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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/24774完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 曾木金 | |
| dc.contributor.author | I-Liang Lee | en |
| dc.contributor.author | 李一良 | zh_TW |
| dc.date.accessioned | 2021-06-08T05:56:17Z | - |
| dc.date.copyright | 2008-02-18 | |
| dc.date.issued | 2008 | |
| dc.date.submitted | 2008-01-30 | |
| dc.identifier.citation | Breithaupt H (1976) Enzymatic characteristics of crotalus phospholipase A2 and the crotoxin complex. Toxicon 14(3):221-233.
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Hseu MJ, Yen CY, Tseng CC and Tzeng MC (1997) Purification and partial amino acid sequence of a novel protein of the reticulocalbin family. Biochemical and biophysical research communications 239(1):18-22. Jeng TW, Hendon RA and Fraenkel-Conrat H (1978) Search for relationships among the hemolytic, phospholipolytic, and neurotoxic activities of snake venoms. Proceedings of the National Academy of Sciences of the United States of America 75(2):600-604. Jung DH, Mo SH and Kim DH (2006) Calumenin, a multiple EF-hands Ca2+-binding protein, interacts with ryanodine receptor-1 in rabbit skeletal sarcoplasmic reticulum. Biochemical and biophysical research communications 343(1):34-42. Kaletta K, Kunze I, Kunze G and Kock M (1998) The peptide HDEF as a new retention signal is necessary and sufficient to direct proteins to the endoplasmic reticulum. FEBS letters 434(3):377-381. 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Radvanyi F, Saliou B, Bon C and Strong PN (1987) The interaction between the presynaptic phospholipase neurotoxins beta-bungarotoxin and crotoxin and mixed detergent-phosphatidylcholine micelles. A comparison with non-neurotoxic snake venom phospholipases A2. The Journal of biological chemistry 262(19):8966-8974. Radvanyi F, Saliou B, Lembezat MP and Bon C (1989b) Binding of crotoxin, a presynaptic phospholipase A2 neurotoxin, to negatively charged phospholipid vesicles. Journal of neurochemistry 53(4):1252-1260. Radvanyi FR and Bon C (1982) Catalytic activity and reactivity with p-bromophenacyl bromide of the phospholipase subunit of crotoxin. Influence of dimerization and association with the noncatalytic subunit. The Journal of biological chemistry 257(21):12616-12623. Rowan EG (2001) What does beta-bungarotoxin do at the neuromuscular junction? Toxicon 39(1):107-118. Rubsamen K, Breithaupt H and Habermann E (1971) Biochemistry and pharmacology of the crotoxin complex. I. 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Biochimica et biophysica acta 1386(1):121-131. Wajih N, Sane DC, Hutson SM and Wallin R (2004) The inhibitory effect of calumenin on the vitamin K-dependent gamma-carboxylation system. Characterization of the system in normal and warfarin-resistant rats. The Journal of biological chemistry 279(24):25276-25283. Wallin R, Hutson SM, Cain D, Sweatt A and Sane DC (2001) A molecular mechanism for genetic warfarin resistance in the rat. Faseb J 15(13):2542-2544. Yabe D, Nakamura T, Kanazawa N, Tashiro K and Honjo T (1997) Calumenin, a Ca2+-binding protein retained in the endoplasmic reticulum with a novel carboxyl-terminal sequence, HDEF. The Journal of biological chemistry 272(29):18232-18239. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/24774 | - |
| dc.description.abstract | 蛇類經過長年的演化後，有許多的蛇毒蛋白質分子都具有藥效，南美響尾蛇蛇毒的主要成分crotoxin具有強烈的神經毒性，會阻斷周邊運動神經的訊息傳導分子的釋放，造成獵物四肢麻痺、窒息而死亡。Crotoxin乃是由crotoxin A（CA）及crotoxin B（CB）兩個次單元體以非共價鍵所組合而成，CA不帶有生物活性卻能使CB的毒性增加數十倍，所以一般認為CA是要彌補CB缺陷的chaperon。
對於crotoxin的研究從30年代就已經開始，但至今對分子層級的作用機制並不清楚。實驗顯示CA會出現在溶液相中，只有CB會與神經膜上受體結合，此外CA會與神經膜上受體競爭CB的結合，但生理上CB所引發的神經毒性卻大為增加，彼此間存在著矛盾。進一步的分析CA與CB兩者之間比例，發現CA對CB毒性的增強呈現兩相性之變化，CA隨著比例的增加到CA：CB為1：1時，會逐漸增強CB的生理毒性，但再增加濃度，反而會造成CB的毒性開始慢慢的降低。另外，在對crotoxin的專一性結合蛋白質crocalbin的研究中，意外的發現crocalbin也可以增加CB的毒性。這些實驗在在的顯示出crotoxin與受體的結合反應十分特殊。 在建立crotoxin與神經受體的結合模型的各種參數資料後，輪廓漸漸清晰。CA可視為CB之結合蛋白，類似受體分子。在神經膜以外的位置中，CA和非專一性受體互相競爭CB分子，但由於CA對於CB的結合能力遠大於非專一性受體，所以抑制非專一性的反應；當分子擴散到神經膜上，由於CA和專一性受體對於CB的結合能力接近，CB轉而與專一性受體結合。淨結果則是CA加速了CB在神經膜以外區域的擴散，抵達神經膜後CA的位置會由專一性受體所取代，而發揮生理之毒性。從分子模型觀之，CA其實是CB分子的高溶解性受體，協助CB到達作用位置，將其命名為semi-receptor，這種利用semi-receptor協助CB除去非專一性結合而達成專一性受體結合之機制命名為protective semi-receptor model。從crotoxin的例子來看，semi- receptor不但可以促進藥物在體內的輸送，據此增強藥物的效力，並且抑制了非專一性結合，據此抑制了藥物的副作用，所以semi-receptor可說是攜帶藥物的特殊模式。 | zh_TW |
