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研究生:范馥麟
研究生(外文):Fu-Lin Fan
論文名稱:體抑素中苯丙胺酸殘基對其螢光性質的影響
論文名稱(外文):The role of phenylalanine residues in studying the fluorescence of somatostatin-14
指導教授:錢偉鈞錢偉鈞引用關係
指導教授(外文):Wei-Jyun Chien
學位類別:碩士
校院名稱:朝陽科技大學
系所名稱:應用化學系碩士班
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:2010
畢業學年度:99
語文別:中文
論文頁數:176
中文關鍵詞:苯丙胺酸活性片段區域性結構
外文關鍵詞:phenylalanineactive siteregional structure
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體抑素(Somatostain)為14個胺基酸所組成的環狀胜肽,具調節神經內分泌及新陳代謝之作用。原生體抑素從水溶液進入SDS微胞環境時,其螢光最高吸收波長(λmax)呈現藍位移現象且產生靜態消光。本實驗以丙胺酸取代體抑素序列中的苯丙胺酸,製備二段SRIF-14類似物 (SRIF-14 F6→A、F7→A),並以圓二色光譜、核磁共振光譜及分子模擬探討體抑素類似物在不同環境下(水及SDS微胞溶液)螢光強度及胜肽構型之間的關係。結果顯示體抑素類似物從水溶液進入SDS微胞環境時仍具螢光消光現象,但消光程度皆小於原生體抑素,其中以SRIF-14 F7→A最小。在胜肽二級結構方面,構型皆以無序纏捲(random coil)為主並具有迴路(turn)之構型存在。相較取代第六位置苯丙胺酸,取代第七位置苯丙胺酸之類似物其構型特徵不明顯,尤其在活性部位之區域性結構較為鬆散,顯示第七位置苯丙胺酸的存在對構型區域性結構的穩定度極為重要,故區域性結構愈穩定者其螢光消光程度愈明顯。此外,取代不同位置苯丙胺酸之類似物並不影響與SDS微胞結合之物理性質。
Somatostatin (SRIF-14) is a cyclic tetradecapeptide that that is involved in the regulation of neuroendocrine and metabolic functions. When somatostatin moves into micellar environment from aqueous solution blue shift and quench of the fluorescence intensity can be observed in the fluorescence spectra. In this work two alanine substituted somatostatin analogues(SRIF-14 F6→A、F7→A)are prepared. Upon interacting with SDS micelle, all the analogues as well as native SRIF share similar behavior in the quench of fluorescence intensity, however, the SRIF-14 F7→A degree of quench of fluorescence intensity are less than the native SRIF and the SRIF-14 F6→A. The conformational change for peptides moving from aqueous solution into micellar environment was monitored by circular dichroism, nuclear magnetic resonance and molecular simulation spectroscopy and compared to the results of native peptide. Two somatostatin analogues are mainly in the equilibrium between random coil and a β-turn under aqueous and micellar environments. However, an Ala substituent at the position of the seventh residue in SRIF-14(SRIF-14 F7→A) do not have distinct regional structure, especially active site. For this reason, the more regional structure is distinctness, the stronger degree of quench of fluorescence intensity. Hence the 7th phenylalanine in the somatostatin plays an important role in stability regional structure. In addition, all somatostatin analogue are not change that the binding constants between the peptide and the micelles.
