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研究生:羅啟仁
研究生(外文):Chi-Jen Lo
論文名稱:在lovastatin生產菌AspergillusterreusATCC20542醱酵過程中,探討代謝物之生產與菌株增長形態之變化
論文名稱(外文):Metabolite production and morphological changes by a lovastatin-producing fungus Aspergillus terreus ATCC 20542
指導教授:賴龍山賴龍山引用關係
指導教授(外文):Long-Shan T.Lai
學位類別:碩士
校院名稱:朝陽科技大學
系所名稱:生物技術研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:105
中文關鍵詞:Aspergillus terreuslovastatinitaconic acid (IA)形態學溶氧值
外文關鍵詞:lovastatinitaconic acid (IA)morphologydissolved oxygen (DO)Aspergillus terreus
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一般認為,溶氧(dissolved oxygen,簡稱 DO)控制真菌代謝物之生產;本研究利用Aspergillus terreus ATCC 20542在五公升醱酵槽中進行不同時機(0-144 h)的DO控制實驗。實驗結果顯示itaconic acid (IA)與lovastatin之產量均以DO 20%(0 h)為最高產量,而兩者亦均以攪拌控制(200 rpm)為最低。且在各不同時機之控制條件下,IA 與lovastatin之產量均呈類比關係,隱含「IA分子可能僅提供lovastatin合成之某種官能基團」之意。此外,本研究也發現此菌絲的增長型態在醱酵槽中會影響代謝物的生產,IA產量主要與「菌株平均粒徑」有關,而lovastatin產量則以「菌絲顆粒密度」為最重要。
It is generally recognized that the level of DO (dissolved oxygen) controls metabolite production by fungi. Using Aspergillus terreus ATCC20542, a control of DO 20% was applied starting from a different timing (0-144 h) of a 5 L fermentation. The results showed that both of the production of itaconic acid (IA) and lovastatin were optimized under DO 20% (0 h), whereas the both were minimized under 200 rpm. The experimental results implied that IA might play a role or act as a group donor in the lovastatin synthesis by the fungus since both seemed to display a proportional production kinetics. Furthermore, the fungal morphology strongly influenced metabolite production. IA synthesis was closely associated with pellet size distribution; meanwhile, lovastatin production was mainly related to pellet density.
目 錄
中文摘要 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥I
英文摘要 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥II
謝誌 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥III
表 目 錄‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥VIII
圖 目 錄‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥IX

第一章 緒論
1.1前言‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥01
1.2研究目的‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥04

第二章 文獻回顧
2.1真菌醱酵生理‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥06
2.2真菌代謝與產物生產
2.2.1 真菌一次代謝作用 ‥‥‥‥‥‥‥‥‥‥‥09
2.2.2 衣康酸之生產‥‥‥‥‥‥‥‥‥‥‥‥‥12
2.2.3 真菌二次代謝作用 ‥‥‥‥‥‥‥‥‥‥‥14
2.2.4 膽固醇抑制劑原料藥lovastatin之簡介‥‥‥‥19
2.2.5 lovastatin之生物合成‥‥‥‥‥‥‥‥‥‥23
2.2.6 lovastatin之生產 ‥‥‥‥‥‥‥‥‥‥‥‥25
2.3真菌增長型態與變化 ‥‥‥‥‥‥‥‥‥‥‥‥‥29
2.4真菌醱酵技術‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥34
第三章 材料與方法
3.1菌株‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥37
3.2實驗藥品及培養基
3.2.1實驗藥品‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥39
3.2.2菌株培養環境(含培養基)‥‥‥‥‥‥‥‥‥41
3.3實驗儀器設備‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥44
3.4實驗步驟
3.4.1搖瓶實驗‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥47
3.4.2五升醱酵槽操作‥‥‥‥‥‥‥‥‥‥‥48
3.4.3五升醱酵槽之實驗流程‥‥‥‥‥‥‥‥‥50
3.5分析方法
3.5.1 細胞乾重測量(DCW)‥‥‥‥‥‥‥‥51
3.5.2 粒徑分佈(pellet size distribution)之測量‥52
3.5.3 殘糖濃度分析(RSC)‥‥‥‥‥‥‥‥‥‥53
3.5.4 二次代謝產物(lovastatin)之萃取‥‥‥‥‥‥55
3.5.5 共同代謝產物(itaconic acid)之萃取‥‥‥‥56

