CN111378611B - 一种谷氨酸脱羧酶重组菌及其构建方法和应用 - Google Patents
一种谷氨酸脱羧酶重组菌及其构建方法和应用 Download PDFInfo
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Abstract
本发明公开了一种谷氨酸脱羧酶重组菌，该重组菌为导入了谷氨酸脱羧酶基因的大肠杆菌，其中所述的谷氨酸脱羧酶基因为来源于弓形链霉菌NRRL 15443的StGAD、链霉菌MJ654‑NF4的SsGAD或嗜铬链霉菌ATCC 49982的ScGAD，其核苷酸序列如SEQ ID No：1‑3所示。本发明采用弓形链霉菌NRRL 15443、链霉菌MJ654‑NF4和嗜铬链霉菌ATCC 49982作为菌株，通过PCR扩增技术从上述三种菌株的基因组上扩增得到了谷氨酸脱羧酶的编码基因：SsGAD、StGAD、ScGAD，利用大肠杆菌E.coli BL21(DE3)作为宿主，成功构建了能够高效表达谷氨酸脱羧酶的重组菌，该工程菌经历至少10次的重复利用依然保持极高的转化效率。本发明还提供了上述重组菌的构建方法及该重组菌在制备GABA的应用，上述方法生产易操作，易放大，稳定性好，适于大规模工业化生产。
Description
技术领域
本发明涉及基因工程领域，尤其涉及一种谷氨酸脱羧酶重组菌及其构建方法和应用。
背景技术
目前，γ-氨基丁酸(γ-aminobutyric acid，简称GABA)是哺乳动物神经中枢的一种抑制性递质，具有调节血压、促进精神安定、促进脑部血流、增进脑活力、营养神经细胞、增加生长激素分泌、健肝利肾、预防肥胖、促进乙醇代谢、改善更年期综合征等多种功效。γ-氨基丁酸正被广泛应用于医药、食品保健、化工及农业等行业。GABA的生产可以通过化学合成和生物合成。由于化学合成反应条件剧烈，化学原料和溶剂具有毒性和腐蚀性，副产物多，缺乏安全性，主要应用于化工行业，不适宜作为食品添加剂和医药。生物合成条件温和，专一性强、副产物少、安全性高，因此以生物合成法生产食品或者医药级的GABA是一条较为理想的途径。
谷氨酸脱羧酶(Glutamate decarboxylase，GAD)是生物体内催化谷氨酸发生α-脱羧生成GABA的唯一的酶。目前已经在多种微生物中发现GAD的存在，利用微生物中的GAD催化谷氨酸生产γ-氨基丁酸不受资源、环境和空间的限制，具有显著的有点。目前利用基因工程中常利用过量表达谷氨酸脱羧酶基因，来进一步提高GABA的产量，工业上用的GAD大多是从各种微生物源中分离出来的，包括大肠杆菌、乳酸菌等，存在产量低，操作繁琐，经济效益等不足。
发明内容
为了克服现有技术的不足，本发明的目的之一在于提供一种适合大规模工业化生产的谷氨酸脱羧酶重组菌，采用将来源于不同链霉菌的SsGAD、StGAD、ScGAD克隆后在大肠杆菌E.coli BL21(DE3)进行过量表达，生产谷氨酸脱羧酶。
本发明的目的之二在于提供了一种谷氨酸脱羧酶重组菌的构建方法。
本发明的目的之三在于提供了一种谷氨酸脱羧酶重组菌的应用。
本发明的目的之一采用如下技术方案实现：
一种谷氨酸脱羧酶重组菌，该重组菌为导入了谷氨酸脱羧酶基因的大肠杆菌，其中所述的谷氨酸脱羧酶基因来源于弓形链霉菌NRRL 15443的StGAD、链霉菌MJ654-NF4的SsGAD和嗜铬链霉菌ATCC 49982的ScGAD，其核苷酸序列如SEQ ID No：1-3所示。
本发明的目的之二采用如下技术方案实现：
上述谷氨酸脱羧酶重组菌的构建方法，包括以下步骤：
(1)构建质粒：将分别将SsGAD、StGAD、ScGAD经PCR扩增后，以pJET1.2作为基因克隆载体，将PCR扩增后的基因序列连接在其上，采用限制性内切酶针对酶切位点NdeI和HindIII进行酶切处理，分别将SsGAD结合物、StGAD结合物、ScGAD结合物连接到相应制粒上；
(2)构建重组菌：分别将上述步骤(1)中的目标质粒导入相应菌种中即得所述重组菌。
进一步地，上述步骤(1)的制粒为大肠表达质粒pET-28a(+)，分别得到目标制粒pHY6、pHW4、pHY1；上述步骤(2)将目标制粒pHY6、pHW4、pHY1导入大肠杆菌E.coli BL21(DE3)中即的所述重组菌。
进一步地，该基因序列也可以用于其他菌种的表达，选择不同的质粒时，可在酵母菌、乳酸菌、双歧杆菌等中进行表达。
进一步地，上述步骤(1)中PCR扩增中SsGAD基因的引物序列为：
5′-AACATATGGCCTTGTACAAGGGCACCG
3′-AAAAGCTTTTAGTGGTGGAAGCCGGCGCGGACC；
StGAD基因的引物序列为：
5′-AACATATGGCTCTCCACAAGACGAAGGA
3′-AAAAGCTTTTAGTGGTGGAAGCCGGAGCGGGGA；
ScGAD基因的引物序列为：
5′-AACATATGCCACTCCACCAAGGCGCGGACA
3′-AAAGCTTTTAGTGGTGGAAGGCGGTGGCGGCC。
进一步地，上述步骤(1)中PCR扩增过程的反应条件为：98℃初始变性处理5分钟。随后在相同温度下，每30秒循环变性、退火、延长处理，完成20个循环；持续上述循环，并在每个循环后降温0.5℃，直至75℃；72℃下延伸2分钟，再依次在98℃、65℃下完成变性、退火、延长处理各30秒，72℃延长处理12分钟，即完成。
本发明的目的之三采用如下技术方案实现：
上述谷氨酸脱羧酶重组菌的应用，包括将谷氨酸脱羧酶重组菌进行扩大培养以诱导其大量表达谷氨酸脱羧酶。
