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研究生:黃常宇
研究生(外文):Chang-Yu Huang
論文名稱:白色念珠菌胸腺嘧啶磷酸激酶之探討及發展定量去氧核醣核苷三磷酸的新方法
論文名稱(外文):Insights into thymidylate kinase in Candida albicans and a click reaction-based method in quantitation of deoxynucleoside triphosphates
指導教授:張智芬
指導教授(外文):Zee-Fen Chang
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生化暨分子生物研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2019
畢業學年度:108
語文別:英文
論文頁數:103
中文關鍵詞:白色念珠菌酵母菌胸腺嘧啶磷酸激酶核甘酸抗生素
外文關鍵詞:Candida albicansTMPKdNTP poolgenome integrityanti-fungal drug
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去氧核醣核苷三磷酸 (dNTP)的生合成在細胞中受到嚴密的調控,並且對於去氧核醣核酸 (DNA)的複製與修復是重要的。當細胞中的dNTP的調控不受到控制時,往往伴隨著不正常的生理狀態,尤其是其中的胸腺嘧啶三磷酸(dTTP)。dTTP的生合成是透過新生成(de novo)與回收(salvage)的路徑,形成胸腺嘧啶單磷酸(dTMP)後,再藉由胸腺嘧啶單磷酸激酶(TMPK)磷酸化成胸腺嘧啶雙磷酸(dTDP),最後經由雙核酸激酶(NDPK)形成dTTP。
由於dTTP的生成無論是透過新生成或是再回收的方式都必須透過TMPK調控,TMPK也因此被認為是個有潛力的標靶來治療細菌感染。然而,TMPK抑制劑還尚未應用在治療真菌感染方面。白色念珠菌是主要的院內感染的真菌,在比較了白色念珠菌的TMPK跟人類TMPK的蛋白結構、催化活性、受質專一性等方面的差異性顯示:白色念珠菌的TMPK有一個獨特的環狀結構,而這個結構與它的高酵素活性以及磷酸化去氧尿嘧啶單磷酸(dUMP)的能力有關。在酵母菌中表現白色念珠菌的TMPK相較於表現人類的TMPK會對的5 -氟尿嘧啶 (5-FU)與5 -氟尿嘧啶核苷(5-Fluorouridine, 5-FUrd)較敏感。進一步利用CRISPR編輯技術在白色念珠菌中刪除TMPK該環狀結構的基因序列,不但會嚴重減緩菌株的生長,也會降低對於嘧啶類似物的藥物敏感性。與此發現一致地是,5-FUrd對於致病性以及抗藥性的白色念珠菌皆有毒殺性,可以做為抗真菌藥物的新選項。最後,利用四環黴素的基因抑制系統證明了TMPK在白色念珠菌中是個生長所需的蛋白,能成為研發抗真菌藥物的新標靶。
另外,在本論文研究中,我發展一個新的方法來測量細胞內的dNTP含量。當細胞處於在不正常的生理條件下時,細胞內dNTP的含量並不會維持恆定;許多臨床化療藥物機制是透過影響核苷酸的生合成與基因損傷,因此,測量細胞內dNTP含量可以提供細胞的生長狀況與藥物反應的訊息。以往需要使用放射性同位素及高效液相層析(用紫外線偵測或是搭配質譜偵測)(HPLC-UV or HPLC/MS/MS)來測量細胞內dNTP的含量。這個新方法是利用銅催化疊氮與炔烃環加成反應(CuAAC)將螢光染劑標記在帶有炔烃的新生成DNA上,並用微量盤式分析儀測量螢光數值。使用這個新方法與放射性同位素的方法測細胞內的dNTP可以得到類似的結果,顯示我發展的實驗方法可以取代傳統放射性偵測的方式。而這個方法同時可用96微孔盤增加分析量,用於測量不同藥物處理後,細胞內dNTP量的變化。
Intracellular supplement of deoxyribonucleoside triphosphate (dNTP) is under highly regulated processes and is important for genome integrity. Dysregulation of cellular dNTP level is associated with abnormal physiological conditions, especially thymidine triphosphate (dTTP) pool. The synthesis of dTTP is mediated by both de novo and salvage pathways, by which thymidine monophosphate (dTMP) synthesized. dTMP is further phosphorylated to thymidine diphosphate (dTDP) and dTTP through thymidylate kinase (TMPK) and nucleoside diphosphate kinase (NDPK), respectively.
