CN116949007A - 果糖1,6-二磷酸酶ii突变体及其应用 - Google Patents
果糖1,6-二磷酸酶ii突变体及其应用 Download PDFInfo
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Abstract
本发明提供果糖1,6‑二磷酸酶II突变体及其应用。将芽孢杆菌属微生物中果糖1,6‑二磷酸酶II第175位氨基酸由精氨酸(R)突变为组氨酸(H)或脯氨酸(P)后，使得微生物能够高效率地生产核苷。本发明为大规模生产核苷提供有效手段，应用前景广阔。
Description
技术领域
本发明属于微生物工程技术领域，具体地说，涉及果糖1,6-二磷酸酶II突变体及其应用。
背景技术
核苷是一类糖苷的总称。核苷是核酸和核苷酸的组成成分。核苷是由D-核糖或D-Z-脱氧核糖与嘧啶碱或嘌呤碱缩合而成。核苷一般为无色结晶，不溶于普通有机溶剂，易溶于热水，熔点为160～240℃。由D-核糖生成的核苷称核糖核苷，参与RNA组成；由D-α-脱氧核糖生成的核苷称脱氧核糖核苷，参与DNA组成。D-核糖与腺嘌呤、鸟嘌呤、胞嘧啶、胸腺嘧啶或尿嘧啶缩合生成相应的腺嘌呤核糖核苷、鸟嘌呤核糖核苷、胞嘧啶核糖核苷、胸腺嘧啶核糖核苷和尿嘧啶核糖核苷，它们分别简称为腺苷(A)、鸟苷(G)、胞苷(C)、胸苷(T)和尿苷(U)。
鸟苷和肌苷在食品和医药行业有着广泛的作用。在食品领域，鸟苷和肌苷分别是鸟苷酸二钠和肌苷酸二钠的重要前体，而鸟苷酸二钠与肌苷酸二钠组合使用作为食品增鲜剂，广泛应用于鸡精、酱油等调味品中。在医药领域，鸟苷和肌苷可以作为多种抗病毒药物的医药中间体，如无环鸟苷、三氮唑核苷、三磷酸鸟苷钠等都需要鸟苷作为合成原料。肌苷是肌苷酸的重要前体，而肌苷酸可以作为合成腺苷酸(AMP)和鸟苷酸(GMP)的前体，适用于各种原因引起的白细胞减少症、血小板减少症、各种心脏疾患、急性及慢性肝炎、肝硬化等，此外还可治疗中心视网膜炎、视神经萎缩等。
目前，微生物发酵是生产核苷的主要方法，主要使用的微生物包括枯草芽孢杆菌、解淀粉芽孢杆菌、短小芽孢杆菌等。在生长菌株的选育与改造过程中，通过使用紫外诱变、硫酸二乙酯诱变育种，定向选育核苷高产菌株；或者根据细菌中核苷酸的代谢路径和调节机理，深入了解菌株遗传背景及菌株特性，通过代谢工程手段，有目的性地对菌株进行改造，以获得性状优良、能够高产核苷的生产菌株。但目前核苷菌种的发酵性能仍较差、核苷的转化率仍较低，不能满足大规模工业化生产的需求。
发明内容
本发明的目的是提供果糖1,6-二磷酸酶II突变体及其应用。
为了实现本发明目的，第一方面，本发明提供一种果糖1,6-二磷酸酶II突变体，所述突变体包含果糖1,6-二磷酸酶II第175位氨基酸由R到H或P的突变。
本发明中，果糖1,6-二磷酸酶II在NCBI上的参考序列编号可以是NP_391590.1或CBI44672.1。
第二方面，本发明提供编码所述果糖1,6-二磷酸酶II突变体的核酸分子。
第三方面，本发明提供含有所述核酸分子的生物材料，所述生物材料包括但不限于重组DNA、表达盒、转座子、质粒载体、病毒载体或工程菌。
第四方面，本发明提供所述核酸分子或含有所述核酸分子的生物材料的以下任一应用：
(1)用于核苷的发酵生产；
(2)用于提高核苷的发酵产量；
(3)用于构建产核苷的基因工程菌。
第五方面，本发明提供核苷生产菌株的构建方法，利用基因工程手段，在具有核苷生产能力的微生物基因组中引入突变，使其编码的果糖1,6-二磷酸酶II包含R175H或R175P突变位点。
其中，所述微生物为芽孢杆菌属(Bacillus)菌种，如枯草芽孢杆菌(Bacillussubtilis)、解淀粉芽孢杆菌(Bacillus amyloliquefaciens)、短小芽孢杆菌(Bacilluspumilus)。优选枯草芽孢杆菌或解淀粉芽孢杆菌，更优选B.subtilis A1(参见CN201910599510.8)或B.a 8333。
B.a 8333菌株的构建过程如下(参见CN202111266398.X)：以菌株DSM7(ATCC23350，参见文献Genome sequence of B.amyloliquefaciens type strainDSM7Treveals differences to plant-associated B.amyloliquefaciens FZB42)基因组为模板，guaB-1f/1r和guaB-2f/3r为引物，使用Phusion超保真聚合酶(New EnglandBioLabs)扩增出2个片段。用引物guaB-1f/3r将2个片段融合，获得重组片段(ORF区核苷酸序列如SEQ ID NO:9所示)。将guaBL454F片段与pKSU质粒(pKSU质粒由南开大学王淑芳教授惠赠，参见Amarkerless gene replacement method for B.amyloliquefaciens LL3 andits use in genome reduction and improvement of poly-γ-glutamic acidproduction[J]，Applied Microbiology and Biotechnology,2014,98(21):8963-8973.Zhang W,Gao W,Feng J,et al DOI:10.1007/s00253-014-5824-2)经SalI/PstI双酶切、组装、转化等操作后得到重组质粒pKSU-guaBL454F。转化至B.a 836菌株(参见CN112574934A)中，用含2.5μg/mL氯霉素的LB平板在30℃下筛选转化子，将获得的转化子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布至含5μg/mL氯霉素的LB平板获得一次重组子；将一次重组子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布含0.8μM 5-FU的LB平板筛选二次重组子，筛选获得guaBL454F点突变菌株，获得的菌株为B.a 837。提取pBE43质粒(PBE43质粒为全基因合成，参考文献Effects ofoverexpression of key enzyme genes on guanosine accumulation in Bacillusamyloliquefaciens)，使用KpnI/SalI对质粒进行线性化，将突变的purR序列(简称R2，SEQID NO:10)及突变的tal序列(简称L5，SEQ ID NO:11)进行融合PCR，获得R2+L5片段，使用组装试剂盒连接至线性化的PBE43质粒中，构建获得质粒PBE43-R2+L5。将该质粒转化至B.a837菌株中，得到出发菌株B.a8333。
第六方面，本发明提供产核苷的工程菌的构建方法，以上述方法构建得到的核苷生产菌株作为出发菌株，采用如下①～④中的至少一种方法对出发菌株进行基因工程改造：
①利用基因工程手段，在出发菌株中引入突变，使其编码的丙酮酸激酶包含T101K、T101R或T101P突变位点；
②利用基因工程手段，在出发菌株中引入突变，使其编码丙酮酸羧化酶的pycA基因包含第一个碱基由T到G或A的突变；
③利用基因工程手段，在出发菌株中引入突变，使其编码的磷酸烯醇式丙酮酸羧激酶包含K147R或K147H突变位点；
④利用基因工程手段，在出发菌株中引入突变，使其编码的甘油醛-3-磷酸脱氢酶包含G169D或G169E突变位点。
优选地，采用①～④的组合方法对出发菌株进行基因工程改造。
本发明中，丙酮酸激酶在NCBI上的参考序列编号可以是NP_390796.1，磷酸烯醇式丙酮酸羧激酶在NCBI上的参考序列编号可以是NP_390934.2。甘油醛-3-磷酸脱氢酶在NCBI上的参考序列编号可以是NP_390780.1或CBI43831.1；
pycA基因可以来自枯草芽孢杆菌，其为：
i)SEQ ID NO:7所示的核苷酸序列；
ii)SEQ ID NO:7所示的核苷酸序列经取代、缺失和/或增加一个或多个核苷酸且表达相同功能蛋白质的核苷酸序列；
iii)在严格条件下与SEQ ID NO:7所示序列杂交且表达相同功能蛋白质的核苷酸序列，所述严格条件为在含0.1％SDS的0.1×SSPE或含0.1％SDS的0.1×SSC溶液中，在65℃下杂交，并用该溶液洗膜；
