杜氏藻类胡萝卜素合成关键酶基因的分子克隆及外源表达系统的构建
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摘要
突出的功能效果和人们日益追求天然健康的理念,使得天然类胡萝卜素有着巨大的市场需求。目前,类胡萝卜素已被广泛应用于营养、医药、食品、化妆品以及饲料等方面。耐盐真核绿藻——杜氏藻因其具有高度累积天然β-胡萝卜素的特性而倍受人们的青睐。自上世纪八十年代起,杜氏藻已在多个国家地区被商业开发应用于天然β-胡萝卜素和富含p-胡萝卜素的杜氏藻干粉生产上。然而,杜氏藻生产p-胡萝卜素的传统工艺优化已不能满足当前日益增长的市场需求。从分子生物学角度了解和掌握杜氏藻高度累积β-胡萝卜素的分子机制,借助相关的分子遗传育种手段,从基因水平上提高目的类胡萝卜素在宿主中的产量是缓解当前紧张的市场需求行之有效的方法。此外,具有重要社会意义的是类胡萝卜素合成途径的遗传育种研究有利于增强农作物对土地盐碱化环境的耐受性,保证和提高粮食的产量。
利用遗传育种手段提高目的类胡萝卜素产量的前提条件是具有一个高效多样性的类胡萝卜素合成酶基因库以供遗传操作选择。杜氏藻在环境胁迫条件下能够大量累积β-胡萝卜素,这暗示着杜氏藻类胡萝卜素合成途径相关酶类具有较高的催化效能。根据当前的类胡萝卜素合成途径研究进展,结合本研究室多年来对杜氏藻类胡萝卜素的研究成果,本论文对杜氏藻类胡萝卜素合成途径相关酶类的基因核酸序列进行了克隆。期间,利用简并PCR、cDNA末端快速扩增法(RACE)和重叠延伸PCR等分子克隆技术,首次获得了巴氏杜氏藻类胡萝卜素合成途径中的八氢番茄红素脱氢酶(PDS)、ζ-胡萝卜素脱氢酶(ZDS)、番茄红素β-环化酶(LCY-B)以及杜氏盐藻ZDS的核酸序列。接着,利用各种生物信息学工具对杜氏藻和巴氏杜氏藻类胡萝卜素合成酶类的核酸和蛋白序列进行分析,了解基因的编码情况、蛋白的氨基酸组成和相关的物理化学性质以及蛋白的亚细胞定位等情况。通过密码子偏好性分析和蛋白结构域的特殊性,在基因表达水平和酶催化反应角度解析杜氏藻高度累积β-胡萝卜素的原因。结合蛋白相互作用关系、亚细胞定位分析以及蛋白跨膜结构域预测,推测杜氏藻的类胡萝卜素合成酶是以多亚基聚合物形式行使功能的,而LCY-B起到桥连多亚基聚合物和叶绿体类囊体膜的作用。最后对杜氏藻类胡萝卜素合成酶进行同源建模,了解其的高级结构,为后续的功能研究以及酶工程操作打下基础。
对杜氏藻和欧文氏菌类胡萝卜素合成酶相关基因核酸序列进行不同的组合,构建pACCRT-EIB-DbL、pPaEIDbS-I、pPaEBDbZ-I、pPaEBDbDZ-I、pPaEDbSDZ-I、pPaEIBY-I、pPaEIBDbL-I、pPaEIDbSL-I、pPaEDbSDZL-I、pPaEIYDbS-I、pPaEYDbSDZ-I、 pPaEBYDbDZ-I和pPaEBDbDZL-I等一系列类胡萝卜素外源表达载体于大肠杆菌DH5a中表达以检验杜氏藻类胡萝卜素合成酶的功能和效能。功能性分析显示,杜氏藻DbPDS和DbZDS不能直接代替欧文氏菌crtl实现八氢番茄红素到番茄红素的转化,而产物为中间体ζ-胡萝卜素,推测杜氏藻类胡萝卜素合成途径需要Z-ISO和CRTISO两个异构酶基因的参与。类胡萝卜素的定量分析显示杜氏藻DbLCY-B (pACCRT-EIB-DbL转化子)代替欧文氏菌crtY (pACCAR16AcrtX转化子)使得外源表达系统的β-胡萝卜素含量提高了48.78%。通过单因素实验和响应面分析法优化了转化子产β-胡萝卜素的培养条件和提取工艺。结果显示最佳的培养基成分为16.17g/L胰蛋白胨、10g/L酵母提取物、5g/LNaCl、21.15g/L甘油、78.95g/L NH4Cl和12.68g/L Na2HPO4-7H2O,最佳的培养温度为29℃。在该培养条件下,pACCRT-EIB-DbL转化子的类胡萝卜素实际产量为2.82±0.07mg/L。在最佳培养条件下,发酵罐培养结果显示pACCRT-EIB-DbL转化子的最大β-胡萝卜素产量出现在56h,为6.30mg/L。
Natural carotenoids are high in demand in the global market owing to its effectivefunctional characteristics and the growing natural and healthy preference of consumers today.Currently, carotenoids have been widely applied in fields of nutrition, medicine, food,cosmetic, and feed. The halotolerant eukaryotic green alga Dunaliella has been the people’sfavor for its massive accumulation of natural-carotene. This valuable alga has beenexploited commercially for natural-carotene and-carotene-rich Dunaliella powder in anumber of countries and regions since1980s. However, the traditional process optimization of
-carotene production with Dunaliella can not meet the increasing market demand nowadays.It is an effective method to alleviate the current tense market demand by means of moleculargenetic and breeding techniques to improve the desired carotenoids yield on theunderstanding and mastery of the mechanism of highly-carotene accumulation of Dunaliellafrom the perspective of molecular biology. In addition, it has an important social significanceto ensure and improve food production by enhancing the saline and alkali tolerance of cropthat benefits from genetic breeding study of carotenogenic pathway.
