CN112375725A - 一种生产维生素b6的代谢工程菌株及其构建方法与应用 - Google Patents
一种生产维生素b6的代谢工程菌株及其构建方法与应用 Download PDFInfo
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Abstract
本发明属于生物工程技术领域，具体涉及一种生产维生素B6的代谢工程菌株及其构建方法与应用。将自然界中不存在于同一生物体的两条从头合成维生素B6的途径有机整合到大肠杆菌中，同时敲除起桥梁作用的酶PdxH，形成两条并行的生物合成通道，通道一为内源途径，用来生产维生素B6的产品形式；通道二为外源途径用来生产维生素B6的活性形式以供细胞生命活动。所构建的工程菌株中进一步通过强启动子和/或优化RBS序列适度提高外源途径的表达，因而相对于原菌株具有相同的生长速率。本发明获得的工程菌株发酵生产维生素B6的能力得到了大幅提高，具有较大的应用推广价值。
Description
技术领域
本发明属于生物工程技术领域，具体涉及一种生产维生素B6的代谢工程菌株及其构建方法与应用。
背景技术
维生素 B6在药物、食品和饲料工业中具有广泛的应用，其又叫吡哆素，是人类或其他动物不可缺少的维生素，包括三种天然形式：吡哆醇、吡哆醛和吡哆胺，在体内以磷酸酯衍生物存在。维生素B6以活性形式-磷酸吡哆醛参与近百种酶反应，其中多数与氨基酸代谢有关，例如转氨基、脱羧、脱水及转硫化反应等。维生素B6的产品形式是吡哆醇盐酸盐，目前市场上主要采用噁唑化学合成法进行人工全合成，中间体噁唑合成过程中用到强腐蚀性的三氯氧磷和有毒溶剂苯，反应控制难，潜在安全隐患大；制备工艺繁琐，能耗高，三废多，不利于环境保护等。微生物发酵法目前是生产维生素B6的最绿色环保的方法，具有重要的推广使用意义。
维生素B6的从头生物合成途径包括DXP（赤藓糖-4-磷酸）-依赖性途径和DXP-非依赖性途径。DXP-依赖性途径的直接产物为磷酸吡哆醇，可进一步由磷酸酶PdxP催化形成吡哆醇，或由磷酸吡哆醇氧化酶PdxH催化形成磷酸吡哆醛，后者为细胞的活性形式，这一途径主要存在γ-变形菌纲中，例如大肠杆菌、根瘤菌等。DXP-非依赖性途径经多亚基的PdxST酶复合物催化生成磷酸吡哆醛，供细胞生长所需，也可进一步可去磷酸化形成吡哆醛，这一途径分布广泛，主要存在于除γ-变形菌纲的细菌、真菌和植物中，如枯草芽孢杆菌、酵母和拟南芥等。到目前为止，自然界并未发现同时具有两条从头合成途径的生物体。
维生素B6的生物合成最初是Tazoe等人筛选了1590株菌株后发现，根瘤菌具有天然高产吡哆醇的能力，但产量较低（Tazoe M et al., Production of vitamin B6 inRhizobium. Biosci Biotechnol and Biochem, 1999; 63(8):1378-1382.）。根瘤菌自身的遗传操作复杂，难以进行大规模的遗传研究，这大大限制了根瘤菌作为底盘细胞进行维生素B6生产的研究。
大肠杆菌，其遗传背景清晰，分子手段多样，是一种被广泛用作表达重要化学品的生产宿主。大肠杆菌自身通过DXP-依赖性途径形成磷酸吡哆醇，经氧化酶PdxH催化形成的磷酸吡哆醛作为活性形式参与细胞生命活动。但磷酸吡哆醛具有活泼的醛基，一旦过量会对细胞产生毒性，因此细胞内部具有产物的反馈抑制机制，磷酸吡哆醛过量会抑制从头生物合成途径，而磷酸吡哆醛正是异源的DXP-非依赖性途径经磷酸吡哆醛合成酶复合体（PdxS/T或Pdx1/2）催化生成的直接产物。
因此如何结合两条从头合成途径的特点，提高吡哆醇的发酵产量同时解除反馈抑制，构建可高效生产维生素B6的大肠杆菌的底盘细胞是一个值得探讨的问题。
发明内容
本发明的目的在于解决现有技术中存在的问题，提出一种以并行通道方式高效合成维生素B6的代谢工程菌株及其构建方法与应用，通过构建生产维生素B6的大肠杆菌底盘菌株从而进行维生素B6的细胞工厂的创建，通过结合两条从头合成维生素B6的生物合成途径特点构建了一种以并行通道方式合成维生素B6的工程菌株，通道之一用来生成维生素B6的产品形式-吡哆醇，即用来生产产品；另一通道则用来提供菌体生命活动所需的磷酸吡哆醛，即用来满足细胞生长。由此获得以并行通道方式高效合成维生素B6的代谢工程菌株。而进一步的改进在于，基于桥梁作用的酶-PdxH的敲除引起了细胞生长严重受限，因此结合进一步的强启动子和RBS序列的优化，优化了通道二中生物合成途径相关酶的表达强度，最终实现工程菌株和出发菌株具有同步的生长速率，而且工程菌株本身即可在一定程度上高产维生素B6。因此，构建维生素B6并行通道的方式不仅可解除反馈抑制，且为进一步构建维生素B6的高产菌株奠定了重要的遗传基础。
本发明提供一种以并行通道方式高效合成维生素B6的代谢工程菌株的构建方法，其以大肠杆菌为出发菌株，失活或敲除其磷酸吡哆醇氧化酶基因pdxH，并引入外源DXP-非依赖性途径的磷酸吡哆醛合成酶复合体（由谷氨酰胺脱氨酶和磷酸吡哆醛合成酶组成），形成两条并行的维生素B6从头合成途径。
