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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 吳金洌(Jen-Leih Wu) | |
dc.contributor.author | Chih-Lu Wu | en |
dc.contributor.author | 吳志律 | zh_TW |
dc.date.accessioned | 2021-05-20T21:56:53Z | - |
dc.date.available | 2013-08-22 | |
dc.date.available | 2021-05-20T21:56:53Z | - |
dc.date.copyright | 2011-08-22 | |
dc.date.issued | 2011 | |
dc.date.submitted | 2011-08-18 | |
dc.identifier.citation | Ahuja, I., de Vos, R.C., Bones, A.M. and Hall, R.D. Plant molecular stress responses face climate change. Trends in Plant Science 15, 664 - 674. 2010.
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Biochemical characterization and cloning of transglutaminases responsible for hemolymph clotting in Penaeus monodon and Marsupenaeus japonicus, Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids 1764, 1167 – 1178. 2006. Yeh, Y.H., Kesavulu, M.M., Li, H.M., Wu, S.Z., Sun, Y.J., Konozy, E.H. and Hsiao, C.D. Dimerization is important for the GTPase activity of chloroplast translocon components atToc33 and psToc159. Journal of Biological Chemistry 282, 13845 - 13853. 2007. Zhao, T.J., Feng, S., Wang, Y.L., Liu, Y., Luo, X.C., Zhou, H.M. and Yan, Y. Impact of intra-subunit domain-domain interactions on creatine kinase activity and stability. FEBS Letters 580, 3835 - 3840. 2006a. Zhao, T.J., Liu, Y., Chen, Z., Yan, Y.B. and Zhou, H.M. The evolution from asparagine or threonine to cysteine in position 146 contributes to generation of a more efficient and stable form of muscle creatine kinase in higher vertebrates. International Journal of Biochemistry and Cell Biology 38, 1614 - 1625. 2006b. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/10766 | - |
dc.description.abstract | 全球氣候變遷是生物所需面對的一個重要課題。在台灣,每年寒流所造成水產養殖上的經濟損失高達數千萬元以上。魚類生物學家基於魚類逆境生理的分子機制研究,發展出各種技術來降低經濟損失。在此必須先了解硬骨魚類為了應付溫度的變化,發展出避免周遭溫度的傷害的各種生理生化機制。
由於鯉魚可以生存在35 到5 °C之間,之前研究發現鯉魚肌肉型肌酸激酶可以在低溫有較佳的活性,為了了解肌肉型肌酸激酶的分子機制,我們取兩種鯉魚肌肉型肌酸激酶(M1-, M3-CK)和兔子的肌肉型肌酸激酶(RM-CK)來作比較。發現在15 °C , pH 7.7以上時,M1-CK可以比M3-CK和RM-CK多3-8倍的活性。而且,M1-CK在pH 8.0時,在15 °C的狀況下具有最高活性,同時M1-CK 的酵素動力學特性KmPCr 和 KmADP,在不同溫度和pH值下,相對穩定。其催化反應的活化能(Ea)也比較低。從圓二色光譜也發現,M1-CK在不同的測試溫度和pH值下也都維持不變。 當我們將RM-CK第268個胺基酸,甘胺酸,用M1-CK同位置的天冬醯胺酸來取代後,RM-CK G286N的變異蛋白在10 °C, pH 8.0的狀況下,活性為野生型RM-CK的2倍。動力學特性上,兩者的Km並沒有太大的差異然而圓二色光譜卻發現,RM-CK G286N在5 °C, pH 8.0的狀況下和鯉魚的M1-CK極為相似。RM-CK G286N結晶的X光繞射圖譜解出其受質結合區域的胺基酸互相靠近,反應中心的胱胺酸283則從ADP的結合部位向外突出。在pH 7.4-8.0之間,用體積較小的dADP當受質的話,RM-CK G268N會有較高的反應活性,類似M1-CK。 接著,我們把RM-CK和M1-CK的第268位置的胺基酸分別突變為天冬胺酸,離胺酸和白胺酸,用以研究這個位置對整個酵素的生物物化特性的影響。其中天冬胺酸和離胺酸變異的肌酸激酶則會有和天冬醯胺酸突變的酵素一樣具有低溫活性,而白胺酸變異的肌酸激酶則沒有。在進行催化反應的緩衝液中加入甘油,可以發現親水性的側鏈有助於穩定酵素低溫下的活性。 綜上所述,我們認為鯉魚M1-CK演化出適應低溫環境的功能,從RM-CK G268N結構分析發現,其反應中心空間縮小為其具有低溫活性的原因,從動力學和疏水性環境的試驗中得知,第268個胺基酸側鏈和水分子的作用會影響酵素的構形,減少該側鏈的疏水性也會同時降低酵素的不穩定性而維持其反應活性。基於這個研究結果,希望可以解開酵素如何在低溫下維持其反應活性的原因。 | zh_TW |
