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研究生:張宜叡
研究生(外文):Yi-Ruei Chang
論文名稱:斑馬魚中亞精胺/精胺 N1-乙醯基轉移酵素之結構與功能分析:受質辨認機制探討
論文名稱(外文):Structure and functional analysis of zebrafish spermidine/spermine N1-acetyltransferase: insight into the substrate recognition
指導教授:徐駿森
指導教授(外文):Chun-Hua Hsu
口試委員:詹迺立林翰佳
口試委員(外文):Nei-Li ChanHan-Jia Lin
口試日期:2013-07-08
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:農業化學研究所
學門:農業科學學門
學類:農業化學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:中文
論文頁數:126
中文關鍵詞:精胺亞精胺腐胺亞精胺/精胺 N1-乙醯基轉移酵素蛋白質結晶學恆溫滴定微量熱儀
外文關鍵詞:Sperminespermidineputrescinespermidine/spermine N1-acetyltransferaseprotein crystallographycrystal structure
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多胺 (Polyamines, PA) 是一類擁有兩個或多個一級胺基的有機化合物,如腐胺 (Putrescine)、亞精胺 (Spermidine) 和精胺 (Spermine),廣泛地存在於各物種並對於細胞的生存扮演非常重要的角色,因此 PA 在細胞中必須維持動態平衡,而亞精胺/精胺 N1-乙醯基轉移酵素 (Spermidine/spermine N1-acetyltransferase, Ssat) 則為合成和代謝途徑調控的關鍵酵素。在斑馬魚中有三種 zSsat1s (1a、1b、1c) 和兩種 zSsat2s (2a、2b),並有著不同的受質選擇性。因此我們希望藉由比較酵素結構的差異,進而闡述其不同受質的分子辨識模式。經表現純化此五種 zSsats 的重組蛋白,藉由酵素活性實驗與恆溫滴定微量熱儀的量測,比較出酵素對於不同受質之選擇性,利用蛋白質晶體學獲得 zSsat1a 的晶體且收集到 2.61A 之解析度,經由結構上的觀察與比較,發現了數個可能影響受質選擇性的熱點 (hotspot)。此外,zSsat 在細胞內以同源雙聚體存在,而這些不同的異構體亦會形成異源雙聚體,並發揮有別於同源雙聚體的活性。為證實此推論,我們將兩種 zSsat2 (2a、2b) 混合後測酵素活性,意外發現對原本非受質的 putrescine 產生催化。為模擬異源雙聚體所形成之受質結合區域,於是將兩種異構基因的 N 端和 C 端做嵌合互換後,發現其中一種 zSsat2b2a chimera 對 putrescine 也有活性,此酵素也已被獲得晶體並收集到 2.65A 之解析度,配合酵素活性與 ITC 實驗,發現 zSsat2b2a chimera 在受質辨識的熱點 (hotspot) 與 CoA 的結合位置皆有所不同,因此我們認為酵素可以藉由形成異源雙聚體而產生新的受質辨識區域。

Polyamines (PAs) are organic compound with two of more primary amino groups (such as putrescine, spermidine and spermine), which play vital roles of cells and widely found in the all kinds of species. Spermidine/spermine N1-acetyltransferase (Ssat) is a key enzyme, which maintains PA homeostasis. However, there exist three zSsat1s (1a, 1b, 1c) and two zSsat2s (2a, 2b) in zebrafish, which possess different specificities to the PAs. In order to understand the substrate recognition, biochemical and structural elucidations of these zSsats were performed. We have expressed five zSsats from the cloned cDNA in E. coli and have determined structure of zSsat1a at resolution of 2.61 Ǻ. Comprehensive ITC and enzymatic assays of zSsats were further investigated. By sequence and structure comparison among the zSsats, a number of hotspots involved in the substrate recognition were found. In addition, we demonstrate by enzymatic assays and ITC that zSsat2a exists as a heterodimer with zSsat2b. Surprisingly, heterodimer exerts novel substrate specificity for putrescine, which is different from homodimers’ preferences. Two chimeras with N- and C-terminus exchange of zSsat2s were then created and named as zSsat2a2b and zSsat2b2a. Functionally, the zSsat2b2a possess the unexpected activity for putrescine. Crystal structure of zSsat2b2a was solved to 2.65 A. Hotspots in zSsat2b2a were different, and changed the specificity of the substrate, providing a new mode of substrate binding.