优选地，通过CRISPR-Cas9介导的基因编辑方法，敲除出发菌株中的磷酸吡哆醇氧化酶基因pdxH，特别以大肠杆菌MG1655为出发菌株。
优选地，是以组成型表达异源的磷酸吡哆醛合成酶复合体可以通过质粒表达方式或者基因组整合表达的方式。组成型表达异源途径中的磷酸吡哆醛合成酶复合体基因，以弥补PdxH酶缺失引起的细胞生长抑制。更优选地，通过采用CRISPR-Cas9基因编辑技术将含有编码基因的表达载体导入大肠杆菌中进行过表达，使导入的编码基因整合到pdxH基因位点上。
引入的磷酸吡哆醛合成酶复合体由谷氨酰胺脱氨酶（PdxT或Pdx2）和磷酸吡哆醛合成酶（PdxS或Pdx1）组成；异源基因来自于枯草芽孢杆菌、拟南芥、马铃薯等具有DXP-非依赖性途径的菌株。优选地，异源基因来自于枯草芽孢杆菌。
优选地方案中，引入的磷酸吡哆醛合成酶复合体，以及磷酸吡哆醛合成酶复合体的核糖体结合位点进行优化。具体地，所述磷酸吡哆醛合成酶具有SEQ ID NO：1的氨基酸序列，所述谷氨酰胺脱氨酶具有SEQ ID NO：2的氨基酸序列；所述核糖体结合位点的序列包括如SEQ ID NO：4的核苷酸序列所示的磷酸吡哆醛合成酶核糖体结合位点序列，以及如SEQID NO：5的核苷酸序列所示的谷氨酰胺脱氨酶的核糖体结合位点序列。在另一个实施方式中，所述磷酸吡哆醛合成酶具有SEQ ID NO：7的氨基酸序列，所述谷氨酰胺脱氨酶具有SEQID NO：8的氨基酸序列，进一步地，所述磷酸吡哆醛合成酶的核糖体结合位点的编码序列如SEQ ID NO：9所示；所述谷氨酰胺脱氨酶的核糖体结合位点的编码序列如SEQ ID NO：10所示。
进一步的，所述磷酸吡哆醛合成酶和谷氨酰胺脱氨酶共用启动子，优选地，具体的启动子的核苷酸序列如SEQ ID NO：3所示。
本发明提供采用上述任一项所述构建方法得到的代谢工程菌株。
进一步提供，所述的代谢工程菌株在发酵生产维生素B6中的应用。
本发明的有益效果：本发明首先所提供的构建方法中，有机结合了两条维生素B6从头合成途径的特点，提供了一种以并行通道方式合成维生素B6的工程菌株。
更进一步地，通过强启动子和/或RBS序列的优化有效地进行了异源途径的表达并完全回补了由pdxH基因缺失造成的菌体生长失衡，最终的工程菌株的生长速率与野生型同步且有效的提高了维生素B6的生产能力，实验数据表明维生素B6双通道并行形式的表达对细胞生长完全没有影响。且野生型检测不到B6产量，但工程菌株吡哆醇的发酵产量可达0.758 mg/L。
附图说明
图1为本发明所提供的构建方法的原理示意图；
图2为质粒Pcas9-pdxH KO-pdxSTOE的图谱示例。
图3为本发明所构建的工程菌株LL01、LL02、LL03和野生型的生长曲线对比图。
图4为RBS序列优化后工程菌株LL04、LL05 与野生型、LL01的生长曲线对比图。
图5为本发明所构建的工程菌株在发酵48h后得到的维生素B6-吡哆醇的产量示意图。
图6为维生素B6的高效液相色谱检测的标准曲线图。
具体实施方式
本发明的以下实施例和附图仅说明实现本发明的具体实施方案，这些方案和附图不可以理解为对本发明的限制，任何在不脱离本发明的原理和实质的情况下所做的任何改变，均落在本发明的保护范围之内。
本实施例中所用到的实验技术与实验方法，如无特殊说明均为常规技术方法。本实施例中所使用的材料、试剂等，如无特殊说明，均可通过正规商业渠道获得。
其中，实施例中用到的引用信息如下表。
表1实施例中用到的引物。
实施例1 载体Pcas9-pdxH KO、Pcas9-pdxH KO-pdxSTOE和Pcas9-pdxH KO-pdx1/ 2OE的构建。
（1）pdxH基因敲除载体的构建。
pdxH基因敲除突变株与野生型一起作为本发明的对照菌株，因此首先对pdxH基因敲除载体进行了构建:
分别利用表1的引物对Liulx-58和Liulx-59，Liulx-60和Liulx-61，以大肠杆菌Escherichia coli MG1655基因组为模板，通过PCR 扩增，得到pdxH基因的上游同源臂Up1和下游同源臂Down，经电泳验证，核酸电泳胶回收后，得到纯化的各300 bp 的Up1和Down片段。利用引物对Liulx-58和Liulx-61将Up1和Down片段融合，通过PCR 扩增得到Up1+Down片段600 bp。分别利用表1的引物对Liulx-62和Liulx-63，Liulx-64和Liulx-65，以Pcas9质粒（Jiang et al., Nat Biotechnol. 2013）为模板，通过PCR 扩增，得到5659 bp片段P1和5679 bp的片段P2，其中N20片段如SEQ ID No.6所示。将上述纯化的Up1+Down片段、P1片段和P2片段利用ClonExpress® MultiS One Step Cloning Kit（Novezyme公司，货号C113）进行连接。将连接产物转化入大肠杆菌DH5α中，涂布于含有100 mg/L 氨苄青霉素（Amp）的LB固体平板上，培养16h后进行菌落PCR检测，送金唯智测序，测序正确后，将得到的阳性菌命名为Pcas9-pdxH KO。用质粒试剂盒提取质粒Pcas9-pdxH KO备用。
