臺灣博碩士論文加值系統

DNA拓樸異構酶（DNA topoisomerases）是細胞核內的重要蛋白質，當細胞在進行DNA複製、RNA轉錄及DNA重組的過程中所產生的DNA拓樸結構問題，均須要DNA拓樸異構酶來解決。DNA拓樸異構酶依其對DNA的作用方式，主要分成兩種類型：（一）. 第一型DNA拓樸異構酶（Type I DNA topoisomerases）：每次切接DNA之一股，作用過程不須消耗ATP。 （二）. 第二型DNA拓樸異構酶（Type II DNA topoisomerases）：每次同時切接雙股DNA，作用過程須消耗ATP。經由這兩種不同的反應機轉，可調節DNA的超螺旋結構，一但DNA拓樸結構酶發生變異，功能喪失或受藥物抑制時，細胞的生理狀況必受嚴重影響，甚至造成細胞死亡。DNA拓樸異構酶已被確認是許多抗癌藥物的標的物，抑制第二型DNA拓樸異構酶的藥物有很多種，但抑制第一型DNA拓樸異構酶雖有新藥推出，但目前仍以喜樹鹼（camptothecin）及其衍生物（topotecin）為主。
過去文獻指出，許多naphthoquinone類化合物具有同時抑制人類DNA拓樸異構酶I及II的能力，本論文選用屬於naphthoquinone類之天然化合物isodiospyrin為研究對象，研究isodiospyrin與DNA拓樸異構酶的交互作用，並深入了解isodiospyrin對DNA拓樸異構酶的抑制機轉。結果指出，isodiospyrin可抑制人類DNA拓樸異構酶I解超螺旋DNA的能力，且當isodiospyrin與人類DNA拓樸異構酶I先行培養後會增加isodiospyrin抑制人類DNA拓樸異構酶I的能力。關於isodiospyrin抑制人類DNA拓樸異構酶I的機轉研究顯示，isodiospyrin不會與DNA作用，不會穩定DNA拓樸異構酶I－DNA切割複合體，會抑制人類DNA拓樸異構酶I與DNA結合的能力。根據以上結果顯示，isodiospyrin抑制人類DNA拓樸異構酶I的作用機轉和喜樹鹼不同，isodiospyrin直接與人類DNA拓樸異構酶I作用並抑制其活性為可能的機轉。另外，人類DNA拓樸異構酶I除了具扮演DNA拓樸結構的調節者外，亦具有蛋白激酶的活性，本論文顯示isodiospyrin會抑制人類DNA拓樸異構酶I的蛋白激酶活性，其抑制方式為抑制ATP與人類DNA拓樸異構酶I的結合。
本研究中也發現，isodiospyrin可抑制人類DNA拓樸異構酶II解環及超螺旋DNA的能力。抑制機轉研究顯示，isodiospyrin會穩定拓樸異構酶II－DNA切割複合體，此結果建議isodiospyrin 和拓樸異構酶II的作用可能經由化學修飾途徑，以達抑制拓樸異構酶II的效果。最後結果顯示isodiospyrin是一種能同時抑制人類DNA拓樸異構酶I及II的新藥物，深具成為以DNA拓樸異構酶作標的之抗癌藥物潛力。

Isodiospyrin is a natural product from the plant Diospyros morrisiana, which consists of an asymmetrical 1,2-binaphthoquinone chromophore. Isodiospyrin exhibits potent antitumor activity but very little is known about its cellular target and mechanism of action. In the present study, we show that isodiospyrin inhibits not only the DNA relaxation and kinase activities of human DNA topoisomerase I (htopo I), but also the relaxation and decatenation activities of human DNA topoisomerase IIa (htopo IIa). Unlike the prototypic htopo I poison camptothecin (CPT), isodiospyrin does not induce htopo I-DNA covalent complexes. However, isodiospyrin antagonizes CPT-induced, htopo I-mediated DNA cleavage. Binding analysis has indicated that isodiospyrin binds htopo I but not DNA. Furthermore, isodiospyrin exhibits strong inhibitory effect on the kinase activity of htopo I toward SF2/ASF in the absence of DNA. Thus, these finding have important implications on naphthoquinone and its derivatives’ cellular mode of actions, i.e. these novel DNA topoisomerase I and IIa inhibitors can prevent not onlt DNA relaxation of htopo I, IIa but also kinase activities of htopo I