iv)与i)、ii)或iii)的核苷酸序列具有90％以上同源性且表达相同功能蛋白质的核苷酸序列。
pycA基因可以来自解淀粉芽孢杆菌，其为：
a)SEQ ID NO:8所示的核苷酸序列；
b)SEQ ID NO:8所示的核苷酸序列经取代、缺失和/或增加一个或多个核苷酸且表达相同功能蛋白质的核苷酸序列；
c)在严格条件下与SEQ ID NO:8所示序列杂交且表达相同功能蛋白质的核苷酸序列，所述严格条件为在含0.1％SDS的0.1×SSPE或含0.1％SDS的0.1×SSC溶液中，在65℃下杂交，并用该溶液洗膜；
d)与a)、b)或c)的核苷酸序列具有90％以上同源性且表达相同功能蛋白质的核苷酸序列。
第七方面，本发明提供按照所述方法构建得到的核苷生产菌株或工程菌。
第八方面，本发明提供一种生产核苷的方法，所述方法包括如下步骤：
1)培养所述核苷生产菌株或工程菌，以获得微生物的培养物；
2)从步骤1)中获得的所述培养物中收集所产生的核苷。
所述核苷包括腺苷、肌苷、鸟苷及其对应的核苷衍生物，如次黄嘌呤、肌苷酸、鸟嘌呤、鸟苷酸、核黄素、二乙酰鸟苷酸等。
借由上述技术方案，本发明至少具有下列优点及有益效果：
果糖1,6-二磷酸酶II突变体和/或甘油醛-3-磷酸脱氢酶突变体对枯草芽孢杆菌腺苷、肌苷产量提升有正效果。果糖1,6-二磷酸酶II第175位氨基酸由精氨酸(R)突变为组氨酸(H)或脯氨酸(P)后，腺苷、肌苷产量均有提升，尤其以精氨酸(R)突变为组氨酸(H)后效果最好。突变体glpXR175H工程菌株A368腺苷产量由4.4g/L提高到5.6g/L最优。
果糖1,6-二磷酸酶II突变体与甘油醛-3-磷酸脱氢酶突变体叠加，对腺苷、肌苷产量提升有正效果，突变体glpXR175H叠加突变体gapBG169E工程菌株A372腺苷产量由4.4g/L提高到6.8g/L，肌苷产量由2.2g/L提高到2.9g/L。
果糖1,6-二磷酸酶II突变体和/或甘油醛-3-磷酸脱氢酶突变体对解淀粉芽孢杆菌鸟苷、肌苷产量提升有正效果。果糖1,6-二磷酸酶II第175位氨基酸由精氨酸(R)突变为组氨酸(H)或脯氨酸(P)后，鸟苷、肌苷产量均有提升，尤其以精氨酸(R)突变为组氨酸(H)后效果最好。突变体glpXR175H工程菌株8461鸟苷产量由17.1g/L提高到18.9g/L，肌苷产量由1.5g/L提高到1.9g/L最优。
果糖1,6-二磷酸酶II突变体与甘油醛-3-磷酸脱氢酶突变体叠加，对鸟苷、肌苷产量提升有正效果，突变体glpXR175H叠加突变体gapBG169E工程菌株8471鸟苷产量由17.1g/L提高到20.6g/L，肌苷产量由1.5g/L提高到2.0g/L。
具体实施方式
本发明旨在提供一种利用微生物生产嘌呤核苷的方法，以及能够高效率生产嘌呤核苷的新微生物。
研究发现，经过修饰枯草芽孢杆菌或解淀粉芽孢杆菌的果糖1,6-二磷酸酶II和/或甘油醛-3-磷酸脱氢酶，使得微生物能够高效率地生成核苷，并且成功创制出能够高效生产核苷的新微生物，从而完成本发明。
本发明采用如下技术方案：
本发明提供一种枯草芽孢杆菌，其细胞内由gapB基因(在NCBI上的参考序列编号为Gene ID:937393)编码的甘油醛-3-磷酸脱氢酶(在NCBI上的参考序列编号为NP_390780.1)第169位氨基酸由甘氨酸(G)突变为天冬氨酸(D)或谷氨酸(E)。
gapB基因编码的甘油醛-3-磷酸脱氢酶，参与糖异生，催化3-磷酸甘油醛(G3P)氧化磷酸化为1,3-二磷酸甘油酯(BPG)，这个过程可以分为两步反应，需要辅助因子NADP(或NAD)的参与。第一步反应涉及在G3P和半胱氨酸残基之间形成半缩醛中间体，然后将该半缩醛中间体氧化为硫酯，同时将NADP(或NAD)还原为NADPH(或NADH)。第二步反应涉及还原性的NADPH(或NADH)与第二个NADP(或NAD)交换，硫酯被亲核无机磷酸盐攻击生成BPG。总反应方程式为：G3P+磷酸+NAD(P)(+)<＝>BPG+NAD(P)H。
本发明通过对gapB基因修饰，实现了对甘油醛-3-磷酸脱氢酶的突变，使得所述微生物产生核苷的能力与未修饰的菌株相比增强，最终提高了核苷的产量。
本发明还提供一种枯草芽孢杆菌，其细胞内由glpX基因(在NCBI上的参考序列编号为Gene ID：937035)编码的果糖1,6-二磷酸酶II(在NCBI上的参考序列编号为NP_391590.1)第175位氨基酸由精氨酸(R)突变为组氨酸(H)或脯氨酸(P)。枯草芽孢杆菌来源的野生型果糖1,6-二磷酸酶II及其突变体glpXR175H、glpXR175P的氨基酸序列分别如SEQ IDNO:1～3所示。
glpX基因编码的果糖1,6-二磷酸酶II，参与糖异生，催化1,6-二磷酸果糖(FBP)水解反应生成6-磷酸果糖(F6P)和磷酸。总反应方程式为：FBP+H2O<＝>F6P+磷酸。
本发明通过对glpX基因修饰，实现了对果糖1,6-二磷酸酶II的突变，使得所述微生物产生核苷的能力与未修饰的菌株相比增强，最终提高了核苷的产量。
本发明所用的枯草芽孢杆菌出发菌株为Bacillus subtilis A1(以下简称A1)，其构建方法可参见CN201910599510.8。
本发明所用的枯草芽孢杆菌突变菌株A342-pckAK147R(以下简称A358)为自行构建，其构建方法还可以参见CN202210255870.8。
本发明还提供一种解淀粉芽孢杆菌，其细胞内由gapB基因(在NCBI上的参考序列位置为BAMF_2705)编码的甘油醛-3-磷酸脱氢酶(在NCBI上的参考序列编号为CBI43831.1)第169位氨基酸由甘氨酸(G)突变为天冬氨酸(D)或谷氨酸(E)。
本发明通过对解淀粉芽孢杆菌来源的gapB基因修饰，实现了对甘油醛-3-磷酸脱氢酶的突变，使得所述微生物产生核苷的能力与未修饰的菌株相比增强，最终提高了核苷的产量。
本发明还提供一种解淀粉芽孢杆菌，其细胞内由glpX基因(在NCBI上的参考序列位置为BAMF_3546)编码的果糖1,6-二磷酸酶II(在NCBI上的参考序列编号为CBI44672.1)第175位氨基酸由精氨酸(R)突变为组氨酸(H)或脯氨酸(P)。解淀粉芽孢杆菌来源的野生型果糖1,6-二磷酸酶II及其突变体glpXR175H、glpXR175P的氨基酸序列分别如SEQ ID NO:4～6所示。
本发明通过对解淀粉芽孢杆菌来源的glpX基因修饰，实现了对果糖1,6-二磷酸酶II的突变，使得所述微生物产生核苷的能力与未修饰的菌株相比增强，最终提高了核苷的产量。
本发明所用的解淀粉芽孢杆菌出发菌株为Bacillus amyloliquefaciens 8333(以下简称B.a 8333)，其构建方法可参见CN202111266398.X。
本发明所用的解淀粉芽孢杆菌突变菌株8333-pycAT1A(以下简称8441)为自行构建，其构建方法还可以参见CN202210255870.8。
以下实施例用于说明本发明，但不用来限制本发明的范围。若未特别指明，实施例均按照常规实验条件，如Sambrook等分子克隆实验手册(Sambrook J&Russell DW,Molecular Cloning:a Laboratory Manual,2001)，或按照制造厂商说明书建议的条件。
以下实施例中涉及的丙酮酸激酶的氨基酸序列如SEQ ID NO:12所示，编码枯草芽孢杆菌来源的丙酮酸羧化酶的核苷酸序列如SEQ ID NO:7所示，编码解淀粉芽孢杆菌来源的丙酮酸羧化酶的核苷酸序列如SEQ ID NO:8所示，磷酸烯醇式丙酮酸羧激酶的氨基酸序列如SEQ ID NO:13所示。枯草芽孢杆菌来源的甘油醛-3-磷酸脱氢酶的氨基酸序列如SEQID NO:14所示，解淀粉芽孢杆菌来源的甘油醛-3-磷酸脱氢酶的氨基酸序列如SEQ ID NO:15所示。
以下实施例中所用引物如表1所示：
表1
实施例1构建丙酮酸激酶突变菌株A1-pykT101K