（2）载体Pcas9-pdxH KO-pdxST OE的构建。
载体Pcas9-pdxH KO-pdxST OE采用了来自枯草芽孢杆菌来源的磷酸吡哆醛合成酶复合体的同源基因pdxS/pdxT进行了通道二的搭建，构建过程如下：构建方式同Pcas9-pdxH KO的构建，区别是利用表1的引物对Liulx-177和Liulx-178，Liulx-179和Liulx-132，以Bacillus subtilis 168（枯草芽孢杆菌）基因组为模板，扩增得到约890bp的PdxS片段和591bp的PdxT片段，通过融合PCR将PdxS和PdxT片段连接在UP2（引物对是Liulx-58和Liulx-124）和Down片段中间，通过Novezyme公司试剂盒（货号C113）构成质粒Pcas9-pdxH KO-pdxST OE，质粒图谱如图2所示。
本发明中通道二的异源途径的表达载体均共用一个强启动子J23118（http://parts.igem.org/Part:BBa_J23118），相关的两个基因的RBS序列均采用了De Novo DNA在线软件在Operon Calculator模块进行了核糖体的结合位点的强度调整，包括上调或下调。其中PdxS的氨基酸序列如SEQ ID No:1所示，PdxT的氨基酸序列如SEQ ID No:2所示（SEQID No:1和SEQ ID No:2是原始的氨基酸序列，不包含核糖体结合位点），共用启动子序列如SEQ ID No:3所示，PdxS和PdxT的核糖体结合位点序列分别如SEQ ID No:11和SEQ ID No:12所示。所述载体是环状表达载体，其连接方式：UP2-J23118(SEQ ID No:3)- SEQ ID No:11-PdxS(SEQ ID No:1)- SEQ ID No:12-PdxT(SEQ ID No:2)-Down-P2-P1-UP2。
（3）载体Pcas9-pdxH KO-pdx1/2 OE（st）的构建
本载体采用了来自植物中马铃薯来源的磷酸吡哆醛合成酶复合体的同源基因Pdx1/Pdx2进行了通道二的搭建，构建过程如下：构建方式同Pcas9-pdxH KO-pdxST OE的构建，区别是利用表1的引物对Liulx-182和Liulx-128，Liulx-180和Liulx-181，以Solanum tuberosum L.（马铃薯）的Pdx1/2的密码子优化的人工合成基因（金唯智基因合成）为模板，通过PCR 扩增，分别得到930 bp的Pdx1和756 bp的Pdx2片段，将Pdx1和Pdx2片段融合在上述的UP2和Down片段中间，通过Gibbson组装构成质粒Pcas9-pdxH KO-pdx1/2 OE（st）。
其中Pdx1氨基酸序列如SEQ ID No:7所示，Pdx2氨基酸序列如SEQ ID No:8所示（SEQ ID No:7和SEQ ID No:8是原始序列），由De Novo DNA在线软件设计的Pdx1和Pdx2的核糖体结合位点序列分别如SEQ ID No:13和SEQ ID No:14所示。所述载体是环状表达载体，其连接方式：UP2-J23118(SEQ ID No:3)- SEQ ID No:13-Pdx1(SEQ ID No:7)- SEQ IDNo:14-Pdx2(SEQ ID No:8)-Down-P2-P1-UP2。
实施例2 含质粒载体的工程菌株的构建。
培养基配方：
LB 培养基：氯化钠 10 g/L，胰蛋白胨10 g/L，酵母提取物5 g/L，固体培养基加琼脂粉2%。
将实施例1中的质粒Pcas9-pdxH KO，Pcas9-pdxH KO-pdxST OE，Pcas9-pdxH KO-pdx1/2 OE（st）按照如下方法转入大肠杆菌MG1655中：
（1）取新鲜活化的大肠杆菌野生型WT（MG1655）单菌落接种于5 mL LB 试管中，37℃摇床，200 rpm振荡培养12 h；
（2）以1%的接种量转接至50 mL LB摇瓶中，37℃的培养箱，200 rpm振荡培养到OD600在0.4~0.6左右；
（3）菌液转移到50 mL离心管，冰浴30 min后，4℃，4000rp离心10 min，去掉上清；
（4）加入30 mL预冷的ddH2O重悬细胞，4℃，4000 rpm离心10 min，去掉上清；
（5）重复步骤（4）；
（6）加入30 mL预冷的10%甘油，重悬细胞，4℃，4000 rpm离心10 min，去掉上清；
（7）加入500 μL 预冷的10%甘油，重悬细胞，即成感受态细胞；
