay based on isotope dilution liquid chromatography/electrospray ionization-tandem mass spectrometry was developed for simultaneous analysis of 3NT and 3BT in human urinary proteins as noninvasive biomarkers for protein nitration and bromination in vivo. The study is the first measureing 3BT level in human urinary protein by LC/MS/MS. The detection limits (S/N =3) of this assay were 9.3 pg for 3NT and 5.0 pg for 3BT. This assay also allows quantification of 20 pg of 3NT and 3BT in 1.0 mL of the urine sample, which is equivalent to corresponding the concentration quantification limit of 88 pM (3NT) and 77 pM (3BT). Using this assay, the levels of 3NT and 3BT ranged from 1.6 ± 0.1 to 39 ± 3 3NT / 105 Tyr and 0.3 ± 0.01 to 16 ± 1.7 3BT / 103 Tyr in the 24 h urinary protein samples of healthy individuals. After levels of 3NT and 3BT were adjusted for creatinine contents, a statistically significant correlation was found between 3BT level of urinary protein and cotinine, the metabolite of nicotine in human urine. To the best our knowledge, this study is the first measurement of 3BT levels in human urinary protein by LC/MS/MS.

2. Study of post-translational modifications of lysozyme induced by oxanine

Abstract
Reactive nitrogen species are implicated in inflammatory diseases and cancers. Oxanine (Oxa) is a DNA lesion derived from the guanine base with nitric oxide and nitrous acid. It was shown by gel electrophoresis that oxanine mediated the formation of DNA-protein cross-links (DPCs) with DNA-binding proteins and in the cell extract. Although 2’-deoxyoxanosine was shown to react with amines including the N-terminal amino group of glycine, the structures of DNA-protein cross-links induced by oxanine have not been characterized. In this study, we chose lysozyme as a protein model to study the modification of DNA-protein cross-links and identified the oxanine modified residues by using HPLC coupled with tandem mass spectrometry.
Our results revealed that the side chain groups of Lys-13, Lys-97, Lys-116, Ser-85 and Ser-86 of lysozyme were reactive toward 2’-deoxyoxanosine, and the major form of modification is modified by oxanine molecule but not 2’-deoxyoxanosine. In addition, only three residues (Lys-116, Ser-85 and Ser-86) are reactive with dOxo-DNA. According the side chain group exposed area and secondary structure of hen egg white lysozyme, we propose that the modification between dOxo-DNA and lysozyme correlates with the extents of solvent exposure of amino acid in protein. Because the repair mechanism of DPCs is not extensively investigated, the characterization of oxanine-derived DPC structures should facilitate studies of their detection in vivo and their biological consequences.
目錄 I
圖表目錄 XI
附圖目錄 XV

