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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 詹迺立(Nei-Li Chan) | |
dc.contributor.author | Wei-Chen Kuo | en |
dc.contributor.author | 郭韋辰 | zh_TW |
dc.date.accessioned | 2021-05-16T16:29:06Z | - |
dc.date.available | 2015-09-24 | |
dc.date.available | 2021-05-16T16:29:06Z | - |
dc.date.copyright | 2013-09-24 | |
dc.date.issued | 2013 | |
dc.date.submitted | 2013-08-19 | |
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(2003) 'Structures of human thymidylate kinase in complex with prodrugs: implications for the structure-based design of novel compounds.' Biochemistry 42: 2568-2577. 30. Haouz, A., Vanheusden, V., Munier-Lehmann, H., Froeyen, M., Herdewijn, P., Van Calenbergh, S. & Delarue, M. (2003) 'Enzymatic and structural analysis of inhibitors designed against Mycobacterium tuberculosis thymidylate kinase. New insights into the phosphoryl transfer mechanism.' J. Biol. Chem. 278: 4963-4971. 31. Munier-Lehmann, H., Chaffotte, A., Pochet, S. & Labesse, G. (2001) 'Thymidylate kinase of Mycobacterium tuberculosis: a chimera sharing properties common to eukaryotic and bacterial enzymes.' Protein Sci. 10: 1195-1205. 32. Garg, D., Henrich, S., Salo-Ahen, O. M., Myllykallio, H., Costi, M. P. & Wade, R. C. (2010) 'Novel approaches for targeting thymidylate synthase to overcome the resistance and toxicity of anticancer drugs.' J. Med. Chem. 53: 6539-6549. 33. Longley, D. B., Harkin, D. P. & Johnston, P. G. 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Z., Chang, C. Y., Lee, M. H., Fang, J. M., Sheu, S. Y., Lin, C. J., Tseng, M. C., Chen, Y. J. & Chang, Z. F. (2012) Tumor cells require thymidylate kinase to prevent dUTP incorporation during DNA repair. Cancer Cell. 22: 36-50. 44. Hu, C. M. & Chang Z. F. (2008) 'Synthetic lethality by lentiviral short hairpin RNA silencing of thymidylate kinase and doxorubicin in colon cancer cells regardless of the p53 status.' Cancer Res. 68: 2831-2840. 45. Niida, H., Katsuno, Y., Sengoku, M., Shimada, M., Yukawa, M., Ikura, M., Ikura, T., Kohno, K., Shima, H., Suzuki, H., Tashiro, S. & Nakanishi, M. (2010) 'Essential role of Tip60-dependent recruitment of ribonucleotide reductase at DNA damage sites in DNA repair during G1 phase.' Genes Dev. 24: 333-338. 46. Traut, T. W. (1994) 'Physiological concentrations of purines and pyrimidines.' Mol. Cell Biochem. 140: 1-22. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/6424 | - |
dc.description.abstract | 在快速分裂的癌細胞中,DNA複製的速度顯著高於正常細胞,使得癌細胞對於DNA的損傷非常敏感,因此DNA修復機制的運作與效率尤為重要。先前研究指出,DNA修復的效率與修復過程所需之dNTPs的濃度高低密切相關。dNTPs的生合成是以核苷酸新合成路徑 (de novo pathway)或是回收路徑 (salvage pathway)所產生的NDPs為原料,再經由ribonucleotide reductase (RNR)催化之還原反應將NDP還原成dNDP,這個步驟在dNTPs的合成扮演關鍵的角色。而大部分的dNDPs包含dADP、dGDP、dCDP和dUDP都可以經由RNR催化NDPs的還原而生成,然而,只有dTDP的合成是經由TMPK (thymidylate kinase)所催化,此酵素以dTMP為其受質,利用ATP做為磷酸根的供給者,藉由對dTMP的磷酸化以合成dTDP,有鑒於hTMPK對於dTTP合成不可或缺的重要性,因此,抑制TMPK或許可作為治療癌症的手段之一 。
目前許多化療藥物仍被廣泛的用於癌症治療,如doxorubicin可以造成DNA雙股斷裂,使癌細胞生長停止或是誘發細胞凋亡。然而這些化療藥物的副作用也不可忽視,病人可能會出現噁心、嘔吐等症狀,亦可能產生心臟毒性。研究發現,當以siRNA技術使癌細胞的TMPK表達下降,會增強doxorubicin的毒殺效果,因此發展針對TMPK的專一性抑制物或許有助於降低doxorubicin的IC50,進而減少不必要的副作用。這個概念在近期使用TMPK抑制物YMU1進行動物實驗後得到進一步的支持:YMU1自身並無顯著的細胞毒性,但與低劑量的doxorubicin合併使用則可以使癌細胞凋亡。因此YMU1應可做為發展抗癌藥物的先導化合物。 為了瞭解YMU1如何與TMPK交互作用並抑制其活性,我們著手TMPK與YMU1複合體的結構解析。首先利用大腸桿菌表現大量的人類TMPK蛋白,並且利用液相層析法純化蛋白,最後再以共結晶的方式培養複合體的晶體,另一方面,我們同樣以共結晶的方式,取得TMPK與dTMP複合體之晶體,之後或許可以將晶體浸泡於含有YMU1的溶液中,取得TMPK與YMU1的複合體晶體。此結構亦可能加深我們對TMPK催化反應機制的認識。 | zh_TW |