以菌株B.subtilis A1基因组为模板，引物pykT101K-UP-1F/pykT101K-UP-1R和pykT101K-DN-2F/pykT101K-DN-2R，使用Phusion超保真聚合酶(New England BioLabs)扩增出2个片段。用引物pykT101K-UP-1F/pykT101K-DN-2R将2个片段融合，获得重组片段。将重组片段与pKSU质粒(pKSU质粒由南开大学王淑芳教授惠赠，参见Amarkerless gene replacementmethod for B.amyloliquefaciens LL3 and its use in genome reduction andimprovement of poly-γ-glutamic acid production[J]，Applied Microbiology andBiotechnology,2014,98(21):8963-8973.Zhang W,Gao W,Feng J,et al DOI:10.1007/s00253-014-5824-2)组装、转化等操作后得到重组质粒pKSU-pykT101K。转化至B.subtilisA1菌株中，用含2.5μg/mL氯霉素的LB平板在30℃下筛选转化子，将获得的转化子接到5mlLB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布至含5μg/mL氯霉素的LB平板获得一次重组子；将一次重组子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布含0.8μM 5-FU的LB平板筛选二次重组子，筛选获得pykT101K点突变菌株，命名为A1-pykT101K，以下简称A325。
实施例2构建丙酮酸羧化酶突变菌株A325-pycAt1a
以菌株B.subtilis A1基因组为模板，引物pycAt1g-UP-1F/pycAt1a-UP-1R和pycAt1a-DN-2F/pycAt1g-DN-2R，使用Phusion超保真聚合酶(New England BioLabs)扩增出2个片段。用引物pycAt1g-UP-1F/pycAt1g-DN-2R将2个片段融合，获得重组片段。将重组片段与pKSU质粒组装、转化等操作后得到重组质粒pKSU-pycAT1A。转化至A325菌株中，用含2.5μg/mL氯霉素的LB平板在30℃下筛选转化子，将获得的转化子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布至含5μg/mL氯霉素的LB平板获得一次重组子；将一次重组子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布含0.8μM 5-FU的LB平板筛选二次重组子，筛选获得pycAt1A点突变菌株，命名为A325-pycAt1a，以下简称A342。
实施例3构建磷酸烯醇式丙酮酸羧激酶突变菌株A342-pckAK147R
以菌株B.subtilis A1基因组为模板，引物pckAK147R-UP-1F/pckAK147R-UP-1R和pckAK147R-DN-2F/pckAK147R-DN-2R，使用Phusion超保真聚合酶(New England BioLabs)扩增出2个片段。用引物pckAK147R-UP-1F/pckAK147R-DN-2R将2个片段融合，获得重组片段。将重组片段与pKSU质粒组装、转化等操作后得到重组质粒pKSU-pckAK147R。转化至A342菌株中，用含2.5μg/mL氯霉素的LB平板在30℃下筛选转化子，将获得的转化子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布至含5μg/mL氯霉素的LB平板获得一次重组子；将一次重组子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布含0.8μM5-FU的LB平板筛选二次重组子，筛选获得pckAK147R点突变菌株，命名为A342-pckAK147R，以下简称A358。
实施例4构建甘油醛-3-磷酸脱氢酶突变菌株A358-gapBG169E
以菌株B.subtilis A1基因组为模板，引物gapBG169D-UP-1F/gapBG169E-UP-1R和gapBG169E-DN-2F/gapBG169D-DN-2R，使用Phusion超保真聚合酶(New England BioLabs)扩增出2个片段。用引物gapBG169D-UP-1F/gapBG169D-DN-2R将2个片段融合，获得重组片段。将重组片段与pKSU质粒组装、转化等操作后得到重组质粒pKSU-gapBG169E。转化至A358菌株中，用含2.5μg/mL氯霉素的LB平板在30℃下筛选转化子，将获得的转化子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布至含5μg/mL氯霉素的LB平板获得一次重组子；将一次重组子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布含0.8μM5-FU的LB平板筛选二次重组子，筛选获得gapBG169E点突变菌株，命名为A358-gapBG169E，以下简称A365。
实施例5构建果糖1,6-二磷酸酶II突变菌株A358-glpXR175H
以菌株B.subtilis A1基因组为模板，引物glpXR175H-UP-1F/glpXR175H-UP-1R和glpXR175H-DN-2F/glpXR175H-DN-2R，使用Phusion超保真聚合酶(New England BioLabs)扩增出2个片段。用引物glpXR175H-UP-1F/glpXR175H-DN-2R将2个片段融合，获得重组片段。将重组片段与pKSU质粒组装、转化等操作后得到重组质粒pKSU-glpXR175H。转化至A358菌株中，用含2.5μg/mL氯霉素的LB平板在30℃下筛选转化子，将获得的转化子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布至含5μg/mL氯霉素的LB平板获得一次重组子；将一次重组子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布含0.8μM5-FU的LB平板筛选二次重组子，筛选获得glpXR175H点突变菌株，命名为A358-glpXR175H，以下简称A368。
实施例6构建果糖1,6-二磷酸酶II突变菌株A358-glpXR175P
以菌株B.subtilis A1基因组为模板，引物glpXR175H-UP-1F/glpXR175P-UP-1R和glpXR175P-DN-2F/glpXR175H-DN-2R，使用Phusion超保真聚合酶(New England BioLabs)扩增出2个片段。用引物glpXR175H-UP-1F/glpXR175H-DN-2R将2个片段融合，获得重组片段。将重组片段与pKSU质粒组装、转化等操作后得到重组质粒pKSU-glpXR175P。转化至A358菌株中，用含2.5μg/mL氯霉素的LB平板在30℃下筛选转化子，将获得的转化子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布至含5μg/mL氯霉素的LB平板获得一次重组子；将一次重组子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布含0.8μM5-FU的LB平板筛选二次重组子，筛选获得glpXR175P点突变菌株，命名为A358-glpXR175P，以下简称A369。
实施例7构建果糖1,6-二磷酸酶II突变菌株A365-glpXR175H
以菌株B.subtilis A1基因组为模板，引物glpXR175H-UP-1F/glpXR175H-UP-1R和glpXR175H-DN-2F/glpXR175H-DN-2R，使用Phusion超保真聚合酶(New England BioLabs)扩增出2个片段。用引物glpXR175H-UP-1F/glpXR175H-DN-2R将2个片段融合，获得重组片段。将重组片段与pKSU质粒组装、转化等操作后得到重组质粒pKSU-glpXR175H。转化至A365菌株中，用含2.5μg/mL氯霉素的LB平板在30℃下筛选转化子，将获得的转化子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布至含5μg/mL氯霉素的LB平板获得一次重组子；将一次重组子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布含0.8μM5-FU的LB平板筛选二次重组子，筛选获得glpXR175H点突变菌株，命名为A365-glpXR175H，以下简称A372。
实施例8构建丙酮酸羧化酶突变菌株8333-pycAt1a