Being the key enzyme in catalyzing the merged pathway of dTTP synthesis, TMPK is well studied as a drug target in many bacterial infections. However, the activity of TMPK inhibitor on antifungal therapy has not been persuaded. Here, I investigated the differences in protein structures, kinetic properties, and substrate specificity between TMPKs that from Homo sapiens (hTMPK) and Candida albicans (CaTMPK), the major fungal pathogens in healthcare-associated infections, and identified a unique loop in CaTMPK that confers hyperactivity and enables the utilization of deoxyuridine monophosphate (dUMP) over hTMPK. Compared with hTMPK, expression of CaTMPK in S. cerevisiae produces more cytotoxic effect of 5-Fluorouracil (5-FU)/ 5-Fluorouridine (5-FUrd). CRISPR-mediated deletion of this loop in C. albicans significantly reduces the growth rate and the susceptibility to pyrimidine analogues. Furthermore, I found 5-fluorouridine (5-FUrd) as a potential anti-fungal that is toxic to both pathogenic and drug resistance C. albicans. In this end, I demonstrated the essentiality of CaTMPK in C. albicans by using repression system. Thus, CaTMPK is a proved target for antifungal reagents development.
In this thesis, I also developed a new method to quantify cellular dNTP pools. When cells under physiological conditions, the levels of dNTP pools are changed. Many chemotherapy drugs disrupt dNTP/rNTP synthesis and cause genome toxicity. Hence, quantification of cellular dNTP pools can provide information about the condition of cell growth or the response to drug treatments. Both of isotopes-based and HPLC-UV or HPLC/MS/MS methods are current methods for dNTP quantitation. The method I developed is based on copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) click reaction to label alkyne-modified DNA with fluorescent dyes for the detection of fluorescence unit by a ELISA reader. I proved that click method is comparable to current isotope-based method on cellular dNTP quantification, suggesting that the new method could replace the old one. Moreover, I applied the magnetic separation to modify this assay in a 96-well microplate format and successfully quantitated the alteration of cellular dNTP pools in response to different drug treatments.

中文摘要 i
Abstract ii
Table of contents iii
Chapter 1. Overview and rational 1
1-1. Pathogenicity and drug resistance in Candida albicans 2
1-1.1. Candida albicans is the common fungal pathogen in healthcare-associated infection 2
1-1.2. The mechanisms of antifungal drugs 2
1-1.3. Fungal drug resistance 3
1-2. Overview of Thymidylate kinase 5
1-2.1. The role of thymidylate kinase in dTTP synthesis 5
1-2.2. Structures of TMPKs 5
1-2.3. Substrate selectivity of TMPKs 6
1-3. Deoxyribonucleoside triphosphates metabolism, imbalance and cancer 9
1-3.1. Biosynthesis of deoxyribonucleoside triphosphates (dNTPs) 9
1-3.2. dNTP level and genome instability 10
1-4. Current methods for cellular dNTP quantification 11
1-4.1. Enzymatic method 11
1-4.2. High-performance liquid chromatography (HPLC)-based assay and HPLC coupled liquid chromatography–tandem mass spectrometry (LC/MS/MS) 11
Chapter 2. The Ca-loop in thymidylate kinase is critical for growth and contributes to pyrimidine drug sensitivity of Candida albicans 13
Abstract 14
Introduction 15
Materials and methods 17
Results 22
Discussion 27
List of figures 29
Chapter 3. Quantitation of deoxynucleoside triphosphates by combining enzymatic and click reactions 53
Abstract 54
Introduction 55
Results 60
Discussion 64
List of figures 66
Perspective 83
Reference 86
Appendix 96
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