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研究生:克利多弗
研究生(外文):G. Christopher Paul Sudhahar
論文名稱:變性劑、有機溶劑和鹽類對烯雙炔抗腫瘤抗生素新抑癌素的蛋白穩定性、藥物的效力、釋放和傳送的影響
論文名稱(外文):Effect of Denaturants, Organic Solvents and Salts on the Protein Stability, Drug Efficacy, Release and Delivery of the Enediyne Antitumor Antibiotic Chromoprotein, Neocarzinostatin
指導教授:金德航
指導教授(外文):Der-Hang Chin
學位類別:博士
校院名稱:國立中興大學
系所名稱:化學系
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:2005
畢業學年度:94
語文別:英文
論文頁數:195
中文關鍵詞:新抑癌素有機溶劑鹽類
外文關鍵詞:NeocarzinostatinOrganic SolventSalts
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新抑癌素是強力抗腫瘤抗生素,由非常穩定、摺版結構的蛋白 (113個胺基酸構成)與不穩定的九元環烯雙炔生色團組合而成,二者以非共價鍵互相結合。新抑癌素蛋白不止能穩定和攜帶生色團,並且會調控生色團的釋放。本論文所呈現的研究是為了想去了解:(i) 新抑癌素的生色團釋放機制,(ii) 氯化鈉抑制生色團切割去氧核醣核酸的機制,和(iii) 新抑癌素蛋白結構的穩定性。本論文的第一章是詳細敘述烯雙炔抗腫瘤抗生素的發現、分類、及結構等,其中特別著重於新抑癌素的機制。第二章是敘述基因重組新抑癌素蛋白的表現、純化及生物物理的特性。第三章呈現三氟乙醇誘導生色團釋放的研究,其中包含新抑癌素蛋白的圓二色光譜、螢光光譜和一維核磁共振光譜的分析,以及生色團釋放的螢光光譜和高效能液相層析分析,結果顯示新抑癌素的蛋白在開散之前,生色團已經開始釋放,顯示生色團的釋放不需要新抑癌素蛋白的構形改變。第四章描述促使生色團釋放的作用力的研究,在有機溶劑和鹽中,分析新抑癌素蛋白的結構變化及生色團的釋放動力學。結果顯示生色團的釋放是因疏水性作用力受到干擾,而不是離子性的作用力,呈現的結果也顯示生色團的釋放是在有機溶劑導致主要構形改變之前。第五章描述的是評估新抑癌素蛋白在化學變性劑及有機溶劑中的穩定性,因為蛋白結構是否穩定,對意圖運用蛋白來輸送藥物的藥物設計,是很重要的選擇標準,實驗結果顯示新抑癌素蛋白在高濃度的有機溶劑中,仍保持它自然摺疊的結構,在最高濃度的尿素和鹽酸胍作用下,新抑癌素蛋白只顯示出部份的開散,而強力變性劑十二烷硫酸納無法誘導新抑癌素蛋白構形的改變,與其他蛋白比較的結果,顯示新抑癌素蛋白的結構穩定性,比細胞色素c,溶菌酶,及其他多種的穩定蛋白要高,可以驗證新抑癌素蛋白不尋常的高穩定性,這結果突顯出新抑癌素蛋白很適合去保護不穩定的生色團。第六章敘述鹽類抑制新抑癌素對去氧核醣核酸的切割研究,早期初步的實驗顯示氯化鈉能抑制新抑癌素對去氧核醣核酸的切割作用。我們在不同濃度的氯化鈉下,於試管中進行去氧核醣核酸的切割實驗,結果顯示鹽與蛋白之間的交互作用並不是主要的抑制因素,氯化鈉對新抑癌素蛋白的熱穩定性影響很小,鹽類對蛋白釋放生色團的速率影響也很小。生色團與去氧核醣核酸的結合實驗顯示氯化鈉的抑制影響主要是在於它能阻止生色團與目標去氧核醣核酸之間的結合。
Neocarzinostatin, the antitumor antibiotic chromoprotein from Streptomyces carzinostaicus, is a non-covalent complex of a highly stable all β-sheet apoprotein of 113 amino acids and a labile 9-membered enediyne chromophore. The apoprotein stabilize and transports its chromophore, also regulates its release in juxtaposition to the target DNA. The present study is intended to understand (i) the mechanism of the release of the chromophore from the chromoprotein complex; (ii) the structural stability of the carrier protein; and (iii) the mechanism of sodium chloride inhibition of DNA cleavage induced by neocarzinostatin. The first chapter of the thesis, the “Introduction”, is an elaborate account describing the system and the objectives along with reviewing the literatures dealing with the discovery, classification, structure, and mechanism of activity of enediyne antitumor antibiotics, with particular references to neocarzinostatin. The second chapter deals with the expression, purification, and preliminary biophysical characterizations of the recombinant aponeocarzinostatin. The third chapter describes the mechanism of the 2,2,2-trifluoroetanol-induced release of the chromophore. The studies involve circular dichroism, fluorescence, HPLC, and 1-dimensional nuclear magnetic resonance analyses of aponeocarzinostatin and the chromophore release. The results show that the release of chromophore occurs before the unfolding of aponeocarzinostatin becomes evident, suggesting that the release does not require a major conformational change in the protein. The fourth chapter describes the exploration of the natural driving force(s) underlying the chromophore release. The studies involved structural changes of aponeocarzinostatin and release kinetics of the chromophore in the presence of organic solvents (alcohols and acetonitrile) and salts. The results, in concert, suggest that the release of the chromophore, which precedes major conformational changes of aponeocarzinostatin induced by organic solvents, is caused by hydrophobic perturbation, rather than ionic. The fifth chapter describes experiments to assess the stability of aponeocarzinostatin against chemical denaturants and organic solvents, since the structural stability is an important requirement for being an efficient proteinaceous drug carrier. While aponeocarzinostatin retains almost its native structure in fairly high concentrations of organic solvents, it shows only partial unfolding at the maximum concentration of urea and guanidine hydrochloride. It also retains its structural integrity in the potent denaturant sodium n-dodecyl sulfate. The structural stability of aponeocarzinostatin against organic solvents and chemical denaturants is higher than that of cytochrome c, lysozyme, and several other proteins which are known to be stable. The comparison among proteins provides evidence to the unusually high stability of aponeocarzinostatin. The results highlight the appropriateness of aponeocarzinostatin to protect its labile chromophoric partner. The sixth chapter presents an attempt to understand the mechanism of salt inhibition of neocarzinostatin-mediated DNA strand scission, an unexplored aspect of neocarzinostatin activity. Earlier studies on neocarzinostatin elsewhere showed that sodium chloride inhibits the neocarzinostatin-mediated DNA strand scission. Our data from in vitro DNA cleavage experiments under different sodium chloride concentrations, performed in the presence of thiols (β-mercaptoethanol or glutathione), show that the salt-protein interaction is not be the major inhibitory factor. There is little effect of sodium chloride on the thermal stability of aponeocarzinostatin. Fluorescence analysis of release kinetics of the chromophore reveals little influence of salt on the rate of release. The DNA binding data suggest that the major inhibitory effect of salt on DNA cleavage is caused by preventing the binding of the chromophore with the target DNA.
Contents