以菌株Bacillus.amyloliquefaciens 8333基因组为模板，引物pycAt1g-UP-3F/pycAt1a-UP-3R和pycAt1a-DN-4F/pycAt1g-DN-4R，使用Phusion超保真聚合酶(New EnglandBioLabs)扩增出2个片段。用引物pycAt1g-UP-3F/pycAt1g-DN-4R将2个片段融合，获得重组片段。将重组片段与pKSU质粒组装、转化等操作后得到重组质粒pKSU-pycAT1A。转化至Bacillus.amyloliquefaciens 8333菌株中，用含2.5μg/mL氯霉素的LB平板在30℃下筛选转化子，将获得的转化子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布至含5μg/mL氯霉素的LB平板获得一次重组子；将一次重组子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布含0.8μM 5-FU的LB平板筛选二次重组子，筛选获得pycAt1a点突变菌株，命名为8333-pycAt1a，以下简称8441。
实施例9构建甘油醛-3-磷酸脱氢酶突变菌株8441-gapBG169E
以菌株Bacillus.amyloliquefaciens 8333基因组为模板，引物gapBG169D-UP-3F/gapBG169E-UP-3R和gapBG169E-DN-4F/gapBG169D-DN-4R，使用Phusion超保真聚合酶(NewEngland BioLabs)扩增出2个片段。用引物gapBG169D-UP-3F/gapBG169D-DN-4R将2个片段融合，获得重组片段。将重组片段与pKSU质粒组装、转化等操作后得到重组质粒pKSU-gapBG169E。转化至8441菌株中，用含2.5μg/mL氯霉素的LB平板在30℃下筛选转化子，将获得的转化子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布至含5μg/mL氯霉素的LB平板获得一次重组子；将一次重组子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布含0.8μM 5-FU的LB平板筛选二次重组子，筛选获得gapBG169E点突变菌株，命名为8441-gapBG169E，以下简称8453。
实施例10构建果糖1,6-二磷酸酶II突变菌株8441-glpXR175H
以菌株Bacillus.amyloliquefaciens 8333基因组为模板，引物glpXR175H-UP-3F/glpXR175H-UP-3R和glpXR175H-DN-4F/glpXR175H-DN-4R，使用Phusion超保真聚合酶(NewEngland BioLabs)扩增出2个片段。用引物glpXR175H-UP-3F/glpXR175H-DN-4R将2个片段融合，获得重组片段。将重组片段与pKSU质粒组装、转化等操作后得到重组质粒pKSU-glpXR175H。转化至8441菌株中，用含2.5μg/mL氯霉素的LB平板在30℃下筛选转化子，将获得的转化子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布至含5μg/mL氯霉素的LB平板获得一次重组子；将一次重组子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布含0.8μM 5-FU的LB平板筛选二次重组子，筛选获得glpXR175H点突变菌株，命名为8441-glpXR175H，以下简称8461。
实施例11构建果糖1,6-二磷酸酶II突变菌株8441-glpXR175P
以菌株Bacillus.amyloliquefaciens 8333基因组为模板，引物glpXR175H-UP-3F/glpXR175P-UP-3R和glpXR175P-DN-4F/glpXR175H-DN-4R，使用Phusion超保真聚合酶(NewEngland BioLabs)扩增出2个片段。用引物glpXR175H-UP-3F/glpXR175H-DN-4R将2个片段融合，获得重组片段。将重组片段与pKSU质粒组装、转化等操作后得到重组质粒pKSU-glpXR175P。转化至8441菌株中，用含2.5μg/mL氯霉素的LB平板在30℃下筛选转化子，将获得的转化子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布至含5μg/mL氯霉素的LB平板获得一次重组子；将一次重组子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布含0.8μM 5-FU的LB平板筛选二次重组子，筛选获得glpXR175P点突变菌株，命名为8441-glpXR175P，以下简称8463。
实施例12构建果糖1,6-二磷酸酶II突变菌株8453-glpXR175H
以菌株Bacillus.amyloliquefaciens 8333基因组为模板，引物glpXR175H-UP-3F/glpXR175H-UP-3R和glpXR175H-DN-4F/glpXR175H-DN-4R，使用Phusion超保真聚合酶(NewEngland BioLabs)扩增出2个片段。用引物glpXR175H-UP-3F/glpXR175H-DN-4R将2个片段融合，获得重组片段。将重组片段与pKSU质粒组装、转化等操作后得到重组质粒pKSU-glpXR175H。转化至8453菌株中，用含2.5μg/mL氯霉素的LB平板在30℃下筛选转化子，将获得的转化子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布至含5μg/mL氯霉素的LB平板获得一次重组子；将一次重组子接到5ml LB液体培养基中，42℃200rpm培养12h并传一代，稀释涂布含0.8μM 5-FU的LB平板筛选二次重组子，筛选获得glpXR175H点突变菌株，命名为8453-glpXR175H，以下简称8471。
实施例13枯草芽孢杆菌工程菌株产苷性能验证
1.培养基：
(1)种子培养基配方(g/L)：葡萄糖20，酵母粉5，玉米浆干粉5，磷酸二氢钾3，硫酸镁0.5，硫酸亚铁0.02，硫酸锰0.01，pH 7.0～7.2，121℃灭菌20min。
(2)发酵培养基配方(g/L)：葡萄糖60，酵母粉3.5，磷酸二氢钾3，硫酸铵25，硫酸锰0.01，硫酸镁5，味精10，玉米浆干粉15，碳酸钙25，pH 7.0～7.2，121℃灭菌20min。
2.培养方法
(1)将菌株三区划线LB平板，37℃过夜培养.
(2)挑取单菌落接种至30mL种子培养基中，110rpm，36℃培养7～8h.
(3)按10％(v/v)接种量转接至30ml发酵培养基中，摇床转速120rpm，36℃培养36h.
3.检测与结果
使用高效液相色谱仪(HPLC)对发酵液中的核苷进行检测，结果见表2。
表2摇瓶发酵生成能力评估结果(三次重复均值)
| 菌株 | 腺苷产量(g/L) | 肌苷产量(g/L) |
| A1 | 1.3 | 0.6 |
| A325 | 2.1* | 1.0* |
| A342 | 3.4* | 1.5* |
| A358 | 4.4* | 2.2* |
| A365 | 5.5* | 2.6* |
| A368 | 5.6* | 2.6* |
| A369 | 5.2* | 2.5* |
| A372 | 6.8* | 2.9* |
注：*表示与出发菌株相比具有显著差异(P＜0.01)。
由以上实验结果可知，果糖1,6-二磷酸酶II突变体对腺苷、肌苷产量提升有正效果，突变体glpXR175H工程菌株A368腺苷产量由4.4g/L提高到5.6g/L最优。果糖1,6-二磷酸酶II突变体与甘油醛-3-磷酸脱氢酶突变体叠加，对腺苷、肌苷产量提升有正效果，突变体glpXR175H叠加突变体gapBG169E工程菌株A372腺苷产量由4.4g/L提高到6.8g/L，肌苷产量由2.2g/L提高到2.9g/L。
实施例14解淀粉芽孢杆菌工程菌株产苷性能验证
1.培养基：
(1)种子培养基配方(g/L)：葡萄糖20，酵母粉5，玉米浆干粉5，磷酸二氢钾3，硫酸镁0.5，硫酸亚铁0.02，硫酸锰0.01，pH 7.0～7.2，121℃灭菌20min。