进一步地，所述重组菌的扩大培养中还包括向培养基中添加IPTG作为诱导剂的步骤。
进一步地，上述扩大培养过程为：将所述重组菌采用含有50μg/mL卡那霉素的LB培养液，37℃，250rpm培养12小时，然后转入含有相同浓度卡那霉素的LB肉汤培养基中，37℃，250rpm培养至OD600达到0.4-0.6，添加IPTG诱导目标蛋白的表达，28℃，250rpm下持续培养16小时，收集培养液，离心，将获得的细胞体通过超声裂解后再次进行离心，取上清液即的目标蛋白。
进一步地，将其或其产生的谷氨酸脱羧酶应用于生产γ-氨基丁酸。
进一步地，本发明还提供一种氨基酸序列，由上述核苷酸序列形成。
进一步地，所述氨基酸序列为SEQ ID No.10-12所示序列、及其多聚物中的任意一种或几种。
相比现有技术，本发明的有益效果在于：本发明采用弓形链霉菌NRRL 15443、链霉菌MJ654-NF4和嗜铬链霉菌ATCC 49982作为菌株，通过PCR扩增技术从上述三种菌株的基因组上扩增得到了谷氨酸脱羧酶的编码基因：SsGAD、StGAD、ScGAD，利用大肠杆菌E.coliBL21(DE3)作为宿主，成功构建了能够高效表达谷氨酸脱羧酶的重组菌，该工程菌经历至少10次的重复利用依然保持极高的转化效率，大大提高了生产效率。本发明还提供了上述重组菌的构建方法及该重组菌在制备GABA的应用，上述方法生产易操作，易放大，稳定性好，适于大规模工业化生产。重组菌表达的GAD可对谷氨酸直接进行脱羧，便于合成GABA，进一步降低生产成本。
附图说明
图1为本发明得到的重组蛋白电泳图；
图2为本发明得到的重组蛋白在一定pH范围的酶活性；
图3为本发明得到的重组蛋白在一定温度范围内的酶活性；
图4为本发明得到的重组蛋白在催化L-谷氨酸生产γ-氨基丁酸过程中，L-谷氨酸的浓度和γ-氨基丁酸产量之间的关系图。
图5为本发明得到的重组蛋白酶在催化L-谷氨酸生产γ-氨基丁酸过程中，L-谷氨酸的浓度和γ-氨基丁酸产量之间的关系图；
图6为本发明实施例制粒构建的流程图。
具体实施方式
下面，结合附图以及具体实施方式，对本发明做进一步描述，需要说明的是，在不相冲突的前提下，以下描述的各实施例之间或各技术特征之间可以任意组合形成新的实施例。
实施例1
一种谷氨酸脱羧酶重组菌的构建方法，包括以下步骤：
(1)构建质粒：分别将来源于弓形链霉菌NRRL 15443的StGAD、链霉菌MJ654-NF4的SsGAD或嗜铬链霉菌ATCC 49982的ScGAD，进行PCR扩增，所用引物序列如表1所示，20μlPCR体系的组成为：前端引物0.2μl，后端引物0.2μl，基因组DNA 0.2μl，DMSO 0.4μl，PhusionDNA聚合酶0.2μl，Phusion DNA聚合酶缓冲液4μl，100mMdNTPs0.4μl，水14.4μl；PCR扩增过程的反应条件为：98℃初始变性处理5分钟。随后在相同温度下，每30秒循环变性、退火、延长处理，完成20个循环；持续上述循环，并在每个循环后降温0.5℃，直至75℃；72℃下延伸2分钟，再依次在98℃、65℃下完成变性、退火、延长处理各30秒，72℃延长处理12分钟，即完成，以pJET1.2作为基因克隆载体，将PCR扩增后的基因序列连接在其上，采用限制性内切酶针对酶切位点NdeI和HindIII进行酶切处理，分别将SsGAD结合物、StGAD结合物、ScGAD结合物连接到大肠表达质粒pET-28a(+)上，形成目标质粒pHY6、pHW4、pHY1，制粒构件流程如图6所示；
(2)构建重组菌：分别将上述步骤(1)中的目标质粒pHY6、pHW4、pHY1导入大肠杆菌E.coli BL21(DE3)中即的所述重组菌。
表1
实施例2
上述谷氨酸脱羧酶重组菌的应用：采用含有50μg/mL卡那霉素的LB培养液，37℃，250rpm培养12小时，转入含有相同浓度卡那霉素的LB肉汤培养基中，37℃，250rpm培养至OD600达到0.4-0.6。添加IPTG诱导目标蛋白的表达。28℃，250rpm下持续培养16小时。收集培养液，4℃下12000×g离心10分钟，获得的细胞体通过超声裂解后再进行12000×g离心10分钟，目标蛋白位于上清液中。
试验例1
重组蛋白的确认：将实施例2得到的目标蛋白进行电泳分析，结果如附图1所示，其中，GADB是已知的大肠杆菌GAD酶，说明构建的重组菌均正常产生GAD酶。
试验例2
最佳酶活性pH测定：采用200mM磷酸氢二钠-柠檬酸缓冲液，37℃下处理30分钟，测定重组蛋白在2.6-6.0的pH范围下的活力，结果如图2所示。由图2可以看出，不同来源的蛋白其最佳酶活pH不同。
试验例3
最佳酶活性温度的测定：采用在稳定pH3.5-5.0下，于18-60℃温度下处理30分钟，测定重组蛋白的最适活性温度，结果如图3所示。
试验例4
酶活力测定：将GADB和本申请的SsGAD、StGAD、ScGAD在相同条件下培养，统计对谷氨酸的转化效率，结果如图4所示，可以看出无论在pH4.6条件下或者是水环境下，SsGAD、ScGAD对谷氨酸的转化效率均远高于GADB，StGAD对谷氨酸的转化效率和GADB基本持平。
试验例5
本申请的重组蛋白酶在催化L-谷氨酸生产γ-氨基丁酸过程中，L-谷氨酸的浓度和γ-氨基丁酸产量之间的关系如图5所示，可以看出本申请的三种重组蛋白均有较好的转化效率。