中文摘要..................................................................................................Ⅰ
英文摘要..................................................................................................Ⅱ
誌謝..........................................................................................................Ⅲ
目錄..........................................................................................................VI
表目錄.......................................................................................................X
圖目錄...................................................................................................XIII
第一章 緒論............................................................................................1
1.1體抑素簡介...................................................................................1
1.2體抑素受體...................................................................................2
1.3體抑素的活性部位.......................................................................3
1.4體抑素類似物與體抑素受體間之選擇性結合...........................4
1.5原生體抑素在不同環境下之構型...............................................5
1.6原生體抑素在不同環境下之螢光光譜.......................................7
1.7微胞種類之選擇...........................................................................9
1.8蛋白質與胜肽之螢光相關論文回顧.........................................10
1.9研究目的.....................................................................................11
第二章 材料與方法..............................................................................21
2.1胜肽樣品製備.............................................................................21
2.2胜肽樣品分子量鑑定及純化.....................................................26
2.3核磁共振光譜實驗.....................................................................28
2.3.1胜肽樣品配製..........................................................................29
2.3.2一維及二維核磁共振光譜實驗條件......................................30
2.3.3一維及二維1H NMR光譜判定..............................................31
2.3.4自旋-晶格弛豫時間(spin-lattic relaxation time)之測定......36
2.3.5核磁共振光譜實驗藥品及儀器..............................................37
2.4胜肽樣品之螢光光譜實驗.........................................................38
2.4.1樣品配製..................................................................................38
2.4.2螢光光譜儀之參數設定..........................................................39
2.4.3螢光光譜實驗所需藥品及器材..............................................39
2.5 胜肽樣品之圓二色光譜實驗樣品鑑定及純化.......................40
2.5.1樣品配製..................................................................................40
2.5.2圓二色光譜儀之參數設定......................................................41
2.5.3圓二色光譜實驗所需藥品及器材..........................................41
2.6脈衝磁場梯度實驗(Pulsed Field Gradient , PFG-NMR).........42
2.6.1樣品配製..................................................................................43
2.6.2磁場梯度實驗之參數條件......................................................44
2.6.3磁場梯度實驗所需藥品及器材..............................................45
2.7分子模擬(Molecular Simulation)..............................................45
2.7.1Insight II ..................................................................................45
2.7.2Insight II參數設定...................................................................48
第三章 實驗結果..................................................................................69
3.1合成體抑素類似物(SRIF-14 F6→A、SRIF-14 F7→A)之鑑定................................................................................................69
3.2合成體抑素類似物(SRIF-14 F6→A、SRIF-14 F7→A)之純化................................................................................................70
3.3胜肽樣品之核磁共振光譜.........................................................72
3.3.1胜肽純度確認及定序..............................................................72
3.3.2胜肽二級結構分析..................................................................74
3.3.3 T1 弛豫時間(T1 relaxation time)之測定................................80
3.4胜肽樣品之螢光實驗.................................................................81
3.5胜肽樣品之圓二色光譜實驗-胜肽二級結構分析.................82