第四章 結果與討論
4.1 IA之生產與菌株之形態變化‥‥‥‥‥‥‥‥‥‥61
4.2 lovastatin之生產與菌株之形態變化 ‥‥‥‥‥‥63
4.3菌株型態與代謝物最大量之相關性‥‥‥‥‥‥‥66

第五章 結論與建議
5.1結論 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥69
5.2建議 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥71

數據圖表‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥72
參考文獻‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥87

附 錄
一、殘糖濃度之校正曲線‥‥‥‥‥‥‥‥‥‥‥‥93
二、lovastatin濃度之校正曲線 ‥‥‥‥‥‥‥‥‥‥94
三、itaconic acid濃度之校正曲線‥‥‥‥‥‥‥‥‥95
註一:孢子濃度計算‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥96
註二:搖瓶實驗 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥97
註三:五升醱酵槽操作步驟‥‥‥‥‥‥‥‥‥‥‥98
註四:pH sensor之校正‥‥‥‥‥‥‥‥‥‥‥‥‥102
註五:DO sensor之校正 ‥‥‥‥‥‥‥‥‥‥‥‥‥103
註六:lovastatin形式 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥104

表目錄
表3.1實驗藥品 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥39
表3.2儀器設備 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥44
表一、不同時機(0-144h)啟動最適溶氧(DO 20%)之代謝物產量的影響‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥72
表二、針對搖瓶(200 rpm)或醱酵槽(200 rpm、DO 20% at 0 h、DO 20% at 144 h)作用二天後對於菌絲顆粒密度、平均粒徑、細胞乾重、IA產量之比較 ‥‥‥‥‥73
表三、針對搖瓶(200 rpm)或醱酵槽(200 rpm、DO 20% at 0 h、DO 20% at 144 h)作用十天後對於菌絲顆粒密度、平均粒徑、細胞乾重、IA產量之比較‥‥‥‥‥74

圖目錄
圖2.1紅麴色素的結構圖‥‥‥‥‥‥‥‥‥‥‥‥‥15
圖2.2 Monacolins相關化合物之構造‥‥‥‥‥‥‥‥16
圖2.3 HMG-CoA 的還原反應‥‥‥‥‥‥‥‥‥‥‥20
圖2.4 Monacolin K的結構 ‥‥‥‥‥‥‥‥‥‥‥‥‥21
圖3.1 Aspergillus terreus的菌絲形態‥‥‥‥‥‥‥‥38
圖一、在5升醱酵槽操作中,攪拌轉速與溶氧控制之關係圖 (a) 溶氧DO 20%之轉速變化 (b) 對照組(200rpm)之溶氧變化趨勢‥‥‥‥‥‥‥‥‥‥75
圖二、在以不同時機( 0-144 h)啟動最適溶氧條件(DO 20%)之(a) IA (b) lovastatin (c) DCW (d) pH (e) RSC趨勢變化圖‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥77
圖三、在搖瓶200 rpm試驗中,觀察真菌A. terreuss菌株增長形態之影響‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥79
圖四、在五升醱酵槽以200 rpm試驗中,觀察真菌A. terreuss菌株增長形態之影響 ‥‥‥‥‥‥‥‥‥‥‥‥81
圖五、在五升醱酵槽試驗中DO 20%在第0天啟動,觀察真菌A. terreuss菌株增長形態之影響 ‥‥‥‥‥83
圖六、在五升醱酵槽試驗中DO 20%在第6天啟動,觀察真菌A. terreuss菌株增長形態之影響‥‥‥‥‥85
圖七、A. terreuss醱酵生產IA之最高產量與最低產量菌絲型態相比 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥86
圖八、A. terreuss醱酵生產lovastatin之最高產量與最低產量菌絲型態相比 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥86
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