誌謝 i
中文摘要 ii
Abstract iii
目錄 iv
圖目錄 viii
表目錄 xi
縮寫表 xii
壹、前言 1
一、多胺的功能 1
二、多胺的合成與運輸途徑 2
三、多胺的交互轉換反應 3
四、Spermidine/spermine N1-acetyltransferase (Ssat) 4
五、研究目的 6
貳、實驗材料與方法 7
ㄧ、實驗材料 7
1. 蛋白質表現載體之構築 (construct) 7
2. 菌株及培養系統 7
二、實驗方法 7
1. 轉形作用 (transformation) 7
2. 質體 DNA 之抽取 7
3. DNA 定序與比對 8
4. 胺基酸序列比對 8
5. SDS 蛋白質膠體電泳分析 (Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis, SDS-PAGE) 8
6. 蛋白質之小量表現 9
7. 蛋白質之大量表現 9
8. 蛋白質之純化 10
9. 膠體過濾層析法 (Gel Filtration Chromatography) 10
10. 蛋白質透析與濃縮 11
11. 蛋白質濃度測定 12
12. 酵素活性測試 12
13. 恆溫滴定微量熱儀 (Isothermal Titration Calorimetry, ITC) 13
三、X-ray 晶體繞射技術解析蛋白質結構 15
四、X-ray 晶體繞射實驗方法 16
1. 蛋白質結晶測試 16
2. 蛋白質結晶條件篩選 16
3. 蛋白質晶體形成條件微調 17
4. 適合抗凍劑之篩選 17
5. X-ray 晶體繞射數據收集及處理 (Data collection and processing) 18
6. 晶格中所包含的分子數分析 18
7. 蛋白質晶體結構建立 19
8. 蛋白質結構模型修正 19
9. 蛋白質結構確校 (Ramachandran plot) 20
10. 蛋白質結構模擬 21
參、實驗結果 23
一、zSsats 表現與純化 23
二、利用膠體過濾層析法分析 zSsats 的分子量 23
三、zSsats 酵素活性測試 24
四、zSsats 與受質的結合能力測試 25
五、zSsat1a 蛋白質晶體培養 27
1. zSsat1a 蛋白質晶體培養 27
2. zSsat1a 與產物 CoA 蛋白複合體晶體培養 28
六、zSsat1a 之 X-ray 繞射數據分析與單位晶格判斷 28
七、zSsat1a 晶格中分子數的分析 29
八、zSsat1a 蛋白晶體結構的建立 29
九、zSsat1a 蛋白結構摺疊 29
十、受質辨識結合區域熱點 (hotspot) 30
十一、胺基酸序列比對 31
十二、zSsats 和 mSsat1 結合區域熱點 (hotspot) 的比較 32
十三、同源雙聚體 (homodime) 與異源雙聚體 (heterodimer) 33
十四、zSsat2 chimeras 表現與純化 34
十五、利用膠體過濾層析法分析 zSsat2 chimeras 的分子量 34
十六、zSsat2 chimeras 酵素活性測試 34
十七、zSsat2 chimeras 與受質的結合能力測試 35
十八、zSsat2b2a chimera 蛋白質晶體培養 36
1. zSsat2b2a chimera蛋白晶體培養 36
2. zSsat2b2a chimera 與產物 CoA 蛋白複合體晶體培養 37
十九、zSsat2b2a chimera 之 X-ray 繞射數據分析與單位晶格判斷 37
二十、zSsat2b2a chimera 晶格中分子數的分析 37
二十一、zSsat2b2a chimera 蛋白晶體結構的建立 38
二十二、zSsat2b2a chimera 蛋白結構摺疊 38
二十三、zSsat2 chimeras 和 mSsat1 結合區域熱點 (hotspot) 的比較 39
肆、討論 41
一、zSsat1a、zSsat1b 和 zSsat1c 受質選擇性的差異探討 41
二、zSsat2a 和 zSsat2b 的受質活性探討 43
三、zSsat2b2a chimera 新的受質辨識結合區與活性 43
伍、圖表 46
陸、參考文獻 109
柒、附錄 116


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