A multiple and efficient carotenogenic genes pool is the prerequisite in genetic breeding forenhancing the production of desired carotenoids. Since the green alga Dunaliella accumulatemassive-carotene under stress conditions, it is implied that the carotenogenic enzymes ofDunaliella have high catalytic activity in the conversion of carotenoids. Considering theprogress of carotenogenic pathway and the results of our groups these years, genes ofcarotenogenic pathway of Dunaliella have been cloned in this work. Based on the molecularcloning techniques, including degenerate PCR, rapid amplification of cDNA end (RACE),and gene splicing by overlap extension PCR (SOE PCR), nucleotide sequences respectivelyfor the phytoene desaturase (PDS),-carotene desaturase (ZDS), and lycopene-cyclase(LCY-B) of Dunaliella bardawil, as well as for the ZDS of Dunaliella salina were firstcloned presently. Subsequently, a series of bioinformatics tools have been used for theanalysis of nucleotide and protein sequences of carotenogenic enzymes of D. salina and D.bardawil to display the coding scheme of carotenogenic genes, amino acid composition andits physicochemical property of carotenogenic enzymes, the subcellular localization of theseenzymes, and so on. A potential mechanism of the massive-carotene accumulation ofDunaliella was defined at the level of gene expression and enzyme catalytic reactionattributing to codon preference analysis and protein domain specificity respectively.According to the results of protein interactions, subcellular localization, and prediction for the transmembrane domain, it was hypothesized that in Dunaliella carotenoids biosynthesis wasperformed by the multisubunit aggregate of carotenogenic enzymes, and LCY-B acts as theconnection point between this multisubunit aggregate and thylakoid membrane. Finally,homology modeling was employed to predict the advanced structures of carotenogenicenzymes of Dunaliella, which would promote study of enzyme function and engineering.
A series of carotenoids-generated vectors, including pACCRT-EIB-DbL, pPaEIDbS-I,pPaEBDbZ-I, pPaEBDbDZ-I, pPaEDbSDZ-I, pPaEIBY-I, pPaEIBDbL-I, pPaEIDbSL-I,pPaEDbSDZL-I, pPaEIYDbS-I, pPaEYDbSDZ-I, pPaEBYDbDZ-I, and pPaEBDbDZL-I,were constructed with different combinations of nucleotide sequences of carotenogenic genesof Dunaliella and Pantoea ananatis to expressed in host cell Escherichia coli DH5for theanalysis of catalytic efficacy and efficiency of carotenogenic enzymes of Dunaliella. It wasproposed that two isomerases, Z-ISO and CRTISO, were required during the carotenogenesisof Dunaliella, because the substitution for the P. ananatis crtI with Dunaliella DbPDS orDbZDS could not achieve the conversion from phytoene to lycopene, but the intermediate-carotene. Interestingly, results also displayed that the substitution for the P. ananatis crtY(pACCAR16crtX) with Dunaliella DbLCY-B (pACCRT-EIB-DbL) leads to a remarkableincreased-carotene accumulation of transformant, by48.78%. Subsequently, univariateanalysis method and response surface methodology have been used to optimize the culturalcondition and extraction process for the-carotene yield of transformant. Results showed thatthe optimal medium composition contained16.17g/L tryptone,10g/L yeast extract,5g/LNaCl,21.15g/L glycerol,78.95g/L NH4Cl, and12.68g/L Na2HPO4·7H2O, and the optimalcultural temperature was29°C. Actually, in this optimal cultural condition the-caroteneyield of pACCRT-EIB-DbL transformant was2.82±0.07mg/L. The experimental data offermentation displayed that the max-carotene yield of pACCRT-EIB-DbL transformant was6.30mg/L at56h under the optimal cultural condition.