dc.description.abstract | Extreme environmental change is an immediately challenge all over the world. The cold fronts sweeping in the winter, which causes millions of losses in aquaculture, is a severe challenge of Taiwan aquaculture industry. Marine biologists have developed some techniques to minimize the economic loss based on the studies of molecular mechanism of fish in stress. To overcome the change of temperature, physiologically, teleost has developed lots of mechanism to avoid harmful damage of ambient environment. The physiological effects of low temperature have mainly focused on following issues: metabolic compensation, homeoviscous adaptation of biological membranes, and thermal hysteresis.
The common carp could live from 35 to 5 °C. Its muscle-specific creatine kinase (M-CK) could maintain enzymatic activity at temperature around 15 °C. The present studies focus on the three common carp M-CK sub-isoforms (M1-, M2- and M3-CK) which are important in energy homeostasis. Specific activities of the common carp M1-CK were 3 to 8-folds higher than specific activities of M3- and rabbit M-CK at temperatures below 15 °C and pHs above 7.7. KmPCr and KmADP of M1-CK were relatively stable at pHs between 7.1 to 8.0, 25 to 5 °C. Its calculated activation energy of catalysis (Ea) at pH 8.0 was lower than at pH 7.1. Circular dichroism spectroscopy results showed that changes in secondary structures of M1-CK at the pHs and temperatures under studied were much less than in the cases of rabbit muscle-specific creatine kinase (RM-CK) and M3-CK. When glycine 268 in RM-CK was substituted with asparagine 268 as found in carp M1-CK, the RM-CK G286N mutant specific activity at pH 8.0, 10 °C was more than 2-fold higher than the wild-type RM-CK at the same condition. Kinetic studies showed that Km values of the RM-CK G268N mutant were similar to those of the RM-CK, yet circular dichroism spectrum showed that the overall secondary structures of the RM-CK G268N, at pH 8.0, 5 °C, was almost identical to the carp M1-CK enzyme. The X-ray crystal structure of the RM-CK G268N revealed that amino acid residues involved in substrate binding were closer to one another than in the native RM-CK, and the side chain of cysteine 283 in active site of the RM-CK G268N pointed away from the ADP binding site. At pH 7.4-8.0, 35-10 °C, with a smaller substrate, dADP, specific activities of the mutant enzyme were consistently higher than the RM-CK and more similar to the carp M1-CK. Then, to study the changes in physico-biochemical properties caused by residue 268 in RM-CK and M1-CK at low temperature, six more mutants, aspartic acid 268, lysine 268 or leucine 268 of RM-CK and M1-CK were generated. The peptide fragments near the active