3.6核磁共振光譜-脈衝磁場梯度實驗.........................................83
3.7分子模擬.....................................................................................84
第四章 討論........................................................................................148
4.1研究個別取代原生體抑素第六、第七位置苯丙胺酸之原因..............................................................................................148
4.2各體抑素類似物在不同環境下T1 弛豫時間的變化........... 148
4.3原生體抑素及其類似物與SDS微胞作用之討論..................149
4.4探討造成螢光消光之原因.......................................................150
4.5在原生體抑素中不同苯丙胺酸對構型的影響.......................151
第五章 結論........................................................................................161
參考文獻................................................................................................162





























表 目 錄
表1-1、體抑素受體各子型分佈與其生理作用......................................19
表1-2、體抑素及類似物對體抑素受體之選擇性..................................19
表1-3、體抑素受體對體抑素及類似物之選擇性..................................20
表1-4、體抑素及類似物對體抑素受體之選擇性..................................20
表2-1、10% D2O / 90% H2O溶液,在不同溫度所測得之化學位移值................................................................................................64
表2-2、200 mM SDS微胞溶液,在不同溫度所測得之化學位移值................................................................................................64
表2-3、二十種共同胺基酸於無序纏捲時的質子化學位移表..............65
表2-4、胜肽二級結構所對應之化學位移差值......................................66
表2-5、胜肽二級結構所對應之耦合常數標準值..................................66
表2-6、胜肽二級結構所對應之雙平面角標準值..................................67
表2-7、胜肽二級結構γ及β-turns所對應之雙平面角結構特徵........68
表3-1、SRIF-14 F6→A於10% D2O / 90% H2O,溫度298K之化學位移表..........................................................................................137
表3-2、SRIF-14 F6→A於100 mM SDS-d25(10% D2O / 90% H2O),溫度298K之化學位移表........................................................138
表3-3、SRIF-14 F7→A於10% D2O / 90% H2O,溫度298K之化學位移表..........................................................................................139
表3-4、SRIF-14 F7→A於100 mM SDS-d25(10% D2O / 90% H2O),溫度298K之化學位移表........................................................140
表3-5、SRIF-14 F6→A於水溶液中,溫度298K所測得之化學位移差
值..............................................................................................141
表3-6、SRIF-14 F6→A於SDS微胞溶液中,溫度298K所測得之化學位移差值..............................................................................141
表3-7、SRIF-14 F7→A於水溶液中,溫度298K所測得之化學位移差
值..............................................................................................142
表3-8、SRIF-14 F7→A於SDS微胞溶液中,溫度298K所測得之化學位移值..................................................................................142
表3-9、SRIF-14 F6→A於水溶液中,溫度298K所測得之耦合常數值,並以不同文獻之常數值(A、B、C)求得雙平面角之結果..............................................................................................143
表3-10、SRIF-14 F6→A於微胞溶液中,溫度298K所測得之耦合常數值,並以不同文獻之常數值(A、B、C)求得雙平面角之結果..............................................................................................143
表3-11、SRIF-14 F7→A於水溶液中,溫度298K所測得之耦合常數值,並以不同文獻之常數值(A、B、C)求得雙平面角之結果…..........................................................................................144
表3-12、SRIF-14 F6→A於水溶液中,溫度298K下各殘基背骨胺基質子之T1弛豫時間.................................................................145
表3-13、SRIF-14 F6→A於SDS微胞中,溫度298K下各殘基背骨胺基質子之T1弛豫時間.............................................................145
表3-14、SRIF-14 F7→A於水溶液中,溫度298K下各殘基背骨胺基質子之T1弛豫時間.................................................................146
表3-15、SRIF-14 F7→A於SDS微胞中,溫度298K下各殘基背骨胺基質子之T1弛豫時間.............................................................146
表3-16、SRIF-14 F6→A於SDS微胞之結構計算限制條件................147
表3-17、SRIF-14 F6→A於SDS微胞之分子結構RMSD....................147
表4-1 、原生體抑素及其類似物於不同環境下所測得擴散係數及其結合常數比較表..........................................................................159
表4-2 、原生體抑素及其類似物化學位移值變化表..........................160





圖 目 錄
圖1-1、原生體抑素及其類似物之胜肽一級結構..................................13
圖1-2、體抑素SRIF-14對於腸胃之作用................................................14
圖1-3、體抑素五類子型受體之一級結構..............................................15