本发明采用弓形链霉菌NRRL 15443、链霉菌MJ654-NF4和嗜铬链霉菌ATCC 49982作为菌株，通过PCR扩增技术从上述三种菌株的基因组上扩增得到了谷氨酸脱羧酶的编码基因：SsGAD、StGAD、ScGAD，利用大肠杆菌E.coli BL21(DE3)作为宿主，成功构建了能够高效表达谷氨酸脱羧酶的重组菌，该工程菌经历至少10次的重复利用依然保持极高的转化效率，大大提高了生产效率。本发明还提供了上述重组菌的构建方法及该重组菌在制备GABA的应用，上述方法生产易操作，易放大，稳定性好，适于大规模工业化生产。重组菌表达的GAD可对谷氨酸直接进行脱羧，便于合成GABA，进一步降低生产成本。
上述实施方式仅为本发明的优选实施方式，不能以此来限定本发明保护的范围，本领域的技术人员在本发明的基础上所做的任何非实质性的变化及替换均属于本发明所要求保护的范围。
序列表
<110> 杭州唯铂莱生物科技有限公司
<120> 一种谷氨酸脱羧酶重组菌及其构建方法和应用
<141> 2018-12-29
<160> 12
<170> SIPOSequenceListing 1.0
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atggctctcc acaagacgaa ggacgtcacc ggcggcgaca ccgggacgga cgtcttcacc 60
accgccctga gcggccgcgt cctccccaag taccggatgc cggaggagca ttcaccgtcg 120
gaggcggtct acgccctgct ccgcaacgag ctcctcctcg acggcaacgc cgcccagaac 180
ctggccacct tctgcaccac ctggtccgac gacggcgtcc accgcctcat gaacgagtgc 240
cttgacaaga acatggtcga caaggacgag tacccgcaga ccgcggagat cgaggcccgc 300
tgcgtcaaca tcctggccca cctgtggcac gccccggccg aggacggccc cgccaccggc 360
tgctccacca ccggctccag cgaggccgcc atgctcggcg gcctcgccct caaatggcgc 420
tggcgggccc gccgccgcgc ccagggcctg ccggccgacc ggcccaacct ggtgtgcggg 480
cccgtccagg tctgctggga gaagttcgcc cgctacttcg acgtcgaact gcgccagatc 540
cccctggagg aggacgccac cggcctgcgg ccccaccagc tcgcggagta cgtcgacgag 600
aacaccatcg gcgtcgtcgc catcctcggc gtcacctaca cctgcgacta cgagcccgtc 660
gccgacatcg cggccgccct cgacgcgatc cagcaggagc acggctggga cgtcccgatc 720
cacgtcgacg gcgccagcgg cgggctcgtc gcccccttcc tccaccccga cgtggtgtgg 780
gacttcgccc tcccccgcgt cgcctccatc aacacctccg ggcacaagta cgggctcgca 840
cccctcggcg tcggctgggt cgtctggcgc accgcggacc tcctgccccc cgagctcgtc 900
ttcgacgtgg actacctggg cggcgacatg ccgaccttcg ccctgaactt ctcccggccc 960
ggcggcgagg ccatcgccca gtactacctc ttcctccggc tcggccgcag cggctaccgg 1020
agcgtccacc agtcctgcgc ggacaccgcc cggttcctcg ccggcgagat cgccgcgatg 1080
ggccccttca ccctgctgta cgacggccag ggcgccctcc ccgccgtctc ctaccggctc 1140
accgaccccg cggccgccgg cttcaccctc tacgacctct ccgaccggct gcggatgcgc 1200
ggctggcagg tccccgcgta cccgctgccc gcccgccgcg acgacaccgt catccagcgc 1260
gtcctgatcc gccacggcgt gaccctggac cagatcgccc tcctggcgga ggacatgcgc 1320
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ggcttccacc actga 1395
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gtctcggccg acatcgcgta ccagctggtc cacgacgagc tgatgctgga cggcagcgcc 180
aagctcaacc tggcgacctt cgtcaccacc tcgatggagg tgcaggccac ccggctgatg 240
accgagtgcc tggacaagaa catgatcgac aaggacgagt acccgcagac cgccgagctg 300
gagcggcgct gcgtggccat cctcgccgac ctctggcacg cccccgaccc ggacaccgcg 360