利用遗传育种手段提高目的类胡萝卜素产量的前提条件是具有一个高效多样性的类胡萝卜素合成酶基因库以供遗传操作选择。杜氏藻在环境胁迫条件下能够大量累积β-胡萝卜素,这暗示着杜氏藻类胡萝卜素合成途径相关酶类具有较高的催化效能。根据当前的类胡萝卜素合成途径研究进展,结合本研究室多年来对杜氏藻类胡萝卜素的研究成果,本论文对杜氏藻类胡萝卜素合成途径相关酶类的基因核酸序列进行了克隆。期间,利用简并PCR、cDNA末端快速扩增法(RACE)和重叠延伸PCR等分子克隆技术,首次获得了巴氏杜氏藻类胡萝卜素合成途径中的八氢番茄红素脱氢酶(PDS)、ζ-胡萝卜素脱氢酶(ZDS)、番茄红素β-环化酶(LCY-B)以及杜氏盐藻ZDS的核酸序列。接着,利用各种生物信息学工具对杜氏藻和巴氏杜氏藻类胡萝卜素合成酶类的核酸和蛋白序列进行分析,了解基因的编码情况、蛋白的氨基酸组成和相关的物理化学性质以及蛋白的亚细胞定位等情况。通过密码子偏好性分析和蛋白结构域的特殊性,在基因表达水平和酶催化反应角度解析杜氏藻高度累积β-胡萝卜素的原因。结合蛋白相互作用关系、亚细胞定位分析以及蛋白跨膜结构域预测,推测杜氏藻的类胡萝卜素合成酶是以多亚基聚合物形式行使功能的,而LCY-B起到桥连多亚基聚合物和叶绿体类囊体膜的作用。最后对杜氏藻类胡萝卜素合成酶进行同源建模,了解其的高级结构,为后续的功能研究以及酶工程操作打下基础。
对杜氏藻和欧文氏菌类胡萝卜素合成酶相关基因核酸序列进行不同的组合,构建pACCRT-EIB-DbL、pPaEIDbS-I、pPaEBDbZ-I、pPaEBDbDZ-I、pPaEDbSDZ-I、pPaEIBY-I、pPaEIBDbL-I、pPaEIDbSL-I、pPaEDbSDZL-I、pPaEIYDbS-I、pPaEYDbSDZ-I、 pPaEBYDbDZ-I和pPaEBDbDZL-I等一系列类胡萝卜素外源表达载体于大肠杆菌DH5a中表达以检验杜氏藻类胡萝卜素合成酶的功能和效能。功能性分析显示,杜氏藻DbPDS和DbZDS不能直接代替欧文氏菌crtl实现八氢番茄红素到番茄红素的转化,而产物为中间体ζ-胡萝卜素,推测杜氏藻类胡萝卜素合成途径需要Z-ISO和CRTISO两个异构酶基因的参与。类胡萝卜素的定量分析显示杜氏藻DbLCY-B (pACCRT-EIB-DbL转化子)代替欧文氏菌crtY (pACCAR16AcrtX转化子)使得外源表达系统的β-胡萝卜素含量提高了48.78%。通过单因素实验和响应面分析法优化了转化子产β-胡萝卜素的培养条件和提取工艺。结果显示最佳的培养基成分为16.17g/L胰蛋白胨、10g/L酵母提取物、5g/LNaCl、21.15g/L甘油、78.95g/L NH4Cl和12.68g/L Na2HPO4-7H2O,最佳的培养温度为29℃。在该培养条件下,pACCRT-EIB-DbL转化子的类胡萝卜素实际产量为2.82±0.07mg/L。在最佳培养条件下,发酵罐培养结果显示pACCRT-EIB-DbL转化子的最大β-胡萝卜素产量出现在56h,为6.30mg/L。
Natural carotenoids are high in demand in the global market owing to its effectivefunctional characteristics and the growing natural and healthy preference of consumers today.Currently, carotenoids have been widely applied in fields of nutrition, medicine, food,cosmetic, and feed. The halotolerant eukaryotic green alga Dunaliella has been the people’sfavor for its massive accumulation of natural-carotene. This valuable alga has beenexploited commercially for natural-carotene and-carotene-rich Dunaliella powder in anumber of countries and regions since1980s. However, the traditional process optimization of
-carotene production with Dunaliella can not meet the increasing market demand nowadays.It is an effective method to alleviate the current tense market demand by means of moleculargenetic and breeding techniques to improve the desired carotenoids yield on theunderstanding and mastery of the mechanism of highly-carotene accumulation of Dunaliellafrom the perspective of molecular biology. In addition, it has an important social significanceto ensure and improve food production by enhancing the saline and alkali tolerance of cropthat benefits from genetic breeding study of carotenogenic pathway.