| dc.description.abstract | Crotoxin from the South American rattlesnake Crotalus durissus terrificus is a potent presynaptic toxin composed of two subunits: component A and component B. Component B exhibits phospholipase A2 activity and is weakly toxic by itself, whereas no activity has been found to be associated with component A alone. In the present study, we found that component A modulates the neurotoxic effect of component B with a biphasic dose-response curve. In contrast, the phospholipase A2 activity of component B is inhibited monotonically by increasing doses of component A (IC50 ~ 115 pM). In order to resolve the seemingly contradictory observations, we propose a protective semi-receptor model, in which component A acts as a soluble, protective semi-receptor to illuminate the modulatory effect of component A on the interactions of component B with bio-membranes. This model can also account for some other data in the literature. We have also determined the equilibrium dissociation constant Kd for crotoxin subunits to be ~130 pM. Using this value and the semi-receptor model, we unambiguously measured the Kd for the binding of component B to its high-affinity receptor in the neuronal membrane to be ~1.8 nM. The present system represents the first with such a mode of action to be mathematic examination in detail. This model may have important implications in more physiological systems and may also promote to design of agents to reduce the side effects of certain pharmaceuticals. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T05:56:17Z (GMT). No. of bitstreams: 0 Previous issue date: 2008 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
中文摘要 iii 英文摘要 v 目錄 vii 圖表目錄 x 英文縮寫字對照表 vi 第一章 導論 1 1.1 磷脂酶酵素 1 1.2 前神經鍵作用之PLA2蛇毒蛋白（SPAN） 3 1.3 SPAN對運動神經的阻斷過程 4 1.4 南美響尾蛇蛇毒蛋白crotoxin的結構與特性 6 1.5 Crocalbin的基因、結構與特性 7 1.6 CREC蛋白質家族 9 1.7 Calumenin與vitamin K cycle 10 第二章 材料和方法 11 2.1 Crotoxin方面 11 2.1.1實驗動物 11 2.1.2層析材料 11 2.1.3 Crotoxin、CA和CB的製備 11 2.1.4 Crotoxin連結體的製備 12 2.1.5 Crotoxin螢光強度的測定 13 2.1.5 磷脂酶活性的測量 14 2.1.6小鼠半致死劑量測定 14 2.1.7小雞二頸肌阻斷測定 15 2.1.9 神經鍵的製備 16 2.1.10 Crotoxin與神經鍵的結合反應 16 2.2 Crocalbin方面 17 2.2.1 一般分生操作 17 2.2.2 大鼠crocalbin的cDNA選殖 18 2.2.3、大鼠之His-tag crocalbin（crocalbin）的表現與純化 18 2.2.4 Far-Western blotting 20 2.2.5 Crocalbin結合蛋白p16的部分純化 20 2.2.6 製備histone 21 2.2.7 製備mononucleosome（nucleosome core particle） 22 2.2.8 Histones與125I-crocalbin的結合反應 23 2.2.9 NCP膠體與125I-crocalbin的結合反應 24 2.2.10 酵母菌相關之操作技術 24 2.2.11 定性pBait 25 2.2.12 用pBait篩選pLibrary 26 第三章 結果 27 3.1 Crotoxin方面 27 3.1.1 製備CA、CB、crotoxin和crotoxin連結體 27 3.1.2 測量crotoxin的螢光變化 28 3.1.3 介面活性劑對CA與CB的結合反應的影響 29 3.1.4 測量CB的PLA2活性 30 3.1.5 測量對小鼠的致死能力 32 3.1.6 測量CB對小雞二頸肌組織的阻斷能力 32 3.1.8 測量crotoxin與SPM的結合反應 33 3.2 Crocalbin方面 34 3.2.1 選殖大鼠crocalbin蛋白的DNA片段 34 3.2.2 表現和純化crocalbin重組蛋白 34 3.2.3 Crocalbin在溶液內的狀態 35 3.2.4 Crocalbin對CB的影響 35 3.2.5 Crocalbin與小鼠脾臟內蛋白質的結合 36 3.2.6 Crocalbin與histones或NCP的結合反應 37 3.2.7 Yeast two-hybrid篩選crocalbin的結合蛋白 37 4.1 Crotoxin方面 39 4.1.1 CB酵素活性之抑制 39 4.1.2 CB的施給方法、效力和效果 40 4.1.3 CB與神經鍵上專一性受體的結合 42 4.1.4 模擬小雞二頸肌的實驗結果 45 4.1.5 CA是一種semi-receptor（drug carrier ） 48 4.2 Crocalbin方面 50 4.2.1 Crocalbin的溶解度與其細胞內外分佈 50 4.2.2 Crocalbin與histone和nucleosome的結合 51 4.2.3 Crocalbin在酵母菌內的表現 53 參考書目 55 | |
| dc.language.iso | zh-TW | |
| dc.subject | 南美響尾蛇毒素 | zh_TW |
| dc.subject | Crotoxin | en |
| dc.title | 南美響尾蛇毒素(Crotoxin)及其結合蛋白質之作用模式 | zh_TW |
| dc.title | Modes of action of crotoxin and of its binding protein crocalbin | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 96-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 陳義雄,高閬仙,果伽蘭,朱善德 | |
| dc.subject.keyword | 南美響尾蛇毒素, | zh_TW |
| dc.subject.keyword | Crotoxin, | en |
| dc.relation.page | 101 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2008-01-31 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科學研究所 | zh_TW |
| 顯示於系所單位： | 生化科學研究所 | |
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