gtcggctgct ccaccaccgg ctccagcgag gcctgcatgc tcgccgggat ggccctcaag 420
cgccgctgga tgcgccgcaa ccccgagcgc tacgcggccg gggcccggcc caacctggtg 480
atgggcgtca acgtccaggt gtgctgggag aagttctgca acttctggga ggtcgaggcc 540
cgcaccgtcc ccatggacgg cgagcgcttc cacctcggcg ccgagcaggc ggtcgcgctg 600
tgcgacgaga acaccatcgg cgtggtcggc gtcctcggct ccaccttcga cgggtcgtac 660
gagccgatcg cggagatctg cgcggccctg gacgagctcc aggagcgcac cggcctggac 720
atcccggtgc acgtggacgg cgcctccggc ggcatggtgg cgcccttcct cgacccggag 780
ctggtctggg acttccggct gccccgggtg gcctcgatca acacctccgg gcacaagtac 840
ggcctggtct acccgggcgt cggctgggcg ctgtggcggg accaggagtc gctgccggag 900
gagctggtct tccgggtcaa ctacctgggc ggcgagatgc cgaccttcgc gctcaacttc 960
tcccggcccg gcgctcaggt ggcggcgcag tactacatct tcctgcggct cggccgggag 1020
ggcttcaagg cggtccaggg cgccagccgg gatgtcgccg tctacctggc cggggagatc 1080
gggaagctgg gctgtttccg gctgctgacc cacggcgacc agctcccggt gttcgcgttc 1140
accaccaccg aggacgtgcc cttcgacgtc ttcgacgtct cgcggcggct gcgcgagcgc 1200
ggctggcagg tacccgcgta caccttcccc gcgaaccggg aggacctctc agcactccgg 1260
gtggtctgcc gcaacggctt ctcccgggac ctcgccgaca tgctgctggc cgacctcaac 1320
cggctgctgc cggagctgaa gcgccagccc gccccgctca aggaactcgg ggtgccggtc 1380
cgcgccggct tccaccacta g 1401
<210> 3
<211> 1437
<212> DNA
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atgccactcc accaaggcgc ggacagggca gccgacattc ccgaggagga ccgcgccgaa 60
ctgcggcggc tgtcgctcaa ccccttctac ggggaggcgg atccggtcag cgagatgacc 120
tcggcgccgc ccacccagcg gcttcccgaa gggccgaccc cgccgcacac cgcctatcag 180
ctcgtccacg acgagctgat gctcgacggc aactcacggc tcaacctggc gaccttcgtc 240
accacctgga tggagccgca ggccggggtg ctgatggcgg agtgccagga caagaacatg 300
atcgacaagg acgagtaccc gcgcaccgcc gaactggagc ggcgctgcgt ggcgatgctc 360
gccgatctgt ggaacgcccc ggacccggcg accgccgtcg gctgctcgac caccgggtcc 420
agcgaggcgt gcatgctcgc cgggctggcg ctcaagcgcc gctgggccaa gcggaacgcg 480
gcgcgctatc cggcgaccgc ccggcccaat ctggtcatgg gcgtcaacgt ccaggtctgc 540
tgggagaagt tctgcacctt ctgggaggtg gaggcgcggc tcgtccccat ggagggcgac 600
cgcttccacc tcgacccgca ggccgccgcc gacctctgcg acgaggacac catcggggtc 660
gtggccgtcc tgggctccac cttcgacgga tcgtacgaac cggtcgccga gctgtgcgcg 720
gtgctggacg ccctccagga gcgtacgggg ctcgatgtcc ccgtccatgt cgacggggcg 780
tcgggcgcca tgatcgcgcc cttcctcgac gaggacctcg tctgggactt ccggctgccg 840
cgcgtctcct ccatcaacac ctcgggccac aagtacgggc tggtgtaccc gggcgtcggc 900