（8）取80 μL感受态细胞和5 μL的质粒（Pcas9-pdxH KO、Pcas9-pdxH KO-pdxST OE和Pcas9-pdxH KO-pdx1/2 OE（st））混匀加入1 mm电转杯，擦干表面水分经电转仪电转，电压U=1.7 KV，5 ms；
（9）电转杯中加入1 mL LB并用移液枪转移到1.5 mL的离心管中，37℃摇床，200 rpm复苏1h，4000 rpm离心后剩余200 μL菌液涂布Amp平板。平板置于30℃培养箱培养直到长出单菌落；
（10）将Amp平板上的单克隆菌落接种至含Amp的5 mL LB试管中，30℃，200 rpm振荡培养直到OD600=0.2，加入终浓度为10 mM阿拉伯糖，继续培养8h，在加有Amp和阿拉伯糖的LB平板上划单菌落，30℃培养箱培养；
（11）利用表1的引物对Liulx-146和Liulx-147引物对菌落进行PCR验证，验证条带正确的菌落说明pdxH基因已敲除或者已经将pdxST或pdx1/2整合到pdxH基因组位置上；
（12）阳性菌落接种于无抗的5 mL的LB试管中，40℃，200 rpm，16 h；
（13）5 μL转接到新的无抗的5 mL的LB试管中，重复传代3-5次；
（14）在无抗的LB平板上划单菌落，挑40-60个单菌落在有或无抗性的LB平板上影印接种，在抗性平板上不生长，在无抗平板相应位置上的单菌落即已丢失质粒的工程菌株，分别命名为LL01（E. coli MG1655，Pcas9-pdxH KO）、LL02（E. coli MG1655，Pcas9-pdxH KO-pdxST OE）、LL03 (E. coli MG1655，Pcas9-pdxH KO-pdx1/2 OE（st）)。
实施例3 菌株的生长曲线测定
在实施例2中的野生型菌株和工程菌株按照如下方法测定生长曲线：
（1）取新鲜活化的WT，LL01，LL02，LL03于5 mL LB 试管中，37℃摇床，200 rpm振荡培养15 h；
（2）测定试管中菌液的OD600，转接到50 mL LB摇瓶，各三个，初始OD600=0.1，37℃摇床，200 rpm振荡培养；
（3）将未接种的LB培养基作为空白对照，对不同时间培养液从0h开始测定OD600，浓度大的菌液进行稀释后测定，结果如图3所示。其中，LL02的生长情况与LL01基本相同，LL03的生长情况明显好于LL01，但是仍弱于野生型菌株，因此进一步对通道二中的相关酶的RBS序列进行了优化，利用De Novo DNA在线软件在Operon Calculator模块进行了核糖体的结合位点的强度调整。
实施例4 通道二-外源途径中RBS的优化研究
（1）载体Pcas9-pdxH KO-pdxST OE-2的构建
本载体对同源基因PdxS/PdxT的RBS序列进行了优化，具体构建过程和所涉及序列如下所述：
载体Pcas9-pdxH KO-pdxST OE-2的构建过程同质粒Pcas9-pdxH KO-pdxST OE的构建，区别是PdxS和PdxT的的扩增引物对分别是表1中的Liulx-129和Liulx-130，Liulx-131和Liulx-132。核糖体结合位点序列分别如SEQ ID No:4和SEQ ID No:5所示。所述载体为环状表达载体的连接方式：UP2-J23118(SEQ ID No:3)- SEQ ID No:4-PdxS(SEQ ID No:1)-SEQ ID No:5-PdxT(SEQ ID No:2)-Down-P2-P1-UP2。
（2）载体Pcas9-pdxH KO-pdx1/2 OE（st）-2的构建
本载体对同源基因Pdx1/Pdx2的RBS序列进行了优化，具体构建过程和所涉及序列如下所述：载体Pcas9-pdxH KO- pdx1/2 OE（st）-2的构建过程同质粒Pcas9-pdxH KO-pdx1/2OE（st）的构建，区别是Pdx1和Pdx2的的扩增引物对分别是表1中的Liulx-127和Liulx-128，Liulx-125和Liulx-126。核糖体结合位点序列分别如SEQ ID No:9和SEQ ID No:10所示。所述载体是环状表达载体，其连接方式是：UP2-J23118(SEQ ID No:3)- SEQ ID No:9-Pdx1(SEQ ID No:7)- SEQ ID No:10-Pdx2(SEQ ID No:8)-Down-P2-P1-UP2。
同样采用实施例2的方法进行了含质粒的工程菌株的构建，工程菌株编号分别为LL04 (E. coli MG1655，Pcas9-pdxH KO-pdx1/2 OE（st）-2)，LL05（E. coli MG1655，Pcas9-pdxH KO-pdxST OE-2）。
采用实施例3的方法进行了生长曲线的测定，结果如图4所示。结果显示，其中，枯草芽孢杆菌来源的酶经过核糖体结合位点优化的工程菌株LL05完全回补了由于PdxH敲除突变株（LL01）造成的生长迟缓，并且LL05的生长与野生型几乎完全同步，而对比马铃薯来源的酶经过核糖体结合位点优化的工程菌株LL04生长仍然受到限制。因此本发明中的工程菌株LL05以两条维生素B6从头合成途径并行的方式构建得到，引入的外源途径经过了不同来源酶的筛选和核糖体结合位点的优化，其具有与野生型相同的生长速率。
