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研究生:蔡志晃
研究生(外文):Chih-Huang Tsai
論文名稱:以Pichiapastoris表現系統進行RhodosporidiumtoruloidesD型胺基酸氧化酵素之異源表現研究
論文名稱(外文):HETEROLOGOUS EXPRESSION OF D-AMINO ACID OXIDASE cDNA GENE FROM RHODOSPORIDIUM TORULOIDES IN PICHIA PASTORIS
指導教授:官宜靜
指導教授(外文):I-Ching Kuan
學位類別:碩士
校院名稱:大同大學
系所名稱:生物工程研究所
學門:工程學門
學類:生醫工程學類
論文種類:學術論文
論文出版年:2003
畢業學年度:91
語文別:中文
論文頁數:86
中文關鍵詞:D型胺基酸氧化酵素異源表現
外文關鍵詞:Pichia pastorisheterologous expressionD-amino acid oxidase
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D-amino acid oxidase (DAO, EC1.4.3.3)為製造頭孢菌素類抗生素(cephalosporins)之先驅物7-aminocephalosporanic acid的重要酵素,深具工業應用價值。 Pichia pastoris為可以代謝甲醇的酵母菌之一,近年已被發展成廣泛使用的真核異源表現系統。
本研究主要探討以P. pastoris表現酵母菌Rhodosporidium toruloides DAO之可行性,並試圖藉由不同培養條件的調整,使DAO表現量與比活性達最佳化,以作為大量生產的參考依據。表現載體─誘導型(inducible) pPIC3.5K和持續型(constitutive) pGAPZA以及表現宿主P. pastoris strain KM71和GS115分別組合應用於異源表現。這其中以P. pastoris strain KM71帶有pGAPZA為表現質體時,所表現的DAO活性較佳;以OD600=0.192為起始酵母菌細胞濃度培養22小時後,可達活性表現高峰約2470 U/L。而以pPIC3.5K為誘導表現載體時,當添加2%甲醇誘導11小時後可達較佳活性約1212 U/L。由pPIC3.5K及pGAPZA重組質體所表現的DAO比活性分別為85及109 U/mg。此外,評比四種破菌方法─震盪(vortexing)、超音波、細胞破碎機及Y-PERTM yeast protein extraction reagent處理的效率,以利後續大量蛋白純化之用。經比較後以Y-PERTM yeast protein extraction reagent處理後效果最佳,可回收最高量之蛋白。
D-amino acid oxidase (DAO, EC1.4.3.3) is a key enzyme for producing 7-aminocephalosporanic acid, the precursor of synthetic cephalosporins. Pichia pastoris is a methylotrophic yeast capable of metabolizing methanol as its sole carbon source. Recently, it has been also develped into an efficent eukaryotic heterologous expression system.
In this study, a DAO cDNA gene from yeast Rhodosporidium toruloides was transformed into P. pastoris for the heterologous expression. To optomize the DAO expression, the expression vector, inducible pPIC3.5K or constitutive pGAPZA in combination with P. pastoris strain KM71 or GS115 as expression host were used. The better DAO expression was obtain from the constitutive KM71 cultures. The DAO activity peak of ~2470 U/L was obtained 22 hours after culturing with an initial yeast concentration of OD600=0.192. The highest DAO activity from inducible KM71 cultures was ~1212 U/L obtained after 11-hour induction by 2% methanol. The specific activities of recombinant DAO from inducible and constitutive cultures were 85 and 109 U/mg, respectively. To maximize the DAO recovery, the efficiency of four cell disruption methods for protein purification was evaluated. The treatment of Y-PERTM yeast protein extraction reagent appeared better than sonication, pressure disruption or vortexing.
誌謝………………………………………………………………………I
中文摘要.………………………………………………………………II
英文摘要………………………………………………………………III
目錄………………………………………………………………………V
圖、表索引 ……………………………………………………………IX
第一章 前言 …………………………………………………………1
1.1 D型胺基酸氧化酵素(DAO) ………………………………………1
1.1.1 DAO之催化反應 …………………………………………………3
1.1.2 頭孢菌素類抗生素(cephalosporins)的生產製備……………4
1.1.3工業應用DAO之來源....…………………………………………6
1.1.4 DAO其他應用...…………………………………………………6
1.2異源表現系統 ………………………………………………………7
1.2.1動物細胞 …………………………………………………………7
1.2.2植物細胞…………………………………………………………11
1.2.3微生物細胞………………………………………………………14
1.3嗜甲醇酵母菌Pichia pastoris …………………………………16
1.3.1嗜甲醇酵母菌P. pastoris應用簡史 …………………………16
1.3.2 P. pastoris利用甲醇的代謝路徑……………………………16
1.3.3酒精氧化酵素啟動子(AOX promoter)…………………………17
1.3.4甘油醛-3-磷酸脫氫酵素啟動子(GAP promoter) ……………18
1.3.5以P. pastoris作為宿主表現外來蛋白質 ……………………18
1.3.6酵母菌之轉化(transformation)………………………………20
1.4論文研究目的………………………………………………………22
第二章 材料與方法 …………………………………………………23
2.1 P. pastoris表現載體與菌種……………………………………23
2.2重組載體的製備……………………………………………………24
2.2.1選殖宿主與其培養基 …………………………………………24
2.2.2 E. coli勝任細胞(competent cell)之製備 ………………24
2.2.3 E. coli轉化作用(transformation) ………………………25
2.2.4少量質體DNA之抽取純化………………………………………25
2.2.5大量質體DNA之抽取純化………………………………………27
2.2.6 DAO基因片斷之製備 …………………………………………28
2.2.7接合作用(ligation) …………………………………………29
2.3 P. pastoris之轉化與帶重組基因菌株的篩選…………………30
2.3.1 P. pastoris之培養及保存 …………………………………30
2.3.2 P. pastoris勝任酵母菌之製備 ……………………………30
2.3.3電穿孔之轉化作用 ……………………………………………31
2.3.4以抗生素篩選具高套數之轉殖菌株 …………………………32
2.4 P. pastoris轉殖株之培養與DAO的誘導表現 …………………32
2.5重組酵母菌之生長檢測……………………………………………33
2.5.1菌體生長濃度測定 ……………………………………………33
2.5.2菌體乾重測定 …………………………………………………33
2.6 P. pastoris重組DAO之純化 ……………………………………34
2.6.1粗酵素液之收集與處理 ………………………………………34
2.6.2 DAO之純化 ……………………………………………………35
2.6.3 DAO活性之測定 ………………………………………………37
2.6.4 DAO之定量 ……………………………………………………37
2.6.5 DAO的電泳分析…………………………………………………38
第三章 結果與討論 …………………………………………………40
3.1誘導型及持續型重組表現質體的構築……………………………40
3.1.1 DAO cDNA基因之擴增 …………………………………………40
3.1.2重組表現質體的構築……………………………………………40
3.2重組酵母菌之轉化與篩選…………………………………………41
3.2.1酵母菌之電穿孔轉化………………………………………41
3.2.2重組酵母菌菌株之篩選……………………………………42
3.3 R. toruloides DAO cDNA基因於P. pastoris之表現…………43
3.3.1誘導型質體之表現…………………………………………44
3.3.2持續型質體之表現…………………………………………45
3.3.3不同破菌方法之比較………………………………………46
3.4 P. pastoris重組DAO之純化 ……………………………………48
第四章 結論 …………………………………………………………51
第五章 參考文獻 ……………………………………………………75
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