tgggcgctgt ggcggtcgcc cgccgaactc cccgaagagc tggtcttccg cgtcaactac 960
ctgggcggcg acatgcccac cttcgcgctg aacttctccc ggccgggcgc ccaggtcgtc 1020
gcgcagtact acaccttcct gcggctcggc agggacggct accgcgccgt ccagcagacc 1080
gcgcgggaca tcgccacgac cctctccgcg cgcatcgagc ggctgggcgg cttccggctg 1140
ctcacccgcg gggaccaact gcccgtgttc gccttcacca ccgcctccga tgtgacgaac 1200
ttcgatgtct tcgacgtctc gcggcggctg cgcgaacacg gctggctggt gcccgcgtac 1260
accttccccg cccaccgcga ggacctgtcc gtcctgcgcg tggtctgccg caacggcttc 1320
tccgcggacc tggcggcgat gctggtggcc gacctgaagc gggtgctgcc cgaactgcgc 1380
gcccaggagc gccccatgga ccgcgacccg tcggccgcca ccgccttcca ccactga 1437
<210> 4
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<212> DNA
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aacatatggc cttgtacaag ggcaccg 27
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aaaagctttt agtggtggaa gccggcgcgg acc 33
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aaaagctttt agtggtggaa gccggagcgg gga 33
<210> 8
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<212> DNA
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aacatatgcc actccaccaa ggcgcggaca 30
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<212> DNA
<213> Artificial Sequence
<400> 9
aaagctttta gtggtggaag gcggtggcgg cc 32
<210> 10
<211> 464
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
Met Ala Leu His Lys Thr Lys Asp Val Thr Gly Gly Asp Thr Gly Thr
1 5 10 15
Asp Val Phe Thr Thr Ala Leu Ser Gly Arg Val Leu Pro Lys Tyr Arg
20 25 30
Met Pro Glu Glu His Ser Pro Ser Glu Ala Val Tyr Ala Leu Leu Arg
35 40 45
Asn Glu Leu Leu Leu Asp Gly Asn Ala Ala Gln Asn Leu Ala Thr Phe
50 55 60
Cys Thr Thr Trp Ser Asp Asp Gly Val His Arg Leu Met Asn Glu Cys
65 70 75 80
Leu Asp Lys Asn Met Val Asp Lys Asp Glu Tyr Pro Gln Thr Ala Glu
85 90 95
Ile Glu Ala Arg Cys Val Asn Ile Leu Ala His Leu Trp His Ala Pro
100 105 110
Ala Glu Asp Gly Pro Ala Thr Gly Cys Ser Thr Thr Gly Ser Ser Glu
115 120 125
Ala Ala Met Leu Gly Gly Leu Ala Leu Lys Trp Arg Trp Arg Ala Arg
130 135 140
Arg Arg Ala Gln Gly Leu Pro Ala Asp Arg Pro Asn Leu Val Cys Gly
145 150 155 160
Pro Val Gln Val Cys Trp Glu Lys Phe Ala Arg Tyr Phe Asp Val Glu
165 170 175
Leu Arg Gln Ile Pro Leu Glu Glu Asp Ala Thr Gly Leu Arg Pro His
180 185 190
Gln Leu Ala Glu Tyr Val Asp Glu Asn Thr Ile Gly Val Val Ala Ile
195 200 205
