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研究生:吳明洲
研究生(外文):Ming-Jo Wu
論文名稱:建構含抗高血壓胜肽之食品級表現載體
論文名稱(外文):Construction of food grade expression vector and expressing antihypertensive peptide
指導教授:蔣啟玲蔣啟玲引用關係
指導教授(外文):Chii-Ling Jeang
學位類別:碩士
校院名稱:國立中興大學
系所名稱:食品科學系
學門:農業科學學門
學類:食品科學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:129
中文關鍵詞:抗高血壓胜肽食品級表現載體
外文關鍵詞:Antihypertensive peptideFood grade expression vector
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本研究係利用遺傳工程技術構築一抗高血壓胜肽之食品級表現載體。首先利用α-澱粉酶(α-amy)為報導基因,此基因來源為Bacillus subtilis DB430,其open reading frame(ORF)為1980 bp,轉譯成659個胺基酸。雙向穿梭質體pHG先以α-amy取代cgt,並利用後者之啟動子進行轉錄作用,命名為pHA。進一步設計α-amy融合trypsin切位及抗高血壓胜肽之核苷酸序列,再將此片段與pHA中之α-amy置換,經定序確定之後將其命名為pHAI。將pHA及pHAI轉形於B. subtilis及Lactobacillus casei中,於轉型株之胞外環境中皆具有α-amy之表現活性,除此之外,比較α-amy及其融合蛋白質之活性,發現並無明顯之差異。
利用nisin免疫基因(nisI)為選擇性標幟,藉以方便質體之篩選與提高質體之穩定性。此選擇性標幟基因之來源為Lactococcus lactis ATCC11454,其ORF為738 bp,轉譯成245個胺基酸,進一步將nisI進行構築並表現於目標食品級表現質體。將pHAI上之四環黴素抗性基因去除,以nisI取代並利用其啟動子來進行轉錄作用,發現此重組質體在B. subtilis中具有抵抗nisin之現象,此重組質體命為pHAINt-。進一步將pHAINt-中之盤尼西林抗性基因與革蘭性陰性菌之複製起啟子去除,藉由α-amy之表現可在含有nisin及澱粉之培養基中篩選出重組質體,將此食品級表現質體命名為pHAINt-a-。另外,B. subtilis/pHAINt-a-之培養液經trypsin剪切後,發現具有抑制ACE之能力。
Genetic engineering was used to construct a food grade expression vector for expressing angiotensin converting enzyme inhibitor (ACEI) in this study. Alpha-amylase gene (α-amy) obtained from Bacillus subtilis DB430 was selected as reporter gene. And a recombinant plasmid pHA was constructed by replacing cgt with α-amy on pHG, which originally made by insertion of cgt to pHY300PLK-a shuttle vector among Escherichia coli, B. subtilis and Lactobacillus casei. Then a DNA fragment containing partial α-amy and nucleotide sequence corresponding trypsin cutting site and ACEI peptide was synthesized by overlapping extension PCR. After replacing the DNA fragment to the corresponding location on pHA, a recombinant plasmid pHAI was constructed. Transformants of B. subtilis and Lb. casei harboring both pHA and pHAI showed amylase activity.
Furthermore, nisin immunity gene (nisI) from Lactococcus lactis ATCC11454 was chosed and cloned as selection marker for screening and increasing stability of transformant. The open reading frame of nisI gene contained 738 bp and was deduced to a polypeptide of 245 amino acid residues. A plasmid pHAINt- was built by replacing tetracycline resistant gene with nisI. Finally, the ampicillin resistant gene and gram negative replicon was removed from pHAINt-, and a food grade plasmid pHAINt-a- was made. The transformant B. subtilis/ pHAINt-a- expresses α-amy phenotype and functionally resists to nisin. And the trypsin treated culture medium of this transformant showed ACEI activity.