dc.description.abstract | In fast-proliferating cancer cells, DNA replication usually occurs at a higher frequency compared to normal cells. Therefore, cancer cells are in general more sensitive to DNA-damaging agents and rely more heavily on the DNA repair mechanisms. Previous studies have established that the efficiency of DNA repair, which involves synthesis of new DNA at the damage site, is tightly linked to the cellular concentration of dNTPs. Several enzymes are known to regulate the level of dNTPs pools by participating in the de novo and salvage pathways. Ribonucleotide reductase (RNR)-mediated reduction reactions play a crucial role in dNTPs biosynthesis by producing dNDPs as precursors. While the majority of dNDPs, including dADP, dGDP, dCDP and dUDP are generated from NDPs by RNR, the synthesis of dTDP is catalyzed by thymidylate kinase (TMPK). Using dTMP as the substrate and ATP as the phosphate donor, TMPK produces dTDP for the subsequent biosynthesis of dTTPs. It has been suggested that the inhibition of TMPK may be exploitable in cancer therapy.
The drug doxorubicin, which is widely used in anticancer chemotherapy, is highly effective in killing cancer cells by inducing DNA double-strand break (DSB). However, patients receiving doxorubicin may develop nausea, vomiting and irreversible myocardial toxicity. Because TMPK knockdown has been shown to sensitize cancer cells toward doxorubicin treatment, thus the use of TMPK inhibitor may suppress the undesired side effects by reducing the IC50 of doxorubicin. This concept is supported by the finding that YMU1, a specific inhibitor of human TMPK with no obvious cytotoxicity, may be used in conjunction with low dose of doxorubicin to induce cancer cell-specific apoptosis. Therefore, it appears that YMU1 is a promising lead compound for drug development. To understand how YMU1 interacts with and inhibits the activity of TMPK, we have initiated structural analysis on the TMPK-YMU1 complex. First, large amount of human TMPK was obtained using the Escherichia coli expression system, and liquid chromatography was performed for protein purification. Co-crystallization of human TMPK with YMU1 has been performed using highly purified protein. As an alternative approach, we have crystallized TMPK in complexes with dTMP. These crystals will be exposed to various soaking buffers that contain YMU1 to produce the inhibitor-bound crystals for structural determination. | en |
dc.description.provenance | Made available in DSpace on 2021-05-16T16:29:06Z (GMT). No. of bitstreams: 1 ntu-102-R00442019-1.pdf: 10686135 bytes, checksum: ff8b536eb107cd08dc81c658e4aaf4f9 (MD5) Previous issue date: 2013 | en |
dc.description.tableofcontents | 目 錄
口試委員會審定書………………………………………………………….i 中文摘要.........................................................................................................ii 英文摘要.........................................................................................................iv 目錄.................................................................................................................vi 圖目錄.............................................................................................................viii 表目錄.............................................................................................................x 一、 前言............................................................................................................1 前言.................................................................................................................1 二、 材料與方法...........................................................................................8 2-1 實驗材料............ ....................................................................................8 2-2 實驗方法.......................................... ........................ .............................8 2-2-1 hTMPK之小量表現測試方法.... ................... ............... ..................8 2-2-2 hTMPK之純化............... .............. ..................... ..............................9 2-2-2-1 hTMPK之大量表現、破菌與萃取.... ..............................................9 2-2-2-2 GSH resin之純化................... ............. .............................................10 2-2-2-3 Thrombin之酵素切割................... ................ ...................................10 2-2-2-4 陰離子交換管柱................... .............. ........................................... 11 2-2-2-5 分子篩膠體過濾管柱................... ...................................................11 2-2-3 hTMPK與YMU1之共結晶........ ........................ .................................11 2-2-4 hTMPK晶體與YMU1之crystal soaking.... ........... ..........................14 2-2-5 hTMPK晶體之X-ray繞射............ .... ......... .... ......... .... ......................14 2-2-5-1 hTMPK晶體之X-ray之資料收集........... ...........................................14 2-2-5-2 hTMPK晶體之結構解析.......... .. .............. .............. ........................15 三、實驗結果........................................ ........................ ................................16 3-1 hTMPK之表現測試................. . ........... . ........... . .................... ..............16 3-2 hTMPK之純化................... ........ ......... ... ...... ...... ...... ...........................16 3-3 hTMPK之結晶................... ............. .......... ........ ........ ........ ...................17 3-4 hTMPK結晶之整體結構解析................... .. ......... ......... .................. ....19 3-5 hTMPK、dUMP、AMPPNP共結晶之結構解析..................................20 3-6 hTMPK、dTMP、AMPPNP共結晶之結構解析..................................21 四、討論................... ................... ............... ........................ ..........................22 4-1 hTMPK之純化.............. ..... ......... ..... ............................................22 4-2 hTMPK之結晶...................... ..........................................................22 4-3 hTMPK與dTMP之結構.............. ....... ................... .....................23 4-4 hTMPK結合dTMP及dUMP之差異.. ....... ................... ............24 4-5 hTMPK與YMU1之交互作用.. ....... ................... ........................25 五、圖........................................ ........................................ ....................................26 六、表........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ....59 七、參考文獻........ ........ ........ ........ ........ ........ ........ ........ ........... ........ ......... ........61 八、附錄…………………………………………………………………………..….67 圖 目 錄 圖1:dNTP pool的新合成路徑(de novo pathway) ..............................................26 圖2:dTTP之合成路徑........................................ ................................................27 圖3:不同物種TMPK之序列分析........................................ .............................28 圖4-1:Doxorubicin之結構........................................ ..........................................29 圖4-2:hTMPK抑制劑YMU1之結構........................................ ........................29 圖5:hTMPK與YMU1之模型模擬結構................................ ............................30 圖6:結晶條件之微調........................................ ...................................................31 圖7:利用crystal soaking製備hTMPK與YMU1複合體晶體之方法..............32 圖8:GST-hTMPK融合蛋白之小量表現............................. ................................33 圖9:hTMPK之GSH純化、thrombin酵素切割及陰離子管柱純化.................34 圖10:hTMPK之分子篩膠體過濾管柱之純化........ ........ ........ ........ ............. ..35 圖11:hTMPK之穩定性........ ........ ........ ........ ........ ........ ........ ........ .............. ..36 圖12:hTMPK與YMU1及dTMP條件下結晶出之晶體........ ........ .............. ...37 圖13:hTMPK、AMPPNP、dTMP與MnCl2之條件所結晶出之蛋白晶體……38 圖14:hTMPK與dTMP之條件所結晶出之蛋白晶體........ ........ ............ ...........41 圖15:hTMPK、AMPPNP、dUMP與MgCl2之條件所結晶出之蛋白晶體…...42 圖16:hTMPK、AMPPNP與MgCl2之條件所結晶出之蛋白晶體........ ........... .43 圖17:hTMPK、AMPPNP與MgCl2條件的微調……………………………..…44 圖18:hTMPK、AMPPNP與MgCl2之條件微調長出之晶體…………………...45 圖19:hTMPK、AMPPNP、dTMP與MnCl2 條件之晶體,以X-ray繞射實驗檢測是否為蛋白晶體........ ........ ........ ........ ........ ........ ........ ........ ........ ........ …….......46 圖20:TMPK、AMPPNP、dTMP與MnCl2 soaking out AMPPNP,16小時後….47 圖21:Crystal soaking的實驗並無法完全去除AMPPNP........ ........ ........ ..............48 圖22:不同條件hTMPK之整體蛋白結構........ ........ ........ ........ ........ ..... ........49 圖23:hTMPK、AMPPNP、dTMP與MnCl2之結構........ ........ ........ ........ ......50 圖24:hTMPK、AMPPNP、dUMP與MgCl2之結構........ ........ ........ ........ ......51 圖25-1:老鼠TMPK同樣可以dUMP為受質催化反應........ ........ ........ ...... ....52 圖25-2:酵母菌TMPK同樣可以dUMP為受質催化反應........ ........ ................52 圖26:dTMP中thymidine之C5的甲基與hTMPK之間的交互作用........ ........53 圖27:hTMPK與dTMP結構中P-loop的結構改變........ ........ ........ ........ ........54 圖28:hTMPK與dTMP之表面結構比較........ ........ ........ ........ ........ ........ .......55 圖29:hTMPK與酵母菌TMPK之dTMP複合體的交互作用比較........ ........ ..56 圖30:AMPPNP與hTMPK之交互作用........ ........ ........ ........ ........ ........ ..........57 圖31:hTMPK與酵母菌TMPK中F105與Y102之差異........ ........ ........ ........58 表 目 錄 表1:hTMPK表面電性之預測........ ........ ........ ........ ........ ........ ........ ........ ........59 表2:hTMPK之受質藥品配製........ ........ ........ ........ ........ ........ ........ ........ ........59 表3:hTMPK與dTMP複合體、hTMPK與dTMP及AMPPNP複合體、hTMPK與dUMP及AMPPNP複合體之資訊………………………………………….…..60 | |
dc.language.iso | zh-TW | |
dc.title | 人類胸腺嘧啶核酸激酶與抑制物YMU1之複合體結構解析 | zh_TW |
dc.title | Structural Analysis of Human Thymidylate Kinase in Complex with Inhibitor YMU1 | en |
dc.type | Thesis | |
dc.date.schoolyear | 101-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 徐駿森,冀宏源 | |
dc.subject.keyword | 癌細胞,DNA修復,dTTP合成,人類胸腺嘧啶核酸激酶,(TMPK),doxorubicin,YMU1, | zh_TW |
dc.subject.keyword | cancer cells,DNA repair,dTTP synthesis,thymidylate kinase (TMPK),doxorubicin,YMU1, | en |
dc.relation.page | 67 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2013-08-19 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
顯示於系所單位: | 生物化學暨分子生物學科研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
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ntu-102-1.pdf | 10.44 MB | Adobe PDF | 檢視/開啟 |
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