Leu Gly Val Thr Tyr Thr Cys Asp Tyr Glu Pro Val Ala Asp Ile Ala
210 215 220
Ala Ala Leu Asp Ala Ile Gln Gln Glu His Gly Trp Asp Val Pro Ile
225 230 235 240
His Val Asp Gly Ala Ser Gly Gly Leu Val Ala Pro Phe Leu His Pro
245 250 255
Asp Val Val Trp Asp Phe Ala Leu Pro Arg Val Ala Ser Ile Asn Thr
260 265 270
Ser Gly His Lys Tyr Gly Leu Ala Pro Leu Gly Val Gly Trp Val Val
275 280 285
Trp Arg Thr Ala Asp Leu Leu Pro Pro Glu Leu Val Phe Asp Val Asp
290 295 300
Tyr Leu Gly Gly Asp Met Pro Thr Phe Ala Leu Asn Phe Ser Arg Pro
305 310 315 320
Gly Gly Glu Ala Ile Ala Gln Tyr Tyr Leu Phe Leu Arg Leu Gly Arg
325 330 335
Ser Gly Tyr Arg Ser Val His Gln Ser Cys Ala Asp Thr Ala Arg Phe
340 345 350
Leu Ala Gly Glu Ile Ala Ala Met Gly Pro Phe Thr Leu Leu Tyr Asp
355 360 365
Gly Gln Gly Ala Leu Pro Ala Val Ser Tyr Arg Leu Thr Asp Pro Ala
370 375 380
Ala Ala Gly Phe Thr Leu Tyr Asp Leu Ser Asp Arg Leu Arg Met Arg
385 390 395 400
Gly Trp Gln Val Pro Ala Tyr Pro Leu Pro Ala Arg Arg Asp Asp Thr
405 410 415
Val Ile Gln Arg Val Leu Ile Arg His Gly Val Thr Leu Asp Gln Ile
420 425 430
Ala Leu Leu Ala Glu Asp Met Arg Arg Ala Leu Asp His Leu Arg Ala
435 440 445
Ala Pro Pro Thr Gln Pro Pro Thr Ala Pro Arg Ser Gly Phe His His
450 455 460
<210> 11
<211> 466
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Met Ala Leu Tyr Lys Gly Thr Gly Ser Asp Arg Arg Leu Asn Val Ser
1 5 10 15
Pro Leu Leu Val Thr Asn Pro Leu Ala Ala Met Glu Leu Ala Pro Pro
20 25 30
Val His Arg Leu Gly Asp Gly Ala Val Ser Ala Asp Ile Ala Tyr Gln
35 40 45
Leu Val His Asp Glu Leu Met Leu Asp Gly Ser Ala Lys Leu Asn Leu
50 55 60
Ala Thr Phe Val Thr Thr Ser Met Glu Val Gln Ala Thr Arg Leu Met
65 70 75 80
Thr Glu Cys Leu Asp Lys Asn Met Ile Asp Lys Asp Glu Tyr Pro Gln
85 90 95
Thr Ala Glu Leu Glu Arg Arg Cys Val Ala Ile Leu Ala Asp Leu Trp
100 105 110
His Ala Pro Asp Pro Asp Thr Ala Val Gly Cys Ser Thr Thr Gly Ser
115 120 125
Ser Glu Ala Cys Met Leu Ala Gly Met Ala Leu Lys Arg Arg Trp Met
130 135 140
Arg Arg Asn Pro Glu Arg Tyr Ala Ala Gly Ala Arg Pro Asn Leu Val
145 150 155 160
Met Gly Val Asn Val Gln Val Cys Trp Glu Lys Phe Cys Asn Phe Trp
165 170 175
Glu Val Glu Ala Arg Thr Val Pro Met Asp Gly Glu Arg Phe His Leu
180 185 190
Gly Ala Glu Gln Ala Val Ala Leu Cys Asp Glu Asn Thr Ile Gly Val
195 200 205
Val Gly Val Leu Gly Ser Thr Phe Asp Gly Ser Tyr Glu Pro Ile Ala
210 215 220
Glu Ile Cys Ala Ala Leu Asp Glu Leu Gln Glu Arg Thr Gly Leu Asp