site were found to be phosphorylated. The specific activity results showed that, as in the case of asparagine 268, the aspartic acid 268 and lysine 268 mutants exhibited higher specific activities at low temperature and at higher pH, but not the leucine 268 mutant. The lower hydrophobicity side chain of residue 268 may help the stability of enzyme in glycerol containing buffer. To sum up, we have found out that, the M1-CK enzyme seems to have evolved to adapt to the synchronized changes in body temperature and intracellular pH of the common carp. The smaller active site of the RM-CK G268N mutant might be one of the reasons for M-CK to improve activity at low temperature. The kinetic results and glycerol influence results indicated that charged side chain of residue 268 of M-CK might cause changes in protein conformation by interacting with water, and decreasing hydrophobicity of M-CK which in turn decreased its instability at low temperature. | en |
dc.description.provenance | Made available in DSpace on 2021-05-20T21:56:53Z (GMT). No. of bitstreams: 1 ntu-100-D91623501-1.pdf: 5238404 bytes, checksum: cbd91681dcd0e60050d7044117cb7022 (MD5) Previous issue date: 2011 | en |
dc.description.tableofcontents | CONTENT
口試委員會審定書 i 誌謝 ii 中文摘要 iii 關鍵字 iv ABSTRACT v KEYWORDS vii ABBREVIATIONS viii CHAPTER 1. LITERATURE REVIEW 1 1.1. GLOBAL CLIMATE CHANGE 1 1.2. FISH THERMO-PHYSIOLOGY UNDER HYPOTHERMIC CONDITION 3 1.2.1. HOMEOVISCOUS ADAPTATION IN BIOLOGICAL MEMBRANE 3 1.2.2. THERMAL HYSTERESIS 4 1.2.3. COMPENSATION OF METABOLISM 4 1.3. CREATINE KINASE 6 1.3.1. ENZYME CHARACTERISTICS 6 1.3.2. ENZYME STRUCTURE 7 1.3.3. THERMODYNAMIC 9 1.3.4. ENZYME STABILITY 9 1.4. AIM OF STUDY 11 CHAPTER 2. MATERIAL AND METHODS 12 2.1. CARP M-CKS ACTIVITY DETERMINATION 12 2.1.1. SAMPLE PREPARATION 12 2.1.2. SPECIFIC ACTIVITY AND THERMAL INACTIVATION ASSAY 12 2.1.3. KINETIC ASSAY AND DATA ANALYSIS 14 2.1.4. CIRCULAR DICHROISM SPECTROSCOPY 15 2.1.5. CALCULATION OF ACTIVE ENERGY (Ea) 15 2.2. COMPARISON OF RM-CK AND M1-CK 17 2.2.1. CONSTRUCTION AND PRODUCTION OF RM-CK MUTANTS 17 2.2.2. SPECIFIC ACTIVITY AND THERMAL INACTIVATION ASSAY 18 2.2.3. KINETIC ASSAY AND DATA ANALYSIS 18 2.2.4 CIRCULAR DICHROISM SPECTROSCOPY 18 2.2.5. CRYSTALLIZATION AND X-RAY DIFFRACTION DATA COLLECTION 18 2.2.6. STRUCTURE DETERMINATION AND REFINEMENT 19 2.2.7. SUBSTRATE SUBSTITUTION 19 2.2.8. CALCULATION OF pKa 20 2.2.9. STATISTICAL ANALYSIS 20 2.3. IDENTIFY THE POSSIBLE ROLE OF RESIDUE 268 OF M-CK 21 2.3.1. CONSTRUCTION OF SITE-DIRECTED MUTAGENESIS OF RM-CK AND M1-CK MUTANTS 21 2.3.2. EXPRESSION AND PURIFICATION OF RM-CK, M1-CK AND MUTANTS PROTEINS 21 2.3.3. MASS SPECTROMETRY ANALYSIS 21 2.3.4. CIRCULAR DICHROISM 23 2.3.5. SPECIFIC ACTIVITY ASSAY 23 2.3.6. KINETIC ASSAY AND DATA ANALYSIS 23 