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研究生:陳朝勝
研究生(外文):Chao-Sheng Chen
論文名稱:人類岩藻醣苷水解酶之抑制研究
論文名稱(外文):Inhibition of human α-L-fucosidase
指導教授:李耀坤李耀坤引用關係
指導教授(外文):Yaw-Kuen Li
學位類別:碩士
校院名稱:國立交通大學
系所名稱:應用化學系所
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:2006
畢業學年度:94
語文別:中文
論文頁數:99
中文關鍵詞:岩藻醣苷水解酶抑制藥物篩選酵素催化特性
外文關鍵詞:α-L-fucosidaseinhibitiondrug screeningcatalytic character
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人類岩藻醣苷水解酶(Human α-L-fucosidase,AFU)屬於醣類水解酵素第29家族的水解酶(EC 3.2.1.51),本研究著重於該酵素的相關催化功能與抑制作用的探討。
將建構在pET22b上的Human α-L-fucosidase基因轉殖進入大腸桿菌BL21(DE3)中表現;經過離子交換管柱(SP、Q)及G-75凝膠管柱的純化處理之後,可以取得均質度達95%的酵素,酵素單體的分子量約為50 kDa左右。以p-nitrophenyl-α-L-fucopyranoside (PNPF) 為基質進行活性分析,實驗顯示AFU在pH 4.5以及pH 6.5左右存在兩活性最佳區域;當pH低於3.5或是高於7.5後酵素會呈現不穩定狀態。以PNPF為反應基質在pH 5.0的環境下,其Km以及kcat分別為0.105 mM和48.6 s-1;相較文獻中人類肝臟萃取的AFU (Km = 0.43 mM,Vmax = 19.6 μmole/mg/min 相當於kcat = 16.3 sec-1),重組酵素的催化能力(kcat/Km)約為肝臟原生酵素的12倍。
為研究酵素反應之機制,我們利用化學合成法合成一系列具有不同離去基之基質進行Brǿnsted relationship之研究,以離去基pKa 大於7.0為基質,得到Brǿnsted constant(βlg)約為-0.27;又因酵素進行催化反應時也觀測到initial burst 現象,推測其催化作用應涉及兩步驟雙取代之機制,且速率決定步驟應為去醣基(deglycosylation)步驟。
本實驗亦進行藥物篩選之研究,利用ELISA reader從藥物庫[Spectrum Collection(MicroSource)]中進行藥物篩選;我們幸運的篩選得到幾種有效之AFU抑制劑分別為,不可逆抑制劑:Cisplatin、Ebselen;競爭型抑制劑:Ethambutol、Mitoxantrone及非競爭型抑制劑:Dequilinium chloride。Cisplatin以及Ebselen推測會與蛋白質中的半胱胺酸(cysteine)形成共價鍵結,使蛋白質結構產生變化或破壞催化區而失去催化活性。競爭型抑制劑Ethambutol對AFU的抑制常數(Ki)為23 μM;以Ethambutol對不同的醣類水解酵素及不同來源之AFU進行抑制研究,發現Ethambutol對人類AFU具有較佳的專一性;此抑制劑為目前治療肺結核第一線藥物之一。
A gene from human encoding α-L-fucosidase (AFU) was cloned into pET22b plasmid. Protein was successfully expressed in E. coli BL21 (DE3). After applying a series of ion-exchange and gel-filtration chromatography purification steps, recombinant AFU with 95% homogeneity can be obtained. The molecular weight of the enzyme was analyzed by SDS-PAGE to be about 50 kDa.
pH-dependent study indicated that AFU exhibited 2 optimal regions at pH 4.5 and pH 6.5, and the enzyme would become unstable when pH is lower than 3.5 or higher than 7.5. Michaelis constant (Km) and catalytic activity were determined with p-nitrophenyl-α-L-fucopyranoside (PNPF) and were found to be 0.105 mM and 48.6 sec-1, respective. Comparing with AFU extracted from human liver (Km = 0.43 mM and maximal velocity = 19.6 μmole/mg/min equal to kcat = 16.3 sec-1),the catalytic power (kcat/Km) of recombinant AFU is 12-fold stronger than native human liver AFU.
In order to investigate the reaction mechanism of AFU, a series of aryl-α-L-fucopyranoside were synthesized for Brǿnsted relationship study. The Brǿnsted constant βlg is -0.27 obtained from Brǿnsted plot constructed with a series of aryl-α-L-fucopyranoside with pKa > 7.0. Initial burst also observed during the enzyme reaction. Based on these two preliminary results, the catalytic mechanism of AFU was purposed to be a two-step double displacement mechanism with the rate-limiting step at the deglucosylation step.
Inhibitor of AFU was also screened. A chemical library from Spectrum Collection® (MicroSource)was used as drug candidate for screening. Fortunately, several inhibitors were found to be effective such as irreversible inhibitor: Cisplatin, Ebselen; competitive inhibitors: Ethambutol、Mitoxantrone and uncompetitive inhibitor: Dequalinium chloride. Cisplatin and Ebselen would covalently bond to the amino acid residue cysteine of AFU; hence, the active site structure of the enzyme may be changed and finally lost its activity through this bonding. The Ki value of Ethambutol for human AFU was 23 μM; specific inhibition study for different glycoside hydrolases and AFU from different sources with Ethambutol was also investigated. Ethambutol is also one of the first-line medications for pulmonary tuberculosis, was found to be a specific inhibitor of recombinant human AFU.
第一章 緒論--------------------------------------------1
1-1 岩藻醣苷水解酶α-L-fucosidase(EC 3.2.1.51)之生物功能-1
1-1-1 岩藻醣苷水解酶之簡介及其重要性-----------------------1
1-1-2 岩藻醣苷水解酶之水解催化反應機制---------------------3
1-2 哺乳類動物岩藻醣苷水解酶概述---------------------------6
1-2-1 哺乳類動物岩藻醣苷水解酶介紹-------------------------6
1-2-2 人類岩藻醣苷水解酶介紹------------------------------11
1-3 岩藻醣苷水解酶抑制劑的介紹----------------------------13
1-4 研究目的----------------------------------------------15