225 230 235 240
Ile Pro Val His Val Asp Gly Ala Ser Gly Gly Met Val Ala Pro Phe
245 250 255
Leu Asp Pro Glu Leu Val Trp Asp Phe Arg Leu Pro Arg Val Ala Ser
260 265 270
Ile Asn Thr Ser Gly His Lys Tyr Gly Leu Val Tyr Pro Gly Val Gly
275 280 285
Trp Ala Leu Trp Arg Asp Gln Glu Ser Leu Pro Glu Glu Leu Val Phe
290 295 300
Arg Val Asn Tyr Leu Gly Gly Glu Met Pro Thr Phe Ala Leu Asn Phe
305 310 315 320
Ser Arg Pro Gly Ala Gln Val Ala Ala Gln Tyr Tyr Ile Phe Leu Arg
325 330 335
Leu Gly Arg Glu Gly Phe Lys Ala Val Gln Gly Ala Ser Arg Asp Val
340 345 350
Ala Val Tyr Leu Ala Gly Glu Ile Gly Lys Leu Gly Cys Phe Arg Leu
355 360 365
Leu Thr His Gly Asp Gln Leu Pro Val Phe Ala Phe Thr Thr Thr Glu
370 375 380
Asp Val Pro Phe Asp Val Phe Asp Val Ser Arg Arg Leu Arg Glu Arg
385 390 395 400
Gly Trp Gln Val Pro Ala Tyr Thr Phe Pro Ala Asn Arg Glu Asp Leu
405 410 415
Ser Ala Leu Arg Val Val Cys Arg Asn Gly Phe Ser Arg Asp Leu Ala
420 425 430
Asp Met Leu Leu Ala Asp Leu Asn Arg Leu Leu Pro Glu Leu Lys Arg
435 440 445
Gln Pro Ala Pro Leu Lys Glu Leu Gly Val Pro Val Arg Ala Gly Phe
450 455 460
His His
465
<210> 12
<211> 478
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Met Pro Leu His Gln Gly Ala Asp Arg Ala Ala Asp Ile Pro Glu Glu
1 5 10 15
Asp Arg Ala Glu Leu Arg Arg Leu Ser Leu Asn Pro Phe Tyr Gly Glu
20 25 30
Ala Asp Pro Val Ser Glu Met Thr Ser Ala Pro Pro Thr Gln Arg Leu
35 40 45
Pro Glu Gly Pro Thr Pro Pro His Thr Ala Tyr Gln Leu Val His Asp
50 55 60
Glu Leu Met Leu Asp Gly Asn Ser Arg Leu Asn Leu Ala Thr Phe Val
65 70 75 80
Thr Thr Trp Met Glu Pro Gln Ala Gly Val Leu Met Ala Glu Cys Gln
85 90 95
Asp Lys Asn Met Ile Asp Lys Asp Glu Tyr Pro Arg Thr Ala Glu Leu
100 105 110
Glu Arg Arg Cys Val Ala Met Leu Ala Asp Leu Trp Asn Ala Pro Asp
115 120 125
Pro Ala Thr Ala Val Gly Cys Ser Thr Thr Gly Ser Ser Glu Ala Cys
130 135 140
Met Leu Ala Gly Leu Ala Leu Lys Arg Arg Trp Ala Lys Arg Asn Ala
145 150 155 160
Ala Arg Tyr Pro Ala Thr Ala Arg Pro Asn Leu Val Met Gly Val Asn
165 170 175
Val Gln Val Cys Trp Glu Lys Phe Cys Thr Phe Trp Glu Val Glu Ala
180 185 190
Arg Leu Val Pro Met Glu Gly Asp Arg Phe His Leu Asp Pro Gln Ala
195 200 205
Ala Ala Asp Leu Cys Asp Glu Asp Thr Ile Gly Val Val Ala Val Leu
210 215 220
Gly Ser Thr Phe Asp Gly Ser Tyr Glu Pro Val Ala Glu Leu Cys Ala
225 230 235 240
Val Leu Asp Ala Leu Gln Glu Arg Thr Gly Leu Asp Val Pro Val His