2.5.7. HYDROPHOBICITY INDEX 23 2.3.8. PROTEIN MODELING 24 2.3.9 STATISTICAL ANALYSIS 24 CHAPTER 3. RESULTS 25 3.1. THE CARP M1 MUSCLE-SPECIFIC CREATINE KINASE SUBISOFORM IS ADAPTIVE TO THE SYNCHRONIZED CHANGES IN BODY TEMPERATURE AND INTRACELLULAR PH THAT OCCUR IN THE COMMON CARP 25 3.1.1. M1-CK WAS MORE ACTIVE AT AND BELOW 30 °C THAN RM-, M2-, AND M3-CK 25 3.1.2. KmPCr AND KmADP OF M1-CK CHANGED LITTLE AT DIFFERENT TEMPERATURES 26 3.1.3. SPECIFICITY CONSTANT (kcat/Km) AND ACTIVATION ENERGY OF CATALYSIS (Ea) OF RM-, M1-, AND M3-CK 27 3.1.4. THERMAL STABILITY OF THE THREE M-CKS AND MONITORING OF THEIR SECONDARY STRUCTURE CONTENT WITH CD SPECTROSCOPY 28 3.2. ACTIVITY OF RABBIT MUSCLE-SPECIFIC CREATINE KINASE AT LOW TEMPERATURE BY MUTATION AT GLYCINE 268 TO ASPARAGINE 268 30 3.2.1. SECONDARY STRUCTURE ANALYSIS OF RM-CK AND ITS MUTANTS 30 3.2.2. SPECIFIC ACTIVITIES OF M-CKs AT DIFFERENT CONDITIONS 30 3.2.3. KINETIC ANALYSIS OF RM-CK AND ITS MUTANTS 32 3.2.4. THE CRYSTAL STRUCTURE OF RM-CK G268N 33 3.2.5. SUBSTRATE SUBSTITUTION OF CKs 34 3.3. ACTIVITY OF MUSCLE FORM CREATINE KINASE AT LOW TEMPERATURE MAY DEPEND ON HYDROPHILICITY OF SIDE CHAIN OF RESIDUE 268 35 3.3.1. MONOPHOSPHORYLATED ENZYMES WERE DETECTED... 35 3.3.2. RESIDUE 268 OF M1-CK AND ITS MUTANTS WITH HYDROPHILIC SIDE CHAIN MAINTAINED BETTER SECONDARY STRUCTURE CONFORMATION AT 15 °C 35 3.3.3. POLAR SIDE CHAINS OF RESIDUE 268 OF M-CK MAINTAIN ACTIVITY AT LOW TEMPERATURE 36 3.3.4. RM-CK G268D AND M1-CK N268D WERE DIFFERENT FROM THE OTHER ENZYMES IN KINETIC PARAMETERS. 37 3.3.5. POLAR SIDE CHAIN OF RESIDUE 268 MODIFIED THE SOLVENT ACCESSIBLE SURFACE OF ENZYME TO DECREASE THE DISTANCE BETWEEN SUBSTRATES IN ACTIVE SITE 38 CHAPTER 4. DISCUSSION 40 4.1. “CARP M1-CK”, AN ENZYME FOR ALL SEASONS 40 4.2. ONE RESIDUE CHANGE EXTENDS CK ACTIVITY TEMPERATURE RANGE 43 4.3. COLD ACTIVATED FUNCTION OF M-CK RESIDUE 268 47 CHAPTER 5. CONCLUSION 49 REFERENCE 51 FIGURES CONTENT 70 Figure 1. Sequences alignment of human, rabbit and carp M-CKs. 72 Figure 2. Molecular modeling of RM-CK.. 74 Figure 3. Specific activities of RM-, M1-, M2- and M3-CK at different temperatures and pHs. 77 Figure 4. Km of RM-, M1-, and M3-CK at different temperatures and pHs. 78 Figure 5. Thermal inactivation curve of RM-, M1-, and M3-CK. 79 Figure 6. Spectra of far-UV CD spectroscopy of RM-, M1-, and M3-CK at different pHs and temperatures. 80 Figure 7. The peptide sequence alignment of RM-CK and carp M1-CK nearby the active site and the CD spectra of RM-CK and RM-CK G268N. 82 Figure 8. The specific activities of RM-CK mutants. 83 Figure 9. Specific activities and thermal inactivation curves of RM-CK, RM-CK G268N, M1-CK and M1-CK N268G at different pH and temperature…. 