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dc.contributorChia-Yin Leeen_US
dc.contributorGwo-Chyuan Shawen_US
dc.contributor.advisorMei-Chin Laien_US
dc.contributor.authorLin, Chih-Chienen_US
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dc.description.abstract許多細菌及少數太古生物生長於營養不平衡的狀態下會將胞內多餘的碳源以聚羥基烷酯(Polyhydroxyalkanoate, PHA)的型式於細胞內累積。PHA具有好的生物相容性與生物降解性,所以在醫學與工業上的應用性。極端高鹽太古生物Haloterrigena sp. H13於低磷高糖誘導下能大量累積極端高鹽太古生物型聚酯顆粒 (hPHA),其單體組成為-[-O-CH(C≡CH)-CH(C2H5)-CHO-]n-,此新型的hPHA具有特殊的不飽和乙炔基(C≡C)。經細胞毒性與貼附性測試,發現hPHA為無毒性,相容性高,細胞貼附性強,顯示hPHA是高潛力的生醫材料。利用已知Haloarcula sp. HLR2 PHA合成酶的基因序列,phaCHLR2當作探針以南方墨漬法偵測Haloterrigena sp. H13中的PHA合成酶基因,從基因體中篩選出一限制酶酵素NotI切割的片段,全長為4599 bp,將序列與基因庫資料分析推測功能與命名,基因組成為maoC、phaR、phaT、phaD、phaC 和phaB。MaoC為enoyl-CoA hydratase,PhaBH13 為NADP-depenent acetoacetyl-CoA reductase,兩者皆是PHA生合成的上游途徑蛋白。PhaRH13 為AbrB-like蛋白質,為轉錄調控蛋白質。PhaCH13為PHA 合成酶,經由序列比對結果,與細菌的第三型PHA 合成酶相似度較高,phaCH13上游為phaDH13,與phaCH13有4 bp的重疊,且只在phaDH13上游有發現推測為啟動子的區域。而第三型或第四型的PHA 合成酶是需要由phaEC或phaRC基因組成分別encode 出的酵素為hetero-subunits PHA 合成酶,所以初步判斷PhaDH13是扮演PhaE或PhaR角色。分析PhaC H13胺基酸序列發現具有PHA合成酶進行聚合反應須具備的胺基酸殘基(Cys-151)-(Asp-306)-(His-335)所組成的活化中心。以北方墨漬法分析發現,phaC與phaD是共轉錄表現。而phaR與phaT也是共轉錄表現。比較營養豐富或不平衡(低磷高醣)的環境下,這些基因的轉錄量,配合PHA合成酶活性測試,分析發現在營養豐富或不平衡的環境下,phaDC的轉錄都會持續表現,轉錄量差異不大,可是在營養不平衡的環境,測試PHA合成酶的活性,比較營養豐富的環境下,PHA合成酶活性卻會大大的提升3倍。而maoC、phaRT和phaB在營養不平衡環境基因轉錄量均會提升0.5~2倍。結果顯示在Haloterrigena sp. H13 PHA生合成受基因轉錄與蛋白質活性的調控,亦可能受PHA合成酶受質的影響。利用大腸桿菌異源表現出PhaDCH13蛋白質與純化,利用3-Hydroxybutyryl-CoA為受質,進行PhaDCH13PHA合成酶特性分析,結果發現只有PhaD H13和PhaC H13同時存在才有活性,PhaDC H13比活性約為5 U/mg。不同溫度測試,PhaDCH13在45℃為最適反應溫度,在熱穩定測試,發現PhaDCH13經過75℃處理5分鐘,依然保有50%的酵素活性。不同離子濃度測試,發現PhaDCH13在1~4M的鉀離子或鈉離子存在下,都有保有活性,在4 M的鉀離子濃度下,有最高的酵素活性。在高鹽環境下經過長時間(三週)的保存,PhaDCH13仍保有90%的活性。綜合上述結果顯示自Haloterrigena sp. H13的PHA生合成酶具有耐高鹽蛋白質的特性,可適應高離子濃度等低水活性的環境,且對熱也有良好的穩定性,適合工業與胞外生產應用,所以對將來在PHA生產與開發上有很好的應用性。zh_TW
dc.description.abstractPolyhydroxyalkanoates (PHAs) are a class of biodegradable polyesters of (R)-hydroxyalkanoates. These biopolymers are accumulated by a wide variety of bacteria and haloarchaea when the carbon source is available in excess but other nutrients are growth limiting. PHAs can be used as biodegradable thermoplastics for a wide range of industrial and medical applications. The extremely halophilic Haloterrigena sp. H13 is capable of accumulating large amounts of hPHA under conditions of nitrogen limitation and abundant carbon source. The monomer of hPHA as -[-O-CH(C≡CH)-CH(C2H5)-CHO-]n- is a novel PHA with C≡C bonding. In this study, Southern blot was performed and a 4.6-kb NotI restriction fragment contained PHA biosynthetic gene cluster was cloned from genomic DNA of Haloterrigena sp. H13. This PHA biosynthetic gene cluster included six open reading frames encoding enoyl-CoA hydratase (MaoCH13), AbrB protein (PhaRH13), transducer