相关质粒及工程菌株的相关性质见表2。
表2
实施例5 工程菌株发酵生产维生素B6及样品预处理。
培养基配方：
种子培养基：甘油10 g/L，蛋白胨10 g/L，酵母提取物5 g/L，NaCl 5 g/L，核糖1 g/L，葡萄糖0.5 g/L。
发酵培养基：甘油20 g/L，蛋白胨10 g/L，酵母提取物5 g/L，NaCl 5 g/L，核糖1g/L，葡萄糖0.5 g/L，MgSO4·7H2O 200 mg/L, FeSO4·7H2O 10 mg/L, MnSO4·5H2O 10 mg/L，pH=0.68。
在实施例2和实施4中的野生型菌株和工程菌株按照如下方法进行发酵培养：
（1）取新鲜活化的WT和LL01-LL05于5 mL 种子培养基的试管中，37℃摇床，200 rpm振荡培养15h；
（2）测定试管中菌液的OD600，转接到50 mL 发酵培养基的摇瓶（250ml摇瓶），初始OD600=0.1，37℃摇床，200 rpm振荡培养70 h。摇瓶发酵每个菌株做3个平行；
（3）菌液离心取上清，加入终浓度为0.8 M的高氯酸，冰上静置15 min；
（4）用0.8 M的K2CO3中和，离心取上清，用0.22 μm滤膜过滤后置入色谱样品瓶进行高效液相色谱检测，高效液相色谱仪配有荧光检测器。
实施例5 维生素B6的检测方法。
标准品的制备，配置梯度维生素B6标准品 (0.1 mg/L，0.5 mg/L，1 mg/L，5 mg/L，10 mg/L，20 mg/L，50 mg/L)。
HPLC检测条件：采用Microsorb-MV C18 分离柱 (150 X 4.6 mm X 5 μm），检测时柱温箱温度为40 ℃，流动相A为33 mM磷酸，8 mM 1-辛烷磺酸钠的水溶液，KOH调pH=2.2，流动相B为33 mM磷酸的水溶液，流动相C为乙腈，液相条件为：98% A/ 2% C 10min，梯度降到78% B/22% C 8 min，再到98% A/ 2% C 2 min，柱平衡5 min；流速为1.2 mL/min，激发波长293 nm,发射波长395 nm; 进样体积为15 μL。吡哆醇的产量如表3和图5所示。
表3 吡哆醇的产量和生物量OD600对比
维生素B6液相色谱检测的标准曲线图如图6所示，其中，在野生型未能检测（ND）到维生素B6的产量，而在本发明中构建的代谢工程菌株LL02-LL04等都能产生维生素B6，但在长时间的发酵过程中其生物量仍然有所影响，而代谢工程菌株LL05的产量可提高到0.758 mg/L，其生物量也高于野生型，因此优势更加明显。因此，本发明为进一步通过其他代谢工程策略构建更加高效的维生素B6细胞工厂提供了重要的底盘细胞模式。
序列表
<110> 中国科学院天津工业生物技术研究所
<120> 一种生产维生素B6的代谢工程菌株及其构建方法与应用
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50 55 60
Thr Ile Val Glu Glu Val Met Asn Ala Val Ser Ile Pro Val Met Ala
65 70 75 80
Lys Ala Arg Ile Gly His Ile Val Glu Ala Arg Val Leu Glu Ala Met
85 90 95
Gly Val Asp Tyr Ile Asp Glu Ser Glu Val Leu Thr Pro Ala Asp Glu
100 105 110
Glu Phe His Leu Asn Lys Asn Glu Tyr Thr Val Pro Phe Val Cys Gly
115 120 125
Cys Arg Asp Leu Gly Glu Ala Thr Arg Arg Ile Ala Glu Gly Ala Ser
130 135 140
Met Leu Arg Thr Lys Gly Glu Pro Gly Thr Gly Asn Ile Val Glu Ala
145 150 155 160
Val Arg His Met Arg Lys Val Asn Ala Gln Val Arg Lys Val Val Ala
165 170 175
Met Ser Glu Asp Glu Leu Met Thr Glu Ala Lys Asn Leu Gly Ala Pro
180 185 190
Tyr Glu Leu Leu Leu Gln Ile Lys Lys Asp Gly Lys Leu Pro Val Val
195 200 205
Asn Phe Ala Ala Gly Gly Val Ala Thr Pro Ala Asp Ala Ala Leu Met