(2)发酵培养基配方(g/L)：葡萄糖120，酵母粉3.5，磷酸二氢钾3，硫酸铵25，硫酸锰0.01，硫酸镁5，味精10，玉米浆干粉15，碳酸钙25，pH 7.0～7.2，121℃灭菌20min。
2.培养方法
(1)将甘油保存的菌种划线LB平板，37℃过夜培养出单克隆。
(2)挑取单菌落接种至30mL种子培养基中，110rpm，37℃培养7～8h。
(3)按10％(v/v)接种量转接至30ml发酵培养基中，摇床转速130rpm，35℃培养70h。
3.检测与结果
使用高效液相色谱仪(HPLC)对发酵液中的核苷进行检测，结果见表3。
表3摇瓶发酵产鸟苷及肌苷评估结果(三次重复均值)
注：*表示与出发菌株相比具有显著差异(P＜0.01)。
由以上实验结果可知，果糖1,6-二磷酸酶II突变体对鸟苷、肌苷产量提升有正效果，突变体glpXR175H工程菌株8461鸟苷产量由17.1g/L提高到18.9g/L，肌苷产量由1.5g/L提高到1.9g/L最优。果糖1,6-二磷酸酶II突变体与甘油醛-3-磷酸脱氢酶突变体叠加，对鸟苷、肌苷产量提升有正效果，突变体glpXR175H叠加突变体gapBG169E工程菌株8471鸟苷产量由17.1g/L提高到20.6g/L，肌苷产量由1.5g/L提高,2.0g/L。
由此可见，本发明提供的果糖1,6-二磷酸酶II突变体和/或甘油醛-3-磷酸脱氢酶突变体，及其突变菌株对目标产物腺苷或鸟苷、肌苷产量的提升具有显著的促进作用。该果糖1,6-二磷酸酶II突变体和/或甘油醛-3-磷酸脱氢酶突变体，及其重组微生物为产腺苷或鸟苷、肌苷及以其为前体的衍生物的生产菌株的构建提供借鉴。
本发明菌株的构建，其步骤的前后顺序不限定，本领域技术人员按照本发明公开的内容达到本发明的目的均属于本发明的保护范围。
本发明中的菌株代号如A1-pykT101K、A325-pycAt1a、A342-pckAK147R、A358-gapBG169D、A358-gapBG169E等是为了方便描述，但不应理解为对本发明的限定。上述方法构建的包含有枯草芽孢杆菌丙酮酸激酶突变pykT101K，丙酮酸羧化酶突变pycAT1A等工程菌，磷酸烯醇式丙酮酸羧激酶突变pckAK147R等工程菌，和甘油醛-3-磷酸脱氢酶突变gapBG169D、gapBG169E等工程菌以及包含有解淀粉芽孢杆菌甘油醛-3-磷酸脱氢酶突变gapBG169D、gapBG169E等工程菌的用途，包括但是不局限于腺苷或鸟苷、肌苷。
虽然，上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述，但在本发明基础上，可以对之做一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。
序列表
<110> 廊坊梅花生物技术开发有限公司
<120> 果糖1,6-二磷酸酶II突变体及其应用
<130> KHP221113207.9
<160> 15
<170> SIPOSequenceListing 1.0
<210> 1
<211> 321
<212> PRT
<213> 枯草芽孢杆菌(Bacillus subtilis)
<400> 1
Met Glu Arg Ser Leu Ser Met Glu Leu Val Arg Val Thr Glu Ala Ala
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Ala Leu Ala Ser Ala Arg Trp Met Gly Arg Gly Lys Lys Asp Glu Ala
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Asp Glu Ala Ala Thr Ser Ala Met Arg Asp Val Phe Asp Thr Val Pro
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Met Lys Gly Thr Val Val Ile Gly Glu Gly Glu Met Asp Glu Ala Pro
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Asp Val Ala Val Asp Pro Leu Glu Gly Thr Asn Ile Leu Ala Ser Gly
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Glu Asp Leu Val Lys Gly Asp Asp Ala Ile Phe Ala Ala Thr Gly Val
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Val Asp Gly Arg His Ser Leu Lys Lys Lys Pro Asn Leu Val Ile Arg
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<210> 2
<211> 321
<212> PRT
<213> 人工序列(Artificial Sequence)
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Met Glu Arg Ser Leu Ser Met Glu Leu Val Arg Val Thr Glu Ala Ala
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Ala Leu Ala Ser Ala Arg Trp Met Gly Arg Gly Lys Lys Asp Glu Ala
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Asp Glu Ala Ala Thr Ser Ala Met Arg Asp Val Phe Asp Thr Val Pro
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Ala Val Ala Lys Ala Lys Asn Lys Asp Val Glu Asp Val Val Ala Thr
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Ile Leu Asn Arg Glu Arg His Ala Lys Ile Ile Ser Glu Leu His Glu
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Glu Asp Leu Val Lys Gly Asp Asp Ala Ile Phe Ala Ala Thr Gly Val
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Thr Asp Gly Glu Leu Leu Lys Gly Val Gln Phe Lys Gly Ser Val Gly
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Val Asp Gly Arg His Ser Leu Lys Lys Lys Pro Asn Leu Val Ile Arg
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<210> 3
<211> 321
<212> PRT
<213> 人工序列(Artificial Sequence)
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Met Glu Arg Ser Leu Ser Met Glu Leu Val Arg Val Thr Glu Ala Ala
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Ala Leu Ala Ser Ala Arg Trp Met Gly Arg Gly Lys Lys Asp Glu Ala
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Asp Glu Ala Ala Thr Ser Ala Met Arg Asp Val Phe Asp Thr Val Pro