第一部分(a) 以質譜法分析人體內的乙烯基DNA加成產物成 1
英文摘要 2
中文摘要 4
第一章 緒論 6
1.1 去氧核糖核酸 (DNA)之簡介 6
1.2 DNA加成產物之種類與影響 8
1.3 外環性乙烯基加成產物之來源 11
1.4 外環性乙烯基加成產物之修復機制與生理意義 15
1.5 負離子化學游離質譜法 18
1.6 液相層析電噴灑游離串聯質譜法 19
1.7 使用之統計相關方法 21
第二章 材料與實驗方法 24
2.1 利用穩定同位素稀釋搭配氣相負離子化學游離法分析人類
尿液中乙烯基腺嘌呤 24
2.1-1 儀器 24
2.1-2 材料 24
2.1-3 藥品 25
2.1-4 高效能液相層析儀分析系統 26
2.1-5 利用C18-OH固相萃取管柱純化濃縮eAde 26
2.1-6 穩定同位素[13C1,15N2]乙烯基腺嘌呤之合成 27
2.1-7 尿液樣品前處理程序 28
2.1-8 利用氣相層析儀搭配負離子化學游離質譜儀分析PFB-eAde
29
2.1-9 eAde之氣相層析負離子化學游離質譜分析法校正曲線建立30
2.1-10 添加eAde至尿液樣品之測試 30
2.1-11 乙烯基腺嘌呤去氧核苷 (edAdo)之親電性衍生化測試 31
2.2 利用穩定同位素稀釋搭配液相層析電噴灑游離串聯質譜法偵
測尿液中之1,N2-乙烯基鳥糞嘌呤 31
2.2-1 儀器 31
2.2-2 材料 32
2.2-3 藥品 32
2.2-4 高效能液相層析儀系統條件 33
2.2-5 液相層析電噴灑游離串聯質譜儀分析系統 33
2.2-6 穩定同位素1,N2-乙烯基鳥糞嘌呤之合成 34
2.2-7 尿液的前處理 34
2.2-8 以陽離子交換固相萃取管收集純化1,N2-乙烯基鳥糞嘌呤 34
2.2-9 以C18-OH固相萃取管純化1,N2-乙烯基鳥糞嘌呤 35
2.2-10 利用液相層析電噴灑游離串聯質譜法對尿液中的1, N2-乙
烯基鳥糞嘌呤進行分析 35
2.2-11 1,N2-乙烯基鳥糞嘌呤之校正曲線 36
2.2-12 反添加1,N2-乙烯基鳥糞嘌呤至吸煙者尿液之測試 36
2.3 小牛腸黏膜腺嘌呤去胺酶對分析DNA中乙烯基腺腺嘌呤之影響37
2.3-1 儀器 37
2.3-2 材料 37
2.3-3 藥品 38
2.3-4 高效能液相層析儀分析系統 39
2.3-5 氣相層析儀搭配負離子化學游離質譜儀分析系統 40
2.3-6 edAdo與edCyd之酸水解條件 41
2.3-7 酵素水解DNA方法 41
2.3-8 利用C18固相萃取管柱純化濃縮eAde與edAdo 42
2.3-9 利用C18-OH固相萃取管柱純化濃縮eCyt與edCyd 43
2.3-10 穩定同位素[13C1,15N2]乙烯基腺嘌呤之合成 43
2.3-11 穩定同位素[13C4,15N3]乙烯基胞嘧啶之合成 44
2.3-12 PFB-eCyt與PFB-eAde的合成 44
2.3-13 經2-氯乙醛處理小牛胸腺DNA之合成方法 45
2.3-14 利用氣相層析儀搭配負離子化學游離質譜儀分析eAde與
eeCyt 校正曲線的建立 45
2.3-15 利用酸水解DNA後以氣相層析儀負離子化學游離質譜儀對
DNA上eAde與eCyt總含量偵測及定量之方法 46
2.3-16 利用酵素水解DNA後使用氣相層析儀負離子化學游離質譜
對DNA上eAde總含量偵測及定量之方法 47
2.3-17 利用HPLC搭配螢光偵檢器偵測小牛腸黏膜嘌呤去胺酶對
edAdo之影響 47
2.3-18 利用HPLC偵測小牛腸黏膜去胺酶對乙烯基加成產物之醣解
活性 48
2.3-19 利用酵素水解DNA後使用液相層析電噴灑游離串聯質譜儀
對DNA上eAde與edAdo總含量分析之方法 48
第三章 實驗結果與討論 50
3.1 利用穩定同位素稀釋搭配氣相負離子化學游離法分析人類尿
液中乙烯基腺嘌呤 50
3.1-1 固相萃取純化乙烯基腺嘌呤 50
3.1-2 利用氣相層析負離子化學游離質譜法分析乙烯基腺嘌呤 51
3.1-3 乙烯基腺嘌呤於人類尿液中的濃度 55
3.2 利用穩定同位素稀釋搭配液相層析電噴灑游離串聯質譜法偵
測尿液中之1,N2-乙烯基鳥糞嘌呤 58
3.2-1 固相萃取純化1,N2-乙烯基鳥糞嘌呤 58
3.2-2 液相層析電噴灑游離串聯質譜法對於1,N2-乙烯基鳥糞嘌呤
之分析 59
3.2-3 LC-ESI/MS/MS分析1,N2-eGua之靈敏度、校正曲線、準確性
與精確度 61
3.2-4 尿液中1,N2-eGua之SRM、子離子掃瞄、母離子掃瞄與統計
結果 63
3.3 小牛腸黏膜腺嘌呤去胺酶對分析DNA中乙烯基腺腺嘌呤之影
響 66
3.3-1 酸水解條件與固相萃取純化步驟 66
3-3.2 利用酸水解以及其他兩種酵素水解方法分析2-氯乙醛處理
過之小牛胸腺DNA中乙烯基腺嘌呤之修飾程度 68
3-3.3 利用 HPLC 搭配螢光偵測器或光電二極體陣列式偵檢器分
析小牛腸黏膜腺嘌呤去胺酶對乙烯基腺嘌呤去氧核醣核苷
之影響 72
3-3.4 利用氣相層析負離子化學游離質譜法分析人類胎盤DNA之
eAde與eCyt之含量 73
3-3.5 利用ESI-LC/MS/MS分析人類胎盤DNA中eAde與edAdo 76
第四章 結論 78
4.1 利用穩定同位素稀釋搭配氣相負離子化學游離法分析人類尿
液中乙烯基腺嘌呤 78
4.2 利用穩定同位素稀釋搭配液相層析電噴灑游離串聯質譜法偵
測尿液中之1,N2-乙烯基鳥糞嘌呤 79
4.3 小牛腸黏膜腺嘌呤去胺酶對分析DNA中乙烯基腺腺嘌呤之影響80