1. Introduction

1.1. Enediyne Antitumor antibiotics ………………………………………….….001

1.2. Classification of enediyne antibiotics…………………….…………………..005

1.3. Neocarzinostatin…….…………..……………………………………………..010

1.4. Aponeocarzinostatin………...………………………………………………...021

1.5. Objective of the present study………………………………………….…….033

2. Aponeocarzinostatin Expression, Purification and Biophysical Characterization

2.1. The source of Neocarzinostatin ………………………………………….……..037

2.2. Source of apoNCS gene………………………………………………….……....038

2.3. Expression and purification of recombinant apoNCS……………….….……..041

2.4. Analyses of purified recombinant apoNCS……………………………….……044

2.5. Biophysical Characterization………………………….………………….……..050

3. Release of the NCS- Chr from the HoloNCS Does Not Require Conformational Change Induced by Trifluoroethanol

3.1. Introduction…………………………………………………………….….…….061

3.2. Materials and Methods……………………………………………………...…..064

3.3. Results….. ………………………………………………………………...……068

3.4. Discussion…………………………………………………………………...……082





4. Effect of Alcohols and Organic Solvent on Neocarzinostatin -A Molecular View of the Drug Delivery System

4.1. Introduction……………………………………………………….………………088
4.2. Materials and Methods………………………………………….………………..090

4.3. Results………………………………………………………………………….….094
.
4.4. Discussion………………………………………………………………..…....…..103

4.5. Conclusions………………………………………………………….……….........108

5 . Aponeocarzinostatin – A Superior Drug Carrier Exhibiting Unusually High Endurance against Denaturants

5.1. Introduction…………………………………………………………..….……..…111

5.2. Materials and Methods………………………………………………..……….....114

5.3. Results……………………………………………………………………………..116

5.4. Discussion…………………………………………………………………...…….127

6. Studies of Salt-Induced Inhibition in Neocarzinostatin-Mediated DNA Cleavage

6.1. Introduction……………………………………………………………………….138

6.2. Materials and Methods…………………………………………………………...140

6.3. Results……………………………………………………………………………..150

6.4. Discussion……………………………………………………………………........160

6.5. Conclusion………………………………………………………………………...163


Future Perspectives………………………………………………………………..165

References.…………………………………………………………………………...166

List of Publication………………………………………………………………….194
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