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Leu Asn Ala Pro Asp Met Tyr Met Gln Lys Ile Ala Val Gly Pro Glu
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Ala Val Gly Cys Ile Asp Ile Glu Ala Pro Val Ile Asp Asn Leu Lys
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Ala Val Ala Lys Ala Lys Asn Lys Asp Val Glu Asp Val Val Ala Thr
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Ile Leu Asn Arg Glu Arg His Ala Lys Ile Ile Ser Glu Leu Pro Glu
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Ala Gly Ala Arg Ile Lys Leu Ile Asn Asp Gly Asp Val Ala Gly Ala
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Ile Asn Thr Ala Phe Asp His Thr Gly Val Asp Ile Leu Phe Gly Ser
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Glu Asp Leu Val Lys Gly Asp Asp Ala Ile Phe Ala Ala Thr Gly Val
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Thr Asp Gly Glu Leu Leu Lys Gly Val Gln Phe Lys Gly Ser Val Gly
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Thr Thr Glu Ser Leu Val Ile Arg Ala Lys Ser Gly Thr Val Arg Phe
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Val Asp Gly Arg His Ser Leu Lys Lys Lys Pro Asn Leu Val Ile Arg
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Pro
<210> 4
<211> 321
<212> PRT
<213> 解淀粉芽孢杆菌(Bacillus amyloliquefaciens)
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Met Glu Arg Ser Leu Ser Met Glu Leu Val Arg Val Thr Glu Ala Ala
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Ala Leu Ala Ser Ala Arg Trp Met Gly Arg Gly Lys Lys Asp Glu Ala
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Asp Asp Ala Ala Thr Ser Ala Met Arg Asp Val Phe Asp Thr Val Pro
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Met Lys Gly Thr Val Val Ile Gly Glu Gly Glu Met Asp Glu Ala Pro
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Met Leu Tyr Ile Gly Glu Lys Leu Gly Asn Gly Tyr Gly Pro Arg Val
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Asp Val Ala Val Asp Pro Leu Glu Gly Thr Asn Ile Val Ala Ser Gly
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Ala Val Ala Lys Ala Lys Asn Lys Asp Ile Glu Asp Val Val Ala Thr
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Ile Asn Thr Ala Phe Asp His Thr Gly Val Asp Ile Leu Phe Gly Ser
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Ala Arg Cys Glu Arg Met Gly Leu Asp Val Ser Lys Val Leu Arg Leu
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Glu Asp Leu Val Arg Gly Asp Asp Ala Ile Phe Ala Ala Thr Gly Val
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Thr Asp Gly Glu Leu Leu Lys Gly Val Gln Phe Lys Gly Ser Val Gly
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Thr Thr Glu Ser Leu Val Ile Arg Ala Lys Ser Gly Thr Val Arg Phe
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<212> PRT
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Met Glu Arg Ser Leu Ser Met Glu Leu Val Arg Val Thr Glu Ala Ala
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Ile Leu Asn Arg Asp Arg His Glu Arg Ile Ile Ser Glu Leu His Glu
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Glu Asp Leu Val Arg Gly Asp Asp Ala Ile Phe Ala Ala Thr Gly Val
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Val Asp Gly Arg His Ser Leu Lys Lys Lys Pro Asn Leu Val Ile Arg
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Pro
<210> 6
<211> 321
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Met Glu Arg Ser Leu Ser Met Glu Leu Val Arg Val Thr Glu Ala Ala
1 5 10 15
Ala Leu Ala Ser Ala Arg Trp Met Gly Arg Gly Lys Lys Asp Glu Ala
20 25 30
Asp Asp Ala Ala Thr Ser Ala Met Arg Asp Val Phe Asp Thr Val Pro