210 215 220
Met Gln Leu Gly Ala Asp Gly Val Phe Val Gly Ser Gly Ile Phe Lys
225 230 235 240
Ser Asp Asn Pro Ala Lys Phe Ala Lys Ala Ile Val Glu Ala Thr Thr
245 250 255
His Phe Thr Asp Tyr Lys Leu Ile Ala Glu Leu Ser Lys Glu Leu Gly
260 265 270
Thr Ala Met Lys Gly Ile Glu Ile Ser Asn Leu Leu Pro Glu Gln Arg
275 280 285
Met Gln Glu Arg Gly Trp
290
<210> 2
<211> 196
<212> PRT
<213> 枯草芽孢杆菌(Bacillus subtilis)
<400> 2
Met Leu Thr Ile Gly Val Leu Gly Leu Gln Gly Ala Val Arg Glu His
1 5 10 15
Ile His Ala Ile Glu Ala Cys Gly Ala Ala Gly Leu Val Val Lys Arg
20 25 30
Pro Glu Gln Leu Asn Glu Val Asp Gly Leu Ile Leu Pro Gly Gly Glu
35 40 45
Ser Thr Thr Met Arg Arg Leu Ile Asp Thr Tyr Gln Phe Met Glu Pro
50 55 60
Leu Arg Glu Phe Ala Ala Gln Gly Lys Pro Met Phe Gly Thr Cys Ala
65 70 75 80
Gly Leu Ile Ile Leu Ala Lys Glu Ile Ala Gly Ser Asp Asn Pro His
85 90 95
Leu Gly Leu Leu Asn Val Val Val Glu Arg Asn Ser Phe Gly Arg Gln
100 105 110
Val Asp Ser Phe Glu Ala Asp Leu Thr Ile Lys Gly Leu Asp Glu Pro
115 120 125
Phe Thr Gly Val Phe Ile Arg Ala Pro His Ile Leu Glu Ala Gly Glu
130 135 140
Asn Val Glu Val Leu Ser Glu His Asn Gly Arg Ile Val Ala Ala Lys
145 150 155 160
Gln Gly Gln Phe Leu Gly Cys Ser Phe His Pro Glu Leu Thr Glu Asp
165 170 175
His Arg Val Thr Gln Leu Phe Val Glu Met Val Glu Glu Tyr Lys Gln
180 185 190
Lys Ala Leu Val
195
<210> 3
<211> 30
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 3
ggctagctca gtcctaggta ttgtgctagc 30
<210> 4
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 4
aaaaacaaaa gacggaggtc aaatt 25
<210> 5
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 5
ttggtttacc catacggagg agggc 25
<210> 6
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 6
ctcaaacatt acgacgaaaa 20
<210> 7
<211> 309
<212> PRT
<213> Solanum tuberosum
<400> 7
Met Ala Gly Ser Gly Val Val Thr Val Tyr Gly Asn Gly Ala Leu Thr
1 5 10 15
Glu Thr Thr Lys Gln Ser Pro Phe Ser Val Lys Val Gly Leu Ala Gln
20 25 30
Met Leu Arg Gly Gly Val Ile Met Asp Val Val Asn Ala Glu Gln Ala
35 40 45
Arg Ile Ala Glu Glu Ala Gly Ala Cys Ala Val Met Ala Leu Glu Arg
50 55 60