圖1-4、G蛋白偶聯受體(G-protein-coupled receptors)與受體結合之示意圖............................................................................................16
圖1-5、體抑素類似物Octreotide、Lanreotide和Vapreotide之一級結構................................................................................................17
圖1-6、各體抑素類似物中芳香環數目及相對距離對各體抑素受體鍵結親和力之關係........................................................................18
圖2-1、固相胜肽合成法之流程圖..........................................................51
圖2-2、斷切試劑之選擇流程圖..............................................................52圖2-3、二十種共同胺基酸之自旋系統示意圖......................................53
圖2-4、標準二級結構MCD型態螺旋結構(α-helix & 310-helix)........54
圖2-5、標準二級結構MCD型態板狀結構(平行板狀結構&反平行板狀結構)......................................................................................55
圖2-6、各種二級結構元素的NOEs的典型型態,在各種二級結構下,其短和中距離之NOE連結及耦合常數...................................56
圖2-7、胜肽骨架上之雙平面角ψ、ψ、ω、χ等示意圖........................57
圖2-8、3J與雙平面角θ=|ψ-60°|之對應圖............................................58
圖2-9、自旋-晶格弛豫中自旋系統由激發態藉放熱方式至平衡狀態之過程,其所需時間即為T1弛豫時間.....................................59
圖2-10、以倒轉-回覆法測量T1值及其脈衝序列................................60
圖2-11、利用NMR 圖譜數據進行分子模擬之步驟.............................61
圖2-12、利用Insight II進行分子模擬之流程與所需之模組功能.........62
圖2-13、分子模擬過程中所設定之重要參數........................................63
圖3-1、SRIF-14 F6→A初產物之MALDI TOF MS圖譜.......................87
圖3-2、SRIF-14 F6→A純化後之MALDI TOF MS圖譜.......................88
圖3-3、SRIF-14 F7→A初產物之MALDI TOF MS圖譜.......................89
圖3-4、SRIF-14 F7→A純化後之MALDI TOF MS圖譜.......................90
圖3-5、SRIF-14 F6→A初產物之HPLC圖譜.........................................91
圖3-6、SRIF-14 F6→A純化後之HPLC圖譜.........................................92
圖3-7、SRIF-14 F7→A初產物之HPLC圖譜.........................................93
圖3-8、SRIF-14 F7→A純化後之HPLC圖譜.........................................94
圖3-9、SRIF-14 F6→A及F7→A於10% D2O/90% H2O之一維1H譜圖................................................................................................95
圖3-10、2 mM SRIF-14 F6→A於10% D2O / 90% H2O中之TOCSY圖................................................................................................96
圖3-11、2 mM SRIF-14 F6→A於10% D2O / 90% H2O中之NOESY圖................................................................................................97
圖3-12、1 mM SRIF-14 F6→A於100 mM SDS-d25(10% D2O / 90% H2O)中之TOCSY圖........................................................................98
圖3-13、1 mM SRIF-14 F6→A於100 mM SDS-d25(10% D2O / 90% H2O)中之NOESY圖........................................................................99
圖3-14、1 mM SRIF-14 F7→A於10% D2O / 90% H2O中之TOCSY圖............................................................................................100
圖3-15、1 mM SRIF-14 F7→A於10% D2O / 90% H2O中之NOESY圖............................................................................................101
圖3-16、1 mM SRIF-14 F7→A於100 mM SDS-d25(10% D2O / 90% H2O)中之TOCSY圖......................................................................102
圖3-17、1 mM SRIF-14 F7→A於100 mM SDS-d25(10% D2O / 90% H2O)中之NOESY圖......................................................................103
圖3-18、SRIF-14 F6→A於不同環境下,溫度298K所測得TOCSY之疊圖........................................................................................104
圖3-19、SRIF-14 F7→A於不同環境下,溫度298K所測得TOCSY之疊圖........................................................................................105
圖3-20、SRIF-14 F6→A於不同環境下,溫度298K所測得化學位移差值之長條圖..........................................................................106
圖3-21、SRIF-14 F6→A於SDS微胞環境下化學位移值減去於水溶液下化學位移值之長條圖..........................................................107
圖3-22、SRIF-14 F7→A於不同環境下,溫度298K所測得化學位移差值之長條圖..........................................................................108
圖3-23、SRIF-14 F7→A於SDS微胞環境下化學位移值減去於水溶液下化學位移值之長條圖..........................................................109
圖3-24、SRIF-14 F6→A於100 mM SDS微胞溶液之NOE連接.........110
圖3-25、SRIF-14 F7→A於100 mM SDS微胞溶液之NOE連接.........111
圖3-26、SRIF-14 F6→A於水溶液(10% D2O / 90% H2O)中,溫度298K下所測得之DQF-COSY圖譜.................................................112