中文摘要----------------------------------------------------------------------- I
英文摘要---------------------------------------------------------------------- II
目錄------------------------------------------------------------------------- III
圖目錄-------------------------------------------------------------------- VII
表目錄-----------------------------------------------------------------------IX
縮寫表----------------------------------------------------------------------X
壹、 前言-------------------------------------------------------------------- 1
一、 高血壓症之簡介---------------------------------------------------- 1
(一) 高血壓成因------------------------------------------------------- 1
(二) 血管收縮素轉換酶(ACE)---------------------------------------1
(三) 血管收縮素轉換酶抑制劑(ACEI)---------------------------- 4
二、 基因改造食品------------------------------------------------------- 4
(一) 定義---------------------------------------------------------------- 4
(二) 載體系統構築技術-----------------------------------------------6
(三) 安全性評估-------------------------------------------------------10
三、 食品級選殖系統----------------------------------------------------12
(一) 簡介----------------------------------------------------------------12
(二) 種類----------------------------------------------------------------12
四、 乳酸菌----------------------------------------------------------------14
(一) 乳酸菌之簡介----------------------------------------------------14
(二) 載體開發----------------------------------------------------------15
(三) 異源蛋白質在乳酸菌中之表現-------------------------------17
五、 枯草桿菌-------------------------------------------------------------19
(一) 枯草桿菌之簡介-------------------------------------------------19
(二) 載體開發----------------------------------------------------------19
(三) 異源蛋白質在枯草桿菌中之表現----------------------------24
六、 α-澱粉酶------------------------------------------------------------25
(一) 性質----------------------------------------------------------------25
(二) 在遺傳工程上之應用-------------------------------------------25
七、 Nisin------------------------------------------------------------------27
(一) 簡介----------------------------------------------------------------27
(二) 結構----------------------------------------------------------------27
(三) 組成之基因-------------------------------------------------------27
(四) 種類及特性-------------------------------------------------------31
(五) 抑菌機制----------------------------------------------------------31
八、 Nisin免疫基因-----------------------------------------------------37
(一) 簡介----------------------------------------------------------------37
(二) 功能----------------------------------------------------------------37
九、 研究動機及目的----------------------------------------------------40
貳、 實驗材料及藥品--------------------------------------------------------41
一、 菌株及質體----------------------------------------------------------41
二、 藥品-------------------------------------------------------------------41
三、 貴重儀器及設備----------------------------------------------------41
參、 實驗方法-----------------------------------------------------------------44
一、 遺傳工程常用之技術----------------------------------------------44
(一) 勝任細胞製作及質體轉形-------------------------------------44
(二) 質體DNA之抽取-----------------------------------------------46
(三) 染色體DNA之抽取--------------------------------------------47
(四) DNA片段之回收-------------------------------------------------48
(五) DNA片段之接合-------------------------------------------------49
(六) pGEM-T Easy vector與藍白篩選法---------------------------49
(七) Total RNA之抽取-------------------------------------------------49
(八) 電泳-----------------------------------------------------------------50
(九) 聚合酶鏈鎖反應--------------------------------------------------50
二、 食品級報導基因之選殖--------------------------------------------50
三、 食品級免疫基因之選殖--------------------------------------------52
四、 食品級表現載體之構築--------------------------------------------52
(一) pHA------------------------------------------------------------------52
(二) α-amy融合trypsin切位及ACEI片段之核苷酸序列設計--53
(三) pHAI-----------------------------------------------------------------53
(四) pGEMAI----------------------------------------------------------------53
(五) pHAINt---------------------------------------------------------------53
(六) pHAINt-a-------------------------------------------------------------54
五、 α-澱粉酶之表現------------------------------------------------------54
(一) 澱粉分解法--------------------------------------------------------54
(二) 碘液染色法--------------------------------------------------------54
(三) 不同時期酵素活性測定-----------------------------------------54
(四) 蛋白質活性染色--------------------------------------------------54
六、 Nisin免疫基因之表現 --------------------------------------------55
(一) Nisin敏感菌株之選擇--------------------------------------------55
(二) RT-PCR--------------------------------------------------------------55
(二) 生長曲線之測定--------------------------------------------------56
七、 質體穩定性之測定--------------------------------------------------56
八、 ACE抑制活性測定--------------------------------------------------56
(一) 樣品製備-----------------------------------------------------------56
(二) ACEI活性測定----------------------------------------------------56
(三) ACE抑制能力----------------------------------------------------57
肆、 結果與討論---------------------------------------------------------------58
一、 食品級報導基因之選殖------------------------------------------------58
二、 食品級選擇性標幟基因之選殖---------------------------------------58
三、 食品級表現載體之構築------------------------------------------------73
(一) pHA-----------------------------------------------------------------73
(二) pHAI----------------------------------------------------------------76
(三) pHAINt-------------------------------------------------------------79
(四) pHAINt-a-----------------------------------------------------------79
四、 α-amy之表現-----------------------------------------------------------88
(一) α-amy之表現-----------------------------------------------------88
(二) α-amy融合蛋白質之表現--------------------------------------88
(三) α-amy及α-amy-acei在不同菌株之表現--------------------89
(四) α-amy在B. subtlis不同生長時期中其胞外表現情形----89
(五) α-amy在La. casei不同生長時期中其胞外表現量-------97
五、 nisI在B. subtilis EE1中之表現------------------------------------101
(一) nisin濃度之選擇-------------------------------------------------101
(二) mRNA方面-------------------------------------------------------103
(三) 生長情形之變化------------------------------------------------103
六、 質體穩定性之探討----------------------------------------------------106
七、 ACE抑制活性之測定------------------------------------------------109
伍、 結論----------------------------------------------------------------------111
陸、 參考文獻----------------------------------------------------------------112
附錄------------------------------------------------------------------------------126
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