protein (PhaTH13), polyhydroxyalkanoate synthase subunit (PhaDH13), polyhydroxyalkanoate synthase (PhaCH13), NADPH-dependent acetoacetyl coenzyme A reductase (PhaBH13) and two putative promoter regions. PhaC H13 and PhaD H13 were composed of 538 and 182 amino acid residues respectively and showed low amino acid identity with other class III type PHA synthases. There were 4 bp overlapping of phaDH13 and phaCH13 and a putative promoter regions located upstream of phaDH13. Result of Northern blot hybridization also demonstrated that phaCH13 and phaDH13 were co-transcribed. The amino acids of (Cys-151)-(Asp-306)-(His-335) were proposed as the catalytic nucleoplile for PHA polymerization at PhaCH13. The PHA biosynthetic gene cluster we identified from Haloterrigena sp. H13 should broaden our knowledge in archaeal PHA biosynthesis.en_US
dc.description.tableofcontents中文摘要 i 英文摘要 iii 目錄 iv 表目錄 vii 圖目錄 viii 壹、 前言 1 貳、 前人研究 4 一、 極端高鹽太古生物 4 二、 極端高鹽太古生物之分類 5 三、 聚羥基烷酯 (Polyhydroxyalkanoate, PHA) 6 (一) 聚羥基烷酯簡介 6 (二) 化學結構 7 (三) 物理特性 8 (四) 生物降解性 8 (五) 應用 9 四、PHA生合成途徑與蛋白質 9 (一) 短碳鏈型 PHA的生合成途徑 9 (二) 中碳鏈型(MCL) PHA的生合成途徑 11 五、PHA生合成酵素 12 (一) PHA生合成基因群組 12 (二) PHA生合成酵素 12 (三) α/β hydrolase superfamily 13 (四) PHA生合成酵素催化機制 14 六、PHA 顆粒組成蛋白與形成機制 15 七、PHA降解酵素 17 八、PHA生合成調控 18 (一) 酵素層次的調控機制 18 (二) 轉錄層次的調控機制 19 (三) PHA降解作用的調控機制 20 九、遺傳工程於PHA生合成上的應用 21 十、極端高鹽太古生物PHA研究 23 參、 材料與方法 27 一、 菌種 27 二、 引子與質體 27 三、 極端高鹽太古生物培養基組成及製備 27 (一) 25% NaCl NHB 液體培養基及NHA固體培養基 27 (二) 25% NaCl A/C及B/C液體培養基 27 四、 極端高鹽太古生物之接種、培養與保存 27 (一) 極端高鹽太古生物的接種及培養 27 (二) 二階段培養誘導生產太古生物型聚酯hPHA 28 (三) 極端高鹽太古生物菌種保存 28 五、 大腸桿菌培養基組成及製備 28 六、 大腸桿菌之培養與保存 29 七、 PHA的的檢測回收 29 八、 核酸膠體電泳分析與紀錄 30 九、 極端高鹽太古生物染色體DNA的萃取 30 十、 聚合酶鏈連鎖反應 31 十一、PCR產物回收與純化 31 十二、DNA黏合反應 32 十三、勝任細胞的製備及質體的轉形作用 32 (一) 製備勝任細胞 32 (二) 質體轉形作用 32 十四、質體的抽取與純化 33 十五、核酸序列定序 33 十六、核酸與胺基酸序列分析 34 十七、南方墨漬分析法 34 (一) 探針的標定 34 (二) 探針標定效率的測定 35 (三) 雜合樣品製備 35 (四) DNA雜合( Hybridization ) 36 十八、北方墨漬分析法 37 十九、蛋白質表現載體的構築 37 二十、全細胞蛋白質之製備 38 二十一、蛋白質電泳分析 38 二十二、西方墨漬法(Western blotting) 39 (一) 轉印前處理 39 (二) 啟動轉印裝置及收集轉印樣品 40 (三) 西方墨漬法 (Western blotting) 40 二十三、蛋白質的大量表現與純化 41 二十四、PHA 聚合酵素活性分析 41 肆、 結果與討論 43 一、 PHA生合成基因的搜尋 43 二、 PHA生合成基因序列分析 47 (一) PhaC&PhaD 47 (二) MaoC 49 (三) PhaR 51 (四) PhaT 52 (五) PhaB 53 (六) PhaA1&PhaA2 54 三、 PhaC與phaD轉錄表現分析 55 四、 異源表現PHA 生合成蛋白質分析 55 五、 PHA生合成酵素活性測試 56 (一) 活性測試的建立 56 (二) 溫度與熱穩定性測試 57 (三) 酵素抑制測試 57 (四) 離子濃度測試 58 (五) 長時間保存活性測試 58 六、營養環境改變對於PHA生合成基因轉錄表現差異分析 59 七、異源表現PHA的大腸桿菌株構築 60 八、PHA的累積與測定 60 九、PHA生合成基因於極端高鹽太古生物間搜尋 61 伍、結論與未來展望 62 一、極端高鹽太古生物PHA生合成基因群組與代謝途徑 62 二、PHA生合成基因的異源表現與PHA的累積 63 陸、表與圖 65 柒、參考文獻 117zh_TW
dc.titleIdentification and Analysis of Polyhydroxyalkanoate Biosynthesis Gene Clusters in the Extreme Halophilic Archaeon Haloterrigena sp. H13en_US
dc.typeThesis and Dissertationzh_TW
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