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標題: 影響人類抗酶與鳥胺酸脫羧酶結合的重要因子
Determination the essential binding residues on human antizyme toward ornithine decarboxylase
作者: 王喻萱
Wang, Yu-Hsuan
關鍵字: antizyme
ornithine decarboxylase
出版社: 生命科學系所
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摘要: 鳥胺酸脫羧酶 (ornithine decarboxylase, ODC; EC 在活化狀態下形成雙聚體,需要輔酶5-磷酸吡哆醛 (pyridoxal 5’-phosphate, PLP) 及不同單體上的胺基酸共同參與,催化鳥胺酸 (ornithine) 生成腐胺 (putrescine),為多胺 (polyamine) 生合成的速率決定步驟。多胺為帶正電的有機分子,藉由調控遺傳物質或蛋白質參與細胞週期、細胞凋亡、蛋白質合成及細胞增生和癌化轉形等過程。多胺影響基因表現的一個例子為抗酶 (antizyme, AZ) 的合成:當多胺濃度過高時,會發生+1片段位移 (frameshift) 轉譯出具功能的全長蛋白,可調控鳥胺酸脫羧酶被26S蛋白酶體 (proteasome) 降解。抗酶會和鳥胺酸脫羧酶結合形成異源雙聚體而抑制它的酵素活性,此外也透過減少多胺的吸收降低多胺濃度,形成負回饋調節機制以維持恆定。抗酶與鳥胺酸脫羧酶的結合區主要為C端片段,針對帶電之側鏈進行定點突變 (site-directed mutagenesis),搭配鳥胺酸脫羧酶的活性抑制分析,找到K153、E164、E165及H171是影響抗酶抑制酵素活性的重要位置。抗酶可透過與鳥胺酸脫羧酶結合改變其四級結構,由活化狀態下的同源雙聚體轉變為異源雙聚體 (AZ-ODC heterodimer);計算解離常數 (dissociation constant, Kd) 的結果顯示突變型抗酶與鳥胺酸脫羧酶結合之親和力較野生型抗酶差。經由探討兩者間交互作用關鍵的影響因素,對於設計有效性的胜肽型抗癌藥物,使用在鳥胺酸脫羧酶與多胺代謝相關的癌症治療上提供了參考資訊。
Ornithine decarboxylase (ODC) catalyzes the first and rate-limiting step in polyamine biosynthesis. The enzyme catalyzes the decarboxylation of ornithine to putrescine. Dimeric ODC is a pyridoxal phosphate (PLP)-dependent enzyme. Two active sites are located in the dimer interface, with both monomers provide the essential residues. Polyamines (putrescine, spermidine and spermine) are small organic cations involved in many cellular processes include cell cycle, apoptosis, protein synthesis, cell proliferation and neoplastic transformation by interact with DNA or RNA. An example of polyamine induced gene expression is the formation of antizyme (AZ). High levels of polyamines stimulate ribosomal +1 frameshift, therefore encode the functional full length of AZ protein. AZ interacts with ODC forming an AZ-ODC heterodimer, inhibits its enzyme activity and also targets the ubiquitin-independent degradation of ODC by 26S proteasome. In additional, AZ negatively regulates polyamine transport. These will form a feedback control to keep cellular polyamine homeostasis. Using site-directed mutagenesis, the charged residues were mutated to alanine on the major binding region of AZ toward ODC. Enzyme activity inhibition assay showed that K153, E164, E165 and H171 are critical residues. According to dissociation constant (Kd) of AZ toward ODC, the values of AZ mutants were higher than WT, supporting that the four residues on AZ binding site play a predominant role for interacting with ODC. These data will be helpful in designing a functional peptide as antineuoplatic drug in ODC and polyamine-related cancer.
其他識別: U0005-1908201113251600
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