84 Figure 10. Thermal inactivation curves of RM-CK, RM-CK G268N, M1-CK and M1-CK N268G at different pH. 85 Figure 11. The kcat/KmPcr and kcat/KmADP of RM-CK mutants. 86 Figure 12. Kinetic analyses of RM-CK, RM-CK G268N, M1-CK and M1-CK N268G at different pH and temperature. 87 Figure 13. Crystal structures of RM-CK (2crk) and RM-CK G268N and fine structures of the active sites. 88 Figure 14. Specific activities RM-CK, M1-CK and RM-CK G268N with dADP substituting ADP as substrate. 90 Figure 15. The mass spectra of RM-CK and M1-CK mutants of residue 268. 91 Figure 16. The CD spectra of RM-CK, M1-CK and mutants at different temperature and pH. 92 Figure 17. The specific activity of RM-CK, M1-CK and mutants. 94 Figure 18. The kinetic data of RM-CK, M1-CK and mutants. 95 Figure 19. The solvent accessible surface of RM-CK and RM-CK G268N. 96 Figure 20. The simulated hydrophobicity of different M-CKs. 98 Figure 21. Cartoons of RM-CK and RM-CK G268N active sites at low temperature and pH above 7.7. 99 Figure 22. The atom positions of cysteine 283, serine 285 and Cr amine group of RM-CK and RM-CK G268N, and pKa values of RM-CK, M1-CK and their mutants derived from kinetic results. 100 TABLES CONTENT 102 Table 1. The primer pairs of site directed mutagenesis of RM-CK and M1-CK residue 268. 103 Table 2. Biochemical kinetic values of RM-, M1-, and M3-CK at different temperatures and pHs. 104 Table 3. The kinetic data of RM-CK, RM-CK mutants and carp M1-CK show the similar pattern in different pHs. 105 Table 4. Crystallographic analysis of RM-CK G268N. 106 Table 5. Distances between residues surrounding the active site of RM-CK and RM-CK G268N. 107 Table 6. The raw data of specific activity of RM-CK, RM-CK A267H, G268N, P270G and M1-CK. 108 Table 7. The kinetic data of dADP substitution demonstrate the effective catalytic ability of RM-CK, RM-CK A267H, G268N, P270G and M1-CK. 109 Table 8. The prediction m/z and observation results of RM-CK and M1-CK residue 268 mutants. 110 Table 9. The distance of C | |
dc.language.iso | en | |
dc.title | 低溫下鯉魚肌肉型肌酸激酶之生化及結構研究 | zh_TW |
dc.title | Biochemical and Structural studies on the Muscle- Specific Creatine Kinase of the Common Carp (Cyprinus carpio) at Low Temperature | en |
dc.type | Thesis | |
dc.date.schoolyear | 99-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 潘子明(Tzu-Ming Pan),黃銓珍(Chang-Jen Huang),蕭傳鐙(Chwan-Deng Hsiao),許祖法(Cho-Fat Hui),林正輝(Cheng-Hui Lin),孫熙文(Hsi-Wen Sun) | |
dc.subject.keyword | 低溫耐受性,肌酸激酶,酵素活性,X光繞射晶體學,疏水性, | zh_TW |
dc.subject.keyword | Cold tolerance,Creatine kinase,Enzyme activity,X-ray crystallography,Hydrophobicity, | en |
dc.relation.page | 112 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2011-08-18 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 生化科技學系 | zh_TW |
顯示於系所單位: | 生化科技學系 |
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