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Met Lys Gly Thr Val Val Ile Gly Glu Gly Glu Met Asp Glu Ala Pro
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Ala Gly Ala Arg Ile Lys Leu Ile Asn Asp Gly Asp Val Ala Gly Ala
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Ile Asn Thr Ala Phe Asp His Thr Gly Val Asp Ile Leu Phe Gly Ser
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Gly Gly Ala Pro Glu Gly Val Leu Ser Ala Val Ala Leu Lys Ala Leu
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Gly Gly Glu Ile Ile Gly Arg Leu Arg Pro Gln Ser Ala Glu Glu Gln
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Ala Arg Cys Glu Arg Met Gly Leu Asp Val Ser Lys Val Leu Arg Leu
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Glu Asp Leu Val Arg Gly Asp Asp Ala Ile Phe Ala Ala Thr Gly Val
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Thr Asp Gly Glu Leu Leu Lys Gly Val Gln Phe Lys Gly Ser Val Gly
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Thr Thr Glu Ser Leu Val Ile Arg Ala Lys Ser Gly Thr Val Arg Phe
290 295 300
Val Asp Gly Arg His Ser Leu Lys Lys Lys Pro Asn Leu Val Ile Arg
305 310 315 320
Pro
<210> 7
<211> 3447
<212> DNA
<213> 枯草芽孢杆菌(Bacillus subtilis)
<400> 7
ttgtctcagc aatcgataca aaaagtatta gtagcaaaca ggggagaaat tgcaatccga 60
atattccggg cgtgtaccga gttgaatatt cgtacagttg cggtctattc aaaagaagat 120
tccggttcct accatcggta caaagcggat gaagcatact tggtcggtga agggaaaaaa 180
ccgattgatg cttacctgga tattgaaggt atcattgata ttgcgaaaag aaacaaagtc 240
gatgcaattc atccgggata cggtttctta tctgaaaata ttcattttgc gagacgatgt 300
gaagaagaag gcatcgtatt catagggcca aaatccgagc atctcgatat gtttggtgac 360
aaggtaaaag cgcgtgagca ggcagaaaaa gcgggaatcc ccgtgattcc gggaagcgac 420
ggtcctgccg aaacgcttga agccgtcgaa caatttggac aagctaacgg ttatccgatc 480
atcattaaag cctcgcttgg cggcggcggc cgcggtatgc ggattgtcag atctgaaagt 540
gaagttaaag aagcatatga gcgtgctaaa tcagaggcga aagcagcctt tggcaatgat 600
gaagtttatg tagaaaaatt aattgagaat ccgaaacata ttgaggttca ggtcattgga 660
gacaagcagg gcaatgtcgt ccatcttttt gagagggatt gctccgttca aagacgccat 720
caaaaagtca ttgaagtggc gccgagtgtc tcgctgtcac ctgaattaag ggaccaaatt 780
tgtgaggctg cagttgcgct tgccaaaaat gtaaactata taaatgcggg gacggtcgaa 840
ttccttgttg caaacaacga gttctacttt attgaagtaa atcctcgcgt acaagttgaa 900
cacacgataa cagaaatgat tactggtgtc gatattgttc aaactcagat ccttgttgcc 960
caagggcaca gccttcacag caaaaaagta aatattcctg agcaaaagga catttttaca 1020
atcggctatg ccattcagtc acgggttacg actgaggatc cgcaaaatga tttcatgcct 1080
gatacaggaa aaatcatggc ttaccgctca ggcggcggtt ttggtgtccg tcttgatacc 1140
ggaaacagct tccagggcgc cgtgatcaca ccatactatg attcacttct cgttaagctt 1200
tcaacttggg ctttaacgtt tgaacaggca gctgccaaaa tggtgcgaaa ccttcaggag 1260
tttagaatca gaggcataaa aacgaacatt ccgttccttg agaacgttgc aaagcatgag 1320
aagttcctga cagggcaata tgatacatct ttcattgata caacgcctga attatttaat 1380
ttccctaaac aaaaagaccg cggaacgaaa atgctcactt acatcggcaa tgtgacagtg 1440
aacggcttcc ctggaatcgg gaaaaaagaa aaaccggcgt ttgacaaacc gttaggcgta 1500
aaggtagacg ttgatcagca gcctgccaga ggaacaaagc aaattctcga tgaaaaaggt 1560
gcagaagggc ttgcaaattg ggttaaggag cagaaatctg tccttttaac tgatacgaca 1620
ttcagggatg cccaccaatc gttattggca actagaatca gatcgcatga tttgaaaaaa 1680
atcgcaaatc cgacggctgc gttatggcct gaactattca gtatggaaat gtggggaggc 1740
gcgaccttcg atgtagccta ccgattcctg aaagaagatc cgtggaaacg tttggaagat 1800
cttcgcaaag aagtgccgaa taccttattc cagatgttgc ttcgctcatc aaatgcggtc 1860
ggctatacga attatccgga caatgtgatt aaagaatttg tgaagcaatc agctcaatcc 1920
ggtattgatg tgtttcgtat tttcgacagc ttaaactggg taaaagggat gacgttagcc 1980
attgatgctg ttagggatac cggcaaagtg gcagaagctg cgatttgtta tacgggagat 2040