Val Pro Ala Asp Ile Arg Ala Gln Gly Gly Val Ala Arg Met Ser Asp
65 70 75 80
Pro Gln Leu Ile Lys Glu Ile Lys Gln Ala Val Thr Ile Pro Val Met
85 90 95
Ala Lys Ala Arg Ile Gly His Phe Val Glu Ala Gln Ile Leu Glu Ala
100 105 110
Ile Gly Val Asp Tyr Val Asp Glu Ser Glu Val Leu Thr Leu Ala Asp
115 120 125
Asp Glu Asn His Ile Asn Lys His Asn Phe Arg Ile Pro Phe Val Cys
130 135 140
Gly Cys Arg Asn Leu Gly Glu Ala Leu Arg Arg Ile Arg Glu Gly Ala
145 150 155 160
Ala Met Ile Arg Thr Lys Gly Glu Ala Gly Thr Gly Asn Ile Ile Glu
165 170 175
Ala Val Arg His Val Arg Ser Val Met Gly Asp Ile Arg Val Leu Arg
180 185 190
Asn Met Asp Asp Asp Glu Val Phe Thr Phe Ala Lys Lys Ile Gln Ala
195 200 205
Pro Tyr Asp Leu Val Met Gln Thr Lys Gln Leu Gly Arg Leu Pro Val
210 215 220
Val His Phe Ala Ala Gly Gly Val Ala Thr Pro Ala Asp Ala Ala Leu
225 230 235 240
Met Met Gln Leu Gly Cys Asp Gly Val Phe Val Gly Ser Gly Ile Phe
245 250 255
Lys Ser Gly Asp Pro Ala Lys Arg Gly Arg Ala Ile Val Gln Ala Val
260 265 270
Thr His Tyr Ser Asp Pro Gln Leu Leu Ala Glu Ile Ser Cys Gly Leu
275 280 285
Gly Glu Ala Met Val Gly Ile Asn Leu Asp Glu Lys Val Glu Arg Tyr
290 295 300
Ala Asn Arg Ser Glu
305
<210> 8
<211> 251
<212> PRT
<213> Solanum tuberosum
<400> 8
Met Val Val Gly Val Leu Ala Leu Gln Gly Ser Phe Asn Glu His Ile
1 5 10 15
Ala Val Leu Lys Arg Leu Gly Val Lys Gly Val Glu Val Arg Lys Pro
20 25 30
Glu Gln Leu Leu Asn Val Ser Ser Leu Ile Ile Pro Gly Gly Glu Ser
35 40 45
Thr Thr Met Ala Lys Leu Ala Glu Leu His Asn Leu Phe Pro Ala Leu
50 55 60
Arg Glu Phe Val Gln Met Gly Lys Pro Val Trp Gly Thr Cys Ala Gly
65 70 75 80
Leu Ile Phe Leu Ala Asn Arg Ala Thr Gly Gln Lys Thr Gly Gly Gln
85 90 95
Lys Leu Ile Gly Gly Leu Asp Cys Thr Val His Arg Asn Phe Phe Gly
100 105 110
Ser Gln Ile Gln Ser Phe Glu Thr Glu Leu Pro Ile Pro Gln Val Val
115 120 125
Ala Glu Glu Gly Gly Pro Pro Ser Phe Arg Ala Val Phe Ile Arg Ala
130 135 140
Pro Ala Ile Leu Asp Val Gly Pro Asp Val Glu Val Leu Ala Asp Ile
145 150 155 160
Pro Leu Ser Ala Ile Glu Thr Ile Asn Ser Asn Pro Ala Ile Pro Lys
165 170 175
Glu Glu Asp Ser Thr Glu Ser Gly Lys Lys Val Ile Val Ala Val Lys