A multiple and efficient carotenogenic genes pool is the prerequisite in genetic breeding forenhancing the production of desired carotenoids. Since the green alga Dunaliella accumulatemassive-carotene under stress conditions, it is implied that the carotenogenic enzymes ofDunaliella have high catalytic activity in the conversion of carotenoids. Considering theprogress of carotenogenic pathway and the results of our groups these years, genes ofcarotenogenic pathway of Dunaliella have been cloned in this work. Based on the molecularcloning techniques, including degenerate PCR, rapid amplification of cDNA end (RACE),and gene splicing by overlap extension PCR (SOE PCR), nucleotide sequences respectivelyfor the phytoene desaturase (PDS),-carotene desaturase (ZDS), and lycopene-cyclase(LCY-B) of Dunaliella bardawil, as well as for the ZDS of Dunaliella salina were firstcloned presently. Subsequently, a series of bioinformatics tools have been used for theanalysis of nucleotide and protein sequences of carotenogenic enzymes of D. salina and D.bardawil to display the coding scheme of carotenogenic genes, amino acid composition andits physicochemical property of carotenogenic enzymes, the subcellular localization of theseenzymes, and so on. A potential mechanism of the massive-carotene accumulation ofDunaliella was defined at the level of gene expression and enzyme catalytic reactionattributing to codon preference analysis and protein domain specificity respectively.According to the results of protein interactions, subcellular localization, and prediction for the transmembrane domain, it was hypothesized that in Dunaliella carotenoids biosynthesis wasperformed by the multisubunit aggregate of carotenogenic enzymes, and LCY-B acts as theconnection point between this multisubunit aggregate and thylakoid membrane. Finally,homology modeling was employed to predict the advanced structures of carotenogenicenzymes of Dunaliella, which would promote study of enzyme function and engineering.
A series of carotenoids-generated vectors, including pACCRT-EIB-DbL, pPaEIDbS-I,pPaEBDbZ-I, pPaEBDbDZ-I, pPaEDbSDZ-I, pPaEIBY-I, pPaEIBDbL-I, pPaEIDbSL-I,pPaEDbSDZL-I, pPaEIYDbS-I, pPaEYDbSDZ-I, pPaEBYDbDZ-I, and pPaEBDbDZL-I,were constructed with different combinations of nucleotide sequences of carotenogenic genesof Dunaliella and Pantoea ananatis to expressed in host cell Escherichia coli DH5for theanalysis of catalytic efficacy and efficiency of carotenogenic enzymes of Dunaliella. It wasproposed that two isomerases, Z-ISO and CRTISO, were required during the carotenogenesisof Dunaliella, because the substitution for the P. ananatis crtI with Dunaliella DbPDS orDbZDS could not achieve the conversion from phytoene to lycopene, but the intermediate-carotene. Interestingly, results also displayed that the substitution for the P. ananatis crtY(pACCAR16crtX) with Dunaliella DbLCY-B (pACCRT-EIB-DbL) leads to a remarkableincreased-carotene accumulation of transformant, by48.78%. Subsequently, univariateanalysis method and response surface methodology have been used to optimize the culturalcondition and extraction process for the-carotene yield of transformant. Results showed thatthe optimal medium composition contained16.17g/L tryptone,10g/L yeast extract,5g/LNaCl,21.15g/L glycerol,78.95g/L NH4Cl, and12.68g/L Na2HPO4·7H2O, and the optimalcultural temperature was29°C. Actually, in this optimal cultural condition the-caroteneyield of pACCRT-EIB-DbL transformant was2.82±0.07mg/L. The experimental data offermentation displayed that the max-carotene yield of pACCRT-EIB-DbL transformant was6.30mg/L at56h under the optimal cultural condition.
引文
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