atccttgaca agaaccggac gaagtacgac cttgcatatt atacatcgat ggcgaaggag 2100
cttgaggcgg ccggagccca tattctcggg attaaagata tggcagggct gttaaaaccg 2160
caggctgcat atgagctcgt ttctgcgttg aaagaaacga tcgacattcc ggttcacctt 2220
catacgcatg atacgagcgg aaacggtatt tatatgtatg cgaaagctgt tgaagccggc 2280
gttgatatca tagacgtggc ggtcagctca atggcgggat taacgtcaca gcctagcgcg 2340
agcggatttt atcatgcgat ggaaggcaac gaccgccgtc cggaaatgaa tgtccaaggc 2400
gttgaattgc tgtcccaata ttgggagtcg gtgcgtaaat attatagtga atttgaaagc 2460
ggaatgaagt ctccgcatac tgaaatttat gaacacgaaa tgccaggggg ccaatacagc 2520
aacctgcagc agcaagccaa gggagtaggc cttggcgacc gctggaacga agtcaaggaa 2580
atgtacagac gcgtgaacga tatgttcggt gacatcgtca aggtaacgcc ttcctcaaaa 2640
gtagtcggag atatggcact ctacatggtg caaaacaatc tgactgaaaa agacgtttac 2700
gaaaaaggtg aatctttaga tttccctgat tctgtcgtgg agctttttaa aggaaatatc 2760
ggccagcctc atggcggatt cccagaaaaa ctgcaaaagc tgatcttaaa agggcaggag 2820
ccgattacag tcagaccggg cgaactgctt gagccggtgt catttgaagc gatcaaacag 2880
gaatttaaag agcagcataa cttggaaatt tcagatcagg atgctgtggc atatgccctt 2940
tatcctaaag tcttcactga ttatgtgaaa acgacagaaa gctatggaga catctcggta 3000
ttagatacac cgacattctt ctacggtatg acattaggtg aagagataga agttgaaatt 3060
gagcgcggca aaacgctgat cgttaagctg atttcaatcg gtgagcctca gcctgatgcc 3120
acccgcgtcg tttatttcga actcaacggg cagccgcgtg aagtagtcat taaagatgaa 3180
agcattaagt cttccgttca ggaaaggctg aaagcagacc ggacaaatcc aagccacatc 3240
gcagcttcca tgcctggaac agttattaag gtattggctg aagcaggcac aaaagtcaat 3300
aaaggtgatc atttgatgat taatgaagcg atgaaaatgg aaacaacggt tcaggcgcct 3360
ttctcaggaa caatcaagca ggttcatgtg aaaaatggtg agccgatcca aacgggagat 3420
ctgctccttg aaattgaaaa agcataa 3447
<210> 8
<211> 3447
<212> DNA
<213> 解淀粉芽孢杆菌(Bacillus amyloliquefaciens)
<400> 8
ttgtcacaac aatccatcca aaaagtgtta gtagcaaaca ggggagaaat tgcgatccgg 60
attttccggg cgtgcacaga attgaacatc agaacggtag ccgtttattc aaaagaagat 120
tcaggttcct accaccgcta taaagcggat gaagcctatc ttgtcggaga aggcaaaaaa 180
ccgattgacg cgtatcttga tattgaaggg attattgaga tcgcgaaaag aaacggcgtt 240
gatgccattc atccgggcta tggatttctg tctgaaaata tccaatttgc gagacgctgt 300
gaagaagagg gcatcgtatt tatcggaccg acgtcagcgc atttggatat gttcggagat 360
aaggtcaagg ccagagagca ggcggaaaaa gccggcatcc ccgttattcc ggggagtgac 420
gggcctgccg aaacattaaa agatgtcgaa caattcgcaa aagtacacgg atttccgttt 480
attattaaag cgtcgctcgg aggcggcggc cgcggaatga gaatcgtcag gaacgaaaac 540
gaattgaaag attcgtttga gcgggccaaa tccgaagcga aagccgcatt cggaaacgac 600
gaagtgtatg ttgaaaaact gatcgaaaat cctaagcata ttgaagttca ggtgatcgga 660
gataaagaag gaaatgtcgt ccatctgtat gagcgggact gttccgttca aagacggcat 720
caaaaggtca ttgaggtggc gccgagcgtg tccttacagc ctgaattaag agacgagatc 780
tgtgaagcgg ctgtcgcact tgcgaaaaat gtcggctata tcaacgctgg aacagtggaa 840
tttctcgtag cggacggtga attttacttt attgaagtga atccgcgcgt acaagtggag 900
catacgatta cggaaatgat tacgggggtt gatatcgttc agacgcaaat cctcgtcgcg 960
cagggccacg gtctgcacag ccgtgccgtc aacatccctc atcagaaaga catttttaca 1020
aacgggtatg cgatacagtc acgcgtgacc actgaagatc cgctgaatga ctttatgcct 1080
gacacgggta aaattatggc ttaccgctca ggcggcggct tcggcgtgcg tcttgatact 1140
gggaacagct tccaaggcgc cgtcatcacg ccttattatg attcactgct cgtcaagctg 1200
tcgacatggg cgctgacgtt tgaacaggca tccgcaaaaa tggtccgcaa cctgcaggaa 1260
ttcagaatca ggggcattaa gaccaatatc ccgtttcttg aaaacgtggc aaagcatgaa 1320
aaattcctga cgggacaata cgatacatcg tttatcgaca caacgcctga gctgtttgtt 1380
tttcctaaac agaaggaccg cggaacaaaa atgctttcct atatcggcaa tgtaacggtg 1440
aacggttttc cgggaatcgg aaaaaaagaa aaacctgcgt ttgataagcc ccagactgtt 1500
acgttaggta tcggcgaaaa gccggcaagc ggcacgaagc agattcttga tgaaagaggc 1