第二章 實驗方法-------------------------------------------16
2-1 Human α-L-fucosidase 重組酵素純化--------------------16
2-1-1 一般敘述--------------------------------------------16
2-1-2 Human α-L-fucosidase 表現系統的建立----------------17
2-1-3 胞內粗提液的取得以及純化----------------------------17
2-1-4 酵素活性測試----------------------------------------19
2-1-5 決定蛋白質分子量以及純度----------------------------19
2-1-6 LC-Mass 決定蛋白質的分子量--------------------------20
2-1-7 蛋白質濃度的測定------------------------------------20
2-2 芳香類α-L-岩藻醣苷化合物以及具抑制效果藥物衍生物的合成 -------------------------------------------------------21
2-2-1 一般敘述--------------------------------------------21
2-2-2 芳香類α-L-岩藻醣苷化合物及Fuconolactone的合成------22
2-2-3 2-(2-aminoethylamino) ethanol衍生物合成-------------25
2-3 酵素催化特性之研究------------------------------------27
2-3-1 一般敘述--------------------------------------------27
2-3-2 酵素kcat、Km以及Brǿnsted plot的研究----------------27
2-3-3 Fuconolactone抑制作用測定---------------------------28
2-4 藥物篩選----------------------------------------------29
2-4-1 一般敘述--------------------------------------------29
2-4-2 抑制劑篩選------------------------------------------29
2-4-3 抑制作用之研究--------------------------------------30
2-4-4 抑制劑對不同酵素專一性測試--------------------------32
2-4-5 抑制劑對不同來源的岩藻醣苷水解酶專一性測試----------33

第三章 結果與討論-----------------------------------------34
3-1 Human α-L-fucosidase 重組酵素表現與純化--------------34
3-1-1 重組酵素的表現--------------------------------------34
3-1-2 Human α-L-fucosidase的酵素粗提液純化---------------35
3-1-3 Human α-L-fucosidase酵素的分子量-------------------39
3-2 酵素催化特性之研究------------------------------------40
3-2-1 酸鹼值對酵素活性的影響------------------------------40
3-2-2 催化速率決定步驟之探討------------------------------43
3-2-3 Fuconolactone抑制作用測定---------------------------45
3-3 藥物篩選----------------------------------------------46
3-4 有效抑制劑衍生物的測試與合成--------------------------48
3-4-1 抑制劑之類型分析與專一性之探討----------------------48
3-4-2 抑制劑對不同酵素專一性測試--------------------------55
3-4-3 抑制劑對不同來源的岩藻醣苷水解酶專一性測試----------56
3-4-4 可逆抑制劑抑制常數的測定----------------------------57
3-4-5 Ethambutol相關類型藥物及衍生物抑制之研究------------58
3-4-6 有效抑制劑結構分析與討論----------------------------61
3-4-7 不可逆抑制劑抑制作用測定----------------------------64
3-5 未來研究方向------------------------------------------66

第四章 結論-----------------------------------------------67
第五章 參考文獻-------------------------------------------69
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