第二部份 以穩定同位素稀釋液相層析電噴灑游離串聯質譜法同
時定量人類尿液中的3-硝基酪胺酸與3-溴基酪胺酸 82
英文摘要 83
中文摘要 84
第五章 緒論 85
5.1 3-硝基酪胺酸與3-溴基酪胺酸之形成 85
5.2 3-硝基酪胺酸與3-溴基酪胺酸之生理意義 87
5.3 3-硝基酪胺酸與3-溴基酪胺酸之分析 88
第六章 材料與實驗方法 91
6.1 儀器 91
6.2 材料 91
6.3 藥品 91
6.4 液相層析儀系統條件 92
6.5 質譜儀系統條件 93
6.6 [d3]3-硝基酪胺酸之合成 94
6.7 [d3]3-溴基酪胺酸之合成 94
6.8 尿液的前處理 95
6.9 尿液蛋白質水解程序 95
6.10 以SCX固相萃取管收集3NT、3BT、與酪胺酸 95
6.11 以C18-OH固相萃取管收集3NT與 3BT與酪胺酸 96
6.12 利用液相層析電噴灑游離串聯質譜法對尿液蛋白質經水解後
產生之3NT與3BT之分析 96
6.13 校正曲線 97
6.14 利用液相層析電噴灑游離串聯質譜法對尿液蛋白質中酪胺酸
進行分析 97
6.15 利用液相層析電噴灑游離串聯質譜法對尿液中free 3NT,
3BT之含量進行分析 97
6.16 利用HPLC偵測人體尿液中之可丁尼含量 98
第七章 實驗結果與討論 99
7.1 利用逆相固相萃取管對3NT與3BT之前處理 99
7.2 利用LC-ESI/MS/MS對3NT與3BT進行之選擇反應偵測(SRM)、靈
敏度、校正曲線 100
7.3 LC-ESI/MS/MS分析法之準確度與精確度 103
7.4 3BT和3NT在尿液蛋白質中的含量並與尿液中可丁尼之關係 105
第八章 結論 109

第三部份 oxanine對溶菌酶之後轉譯修飾研究 110

英文摘要 111
中文摘要 112
第九章 緒論 113
9.1 反應性含氮物種 113
9.2 2’-deoxyoxanosine之形成和對胺基酸的反應 114
9.3 2’-deoxyoxanosine對蛋白質之修飾與研究方向 118
第十章 材料與實驗方法 121
10.1 儀器 121
10.2 藥品與材料 121
10.3 高效能液相層析儀的分析條件 122
10.4 液相層析電噴灑游離四極柱串聯直線式離子阱質譜儀分析
系統122
10.4-1 液相層析系統條件 122
10.4-2 質譜儀全質譜掃瞄模式 (full scan mode) 條件 123
10.4-3 質譜儀資料依歸掃瞄模式(data dependent scan mode)
條件 123
10.4-4 質譜儀選擇反應偵測模式 (SRM mode) 條件 123
10.4-5 Bioworks 3.2軟體之比對條件 123
10.5 2’-deoxyoxanosine之合成 124
10.6 去氧核糖核酸上2’-deoxyoxanosine之合成 124
10.7 含dOxo之去氧核糖核酸與還原態蔓皏?amp;#32957;的交聯反應 124
10.8 溶菌酶之變性 (denature) 、雙硫鍵還原與保護 125
10.9 溶菌酶之胰蛋白酶 (trypsin)水解步驟 (digestion) 125
10.10 dOxo與溶菌酶之交聯反應 126
10.11 含dO之去氧核糖核酸與溶菌酶的交聯反應 127
第十一章 實驗結果與討論 128
11.1 dOxo-DNA與溶菌酶交聯反應之研究方法 127
11.2 含oxanine之DNA之合成 129
11.3 含oxanine之DNA與還原態蔓皏?amp;#32957;(GSH)之反應 130
11.4 溶菌酶之胰蛋白酶水解與質譜分析 130
11.5 dO與溶菌酶之交聯反應 134
11.6 dOxo-DNA與溶菌酶的交聯反應 138
11.7 修飾胜肽之相對定量 143
第十二章 結論 146
第十三章 參考文獻 147
第十四章 附圖 170
中英對照表 212
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