圖3-27、SRIF-14 F6→A於SDS微胞溶液中,溫度298K下所測得之DQF-COSY圖譜......................................................................113
圖3-28、SRIF-14 F7→A於水溶液(10% D2O / 90% H2O)中,溫度298K下所測得之DQF-COSY圖譜.................................................114
圖3-29、SRIF-14 F7→A於SDS微胞溶液中,溫度298K下所測得之DQF-COSY圖譜......................................................................115
圖3-30、SRIF-14 F6→A於水溶液(10% D2O / 90% H2O)中,溫度298K下以倒轉-回覆法(inversion-recovery)實驗量測T1 弛豫時間之結果..........................................................................................116
圖3-31、SRIF-14 F6→A於SDS微胞環境中,溫度298K下以倒轉-回覆法(inversion-recovery)實驗量測T1 弛豫時間之結果..............................................................................................117
圖3-32、SRIF-14 F7→A於水溶液(10% D2O / 90% H2O)中,溫度298K下以倒轉-回覆法(inversion-recovery)實驗量測T1 弛豫時間之結果..........................................................................................118
圖3-33、SRIF-14 F7→A於SDS微胞環境中,溫度298K下以倒轉-回覆法(inversion-recovery)實驗量測T1 弛豫時間之結果..............................................................................................119
圖3-34、SRIF-14 F6→A於不同環境中,於室溫下所測得之螢光光譜..............................................................................................120
圖3-35、SRIF-14 F7→A於不同環境中,於室溫下所測得之螢光光譜..............................................................................................121
圖3-36、SRIF-14 F6→A於不同環境中,於室溫下所測得之圓二色光譜圖..........................................................................................122
圖3-37、SRIF-14 F7→A於不同環境中,於室溫下所測得之圓二色光譜圖..........................................................................................123
圖3-38、1mM SRIF-14 F6→A於100% D2O中,溫度298K下所測得DOSY 一維1H譜疊圖............................................................124
圖3-39、1mM SRIF-14 F6→A於100% D2O中,溫度298K下所測得DOSY 二維光譜.....................................................................125
圖3-40、1mM SRIF-14 F6→A於50 mM SDS微胞環境中,溫度298K下所測得DOSY 一維1H譜疊圖............................................126
圖3-41、1mM SRIF-14 F6→A於50 mM SDS微胞環境中,溫度298K下所測得DOSY 二維光譜.....................................................127
圖3-42、1 mM SRIF-14 F7→A於100% D2O中,溫度298K下所測得DOSY 一維1H譜疊圖............................................................128
圖3-43、1 mM SRIF-14 F7→A於100% D2O中,溫度298K下所測得DOSY 二維光譜.....................................................................129
圖3-44、1 mM SRIF-14 F7→A於50 mM SDS微胞環境中,溫度298K下所測得DOSY 一維1H譜疊圖............................................130
圖3-45、1 mM SRIF-14 F7→A於50 mM SDS微胞環境中,溫度298K下所測得DOSY 二維光譜.....................................................131
圖3-46、經由分子動力模擬焠熄計算後得110個分子結構,以背骨為主要篩選依據進行SRIF-14 F6→A在SDS微胞環境下結構初步篩選......................................................................................132
圖3-47、經過分子動力模擬焠熄計算SRIF-14 F6→A於SDS微胞中之構型,此為第一群分子結構,經初步篩選的分子結構中細分出12個SRIF-14 F6→A結構,其中以Ala6及Phe7作判斷依據而進行分子結構之堆疊..................................................133
圖3-48、經過分子動力模擬焠熄計算SRIF-14 F6→A於SDS微胞中之構型,此為第二群分子結構,經初步篩選的分子結構中細分出15個SRIF-14 F6→A結構,其中以Ala6及Phe7作判斷依據而進行分子結構之堆疊..................................................134
圖3-49、經分子動力模擬焠熄計算SRIF-14 F6→A於SDS微胞溶液中之結構,第一群及第二群分子結構以各殘基推疊狀況為依準之RMSD值以長條圖顯示..................................................135
圖3-50、SRIF-14 F6→A於SDS微胞環境下,分子結構之藥效基團Trp8-Lys9側鏈與芳香環側鏈之空間關係圖..........................136
圖4-1、原生體抑素在水溶液環境下第六位置及第十一位置苯丙胺酸間的空間排列示意圖..............................................................154
圖4-2、1 mM SRIF-14 F6→A於100 mM SDS-d25(10% D2O / 90% H2O)中之NOESY圖(圖示範圍:F1為2.0-0.7 ppm;F2為8.2-6.9 ppm) .........................................................................................155
圖4-3、1 mM SRIF-14 F7→A於100 mM SDS-d25(10% D2O / 90% H2O)中之NOESY圖(圖示範圍:F1為2.0-0.7 ppm;F2為8.2-6.9 ppm) .........................................................................................156
圖4-4、SRIF-14於SDS微胞環境下各殘基胺基質子化學位移值減去於水溶液下各殘基胺基質子化學位移值之化學位移差值長條圖..............................................................................................157
圖4-5、經過分子動力模擬焠熄計算SRIF-14於SDS微胞環境中之構型..............................................................................................158
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