180 185 190
Gln Gly Asn Leu Leu Ala Thr Ala Phe His Pro Glu Leu Thr Ala Asp
195 200 205
Thr Arg Trp His Ser Tyr Phe Leu Lys Met Val Pro Glu Ile Glu Glu
210 215 220
Gly Thr Ser Asp Ile Val Ser Thr Ser Thr Ser Asn Gln Ser Phe Gly
225 230 235 240
Ala Arg Ser Ile Ile Asp Phe Pro Ile Tyr Gln
245 250
<210> 9
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 9
ccgctcttaa ttaggaggtt gttga 25
<210> 10
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
ttaagtcata ccgggaggta tcaat 25
<210> 11
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 11
caatcctaga aaaggaggta gtcta 25
<210> 12
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 12
tttgtaacta ggaggaggga ttata 25
<210> 13
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 13
taatcattaa gtaacagagg gagca 25
<210> 14
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 14
ccattatcta ccgggaggtt gcgag 25
Claims (14)
1.一种生产维生素B6的代谢工程菌株的构建方法，其特征在于，以大肠杆菌为出发菌株，失活或敲除其磷酸吡哆醇氧化酶基因pdxH，并引入磷酸吡哆醛合成酶和谷氨酰胺脱氨酶基因，获得所述代谢工程菌株。
2.如权利要求1所述的构建方法，其特征在于，所述引入磷酸吡哆醛合成酶和谷氨酰胺脱氨酶基因是在所述代谢工程菌株中组成型表达磷酸吡哆醛合成酶和谷氨酰胺脱氨酶。
3.如权利要求1所述的构建方法，其特征在于，所述磷酸吡哆醛合成酶和谷氨酰胺脱氨酶基因来自于枯草芽孢杆菌、拟南芥、或马铃薯。
4.如权利要求3所述的构建方法，其特征在于，所述磷酸吡哆醛合成酶具有SEQ ID NO：1的氨基酸序列，所述谷氨酰胺脱氨酶具有SEQ ID NO：2的氨基酸序列。
5.如权利要求4所述的构建方法，其特征在于，所述磷酸吡哆醛合成酶的核糖体结合位点的编码序列如SEQ ID NO：4所示；所述谷氨酰胺脱氨酶的核糖体结合位点的编码序列如SEQ ID NO：5所示。
6.如权利要求3所述的构建方法，其特征在于，所述磷酸吡哆醛合成酶具有SEQ ID NO：7的氨基酸序列，所述谷氨酰胺脱氨酶具有SEQ ID NO：8的氨基酸序列。
7.如权利要求6所述的构建方法，其特征在于，所述磷酸吡哆醛合成酶的核糖体结合位点的编码序列如SEQ ID NO：9所示；所述谷氨酰胺脱氨酶的核糖体结合位点的编码序列如SEQ ID NO：10所示。
8.如权利要求1至7任一项所述的构建方法，其特征在于，所述磷酸吡哆醛合成酶和谷氨酰胺脱氨酶共用启动子，所述启动子的核苷酸序列如SEQ ID NO：3所示。
9.如权利要求1至7任一项所述的构建方法，其特征在于，所述磷酸吡哆醇氧化酶基因pdxH的敲除是通过基因编辑方法实现。
10.如权利要求2所述的构建方法，其特征在于，所述组成型表达磷酸吡哆醛合成酶和谷氨酰胺脱氨酶是通过质粒表达方式或者基因组整合表达的方式。
11.如权利要求10所述的构建方法，其特征在于，通过采用CRISPR-Cas9基因编辑方法将含有编码磷酸吡哆醛合成酶基因和谷氨酰胺脱氨酶的表达载体导入大肠杆菌中进行过表达，导入的基因整合到pdxH基因位点上。
12.如权利要求1至7任一项所述的构建方法，其特征在于，以大肠杆菌MG1655为出发菌株。
13.如权利要求1-12任一项所述构建方法得到的代谢工程菌株。
14.如权利要求13所述的代谢工程菌株在发酵生产维生素B6中的应用。
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| CN114438051A (zh) * | 2022-04-07 | 2022-05-06 | 中国科学院天津工业生物技术研究所 | 磷酸吡哆醇合酶PdxJ突变体及其在制备维生素B6中的应用 |
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