中文摘要1
英文摘要3
壹、緒論
1. DNA 拓樸異構酶4
2. DNA 拓樸異構酶分類4
3. DNA 拓樸異構酶功能6
4. 人類DNA 拓樸異構酶8
5. DNA 拓樸異構酶為抗癌藥物的標的11
6. DNA 拓樸異構酶抑制劑機轉及抗藥性15
7. Isodiospyrin 16
貳、實驗材料與方法
一.實驗材料18
二.實驗方法21
(1) 製備E. coli competent cells 21
(2) 大腸桿菌的轉型21
(3) 少量純化質體的方法21
(4) 利用CsCl banding 的方式純化質體的方法22
(5) 以限制酶切割DNA 與電泳分離23
(6) DNA 片段的純化23
(7) DNA 的連接24
(8) 蛋白質電泳膠片的製備及分離24
(9) Coomassie blue 作蛋白質染色25
(10) 西方墨點法25
(11) 利用昆蟲細胞表現及純化人類第一型DNA 拓樸異構酶25
(12) 3’端DNA 放射性標定反應29
(13) 人類第一型DNA 拓樸異構酶超螺旋DNA 的鬆解反應30
(14) 第一型DNA 拓樸異構酶切割反應30
(15) 人類第二型DNA 拓樸異構酶超螺旋DNA 的鬆解反應及解環反應31
(16) 第二型DNA 拓樸異構酶切割反應31
(17) 濾膜結合分析32
(18) 利用紫外光作交互連結的分析32
(19) 激酶活性分析32
(20) In vitro K-SDS 共沉澱分析33
(21) 電泳移動改變分析法33
(22) Isodiospyrin 與DNA之交互作用分析34
(23) UV-可見光光譜分析35
參、結果
一.利用桿狀病毒大量表現並純化人類DNA 拓樸異構酶I 36
二. Isodiospyrin 抑制人類DNA 拓樸異構酶I之機轉36
1. Isodiospyrin 抑制人類DNA 拓樸異構酶I 解超螺旋DNA 之能力37
2. Isodiospyrin 不具有DNA 結合能力39
3. Isodiospyrin 抑制人類DNA 拓樸異構酶I 的活性不經由誘導
DNA 斷裂的方式達成41
4. Isodiospyrin 抑制喜樹鹼誘導之人類DNA 拓樸異構酶I－DNA
切割複合體形成42
5. Isodiospyrin 抑制人類DNA 拓樸異構酶I 與DNA 結合42
6. Isodiospyrin 抑制人類DNA 拓樸異構酶I 與ATP 之結合43
7. Isodiospyrin 抑制人類DNA 拓樸異構酶I 的激.活性44
8. Isodiospyrin 抑制人類DNA 拓樸異構酶I 活性是經由直接的
化學修飾而達成45
三.Isodiospyrin 抑制人類DNA 拓樸異構酶IIα之機轉45
1. Isodiospyrin 抑制人類DNA 拓樸異構酶IIα解超螺旋DNA
及解DNA 環的能力46
2. Isodiospyrin 抑制人類DNA 拓樸異構酶IIα活性經由誘導
DNA 斷裂方式達成46
肆、討論
一.Isodiospyrin 抑制人類DNA 拓樸異構酶I 的機轉48
二.Isodiospyrin 抑制人類DNA 拓樸異構酶I 激酶活性的機轉50
三.Isodiospyrin 抑制人類DNA 拓樸異構酶I 及II 的機轉差異51
四.Naphthoquinone 具有抑制人類DNA 拓樸異構酶I 及II 的
雙重抑制能力52
伍、圖表54
陸、參考文獻86
附錄

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