245 250 255
Val Asp Gly Ala Ser Gly Ala Met Ile Ala Pro Phe Leu Asp Glu Asp
260 265 270
Leu Val Trp Asp Phe Arg Leu Pro Arg Val Ser Ser Ile Asn Thr Ser
275 280 285
Gly His Lys Tyr Gly Leu Val Tyr Pro Gly Val Gly Trp Ala Leu Trp
290 295 300
Arg Ser Pro Ala Glu Leu Pro Glu Glu Leu Val Phe Arg Val Asn Tyr
305 310 315 320
Leu Gly Gly Asp Met Pro Thr Phe Ala Leu Asn Phe Ser Arg Pro Gly
325 330 335
Ala Gln Val Val Ala Gln Tyr Tyr Thr Phe Leu Arg Leu Gly Arg Asp
340 345 350
Gly Tyr Arg Ala Val Gln Gln Thr Ala Arg Asp Ile Ala Thr Thr Leu
355 360 365
Ser Ala Arg Ile Glu Arg Leu Gly Gly Phe Arg Leu Leu Thr Arg Gly
370 375 380
Asp Gln Leu Pro Val Phe Ala Phe Thr Thr Ala Ser Asp Val Thr Asn
385 390 395 400
Phe Asp Val Phe Asp Val Ser Arg Arg Leu Arg Glu His Gly Trp Leu
405 410 415
Val Pro Ala Tyr Thr Phe Pro Ala His Arg Glu Asp Leu Ser Val Leu
420 425 430
Arg Val Val Cys Arg Asn Gly Phe Ser Ala Asp Leu Ala Ala Met Leu
435 440 445
Val Ala Asp Leu Lys Arg Val Leu Pro Glu Leu Arg Ala Gln Glu Arg
450 455 460
Pro Met Asp Arg Asp Pro Ser Ala Ala Thr Ala Phe His His
465 470 475
Claims (7)
1.一种谷氨酸脱羧酶重组菌，其特征在于，该重组菌为导入了谷氨酸脱羧酶基因的大肠杆菌，其中所述谷氨酸脱羧酶基因为来源于弓形链霉菌NRRL 15443的StGAD、链霉菌MJ654-NF4的SsGAD或嗜铬链霉菌ATCC 49982的ScGAD，其核苷酸序列如SEQ ID No：1-3所示。
2.一种如权利要求1所述谷氨酸脱羧酶重组菌的构建方法，其特征在于，包括以下步骤：
(1)构建质粒：分别将SsGAD、StGAD、ScGAD进行PCR扩增，以pJET1.2作为基因克隆载体，将PCR扩增后的基因序列连接在其上，采用限制性内切酶针对酶切位点NdeI和HindIII进行酶切处理，分别将SsGAD结合物、StGAD结合物、ScGAD结合物连接到相应质粒上；(2)构建重组菌：分别将上述步骤(1)中的目标质粒导入相应菌种中即得所述重组菌。
3.根据权利要求2所述谷氨酸脱羧酶重组菌的构建方法，其特征在于，上述步骤(1)的制粒为大肠表达质粒pET-28a(+)，分别得到目标质粒pHY6、pHW4、pHY1；上述步骤(2)将目标制粒pHY6、pHW4、pHY1导入大肠杆菌E.coli BL21(DE3)中即得所述重组菌。
4.根据权利要求2所述谷氨酸脱羧酶重组菌的构建方法，其特征在于，上述步骤(1)中PCR扩增中SsGAD基因的引物序列为：
5′-AACATATGGCCTTGTACAAGGGCACCG
3′-AAAAGCTTTTAGTGGTGGAAGCCGGCGCGGACC；
StGAD基因的引物序列为：
5′-AACATATGGCTCTCCACAAGACGAAGGA
3′-AAAAGCTTTTAGTGGTGGAAGCCGGAGCGGGGA；
ScGAD基因的引物序列为：
5′-AACATATGCCACTCCACCAAGGCGCGGACA
3′-AAAGCTTTTAGTGGTGGAAGGCGGTGGCGGCC。
5.根据权利要求1所述谷氨酸脱羧酶重组菌的应用，其特征在于，包括将谷氨酸脱羧酶重组菌进行扩大培养以诱导其大量表达谷氨酸脱羧酶。
6.根据权利要求2所述谷氨酸脱羧酶重组菌的应用，其特征在于，所述重组菌的扩大培养中还包括向培养基中添加IPTG作为诱导剂的步骤，上述扩大培养过程为：将所述重组菌采用含有50μg/mL卡那霉素的LB培养液，37℃，250rpm培养12小时，然后转入含有相同浓度卡那霉素的LB肉汤培养基中，37℃，250rpm培养至OD600达到0.4-0.6，添加IPTG诱导目标蛋白的表达，28℃，250rpm下持续培养16小时，收集培养液，离心，将获得的细胞体通过超声裂解后再次进行离心，取上清液即得目标蛋白。
7.根据权利要求2所述谷氨酸脱羧酶重组菌的应用，其特征在于，将所述谷氨酸脱羧酶重组菌的构建方法或所述谷氨酸脱羧酶重组菌的构建方法产生的谷氨酸脱羧酶应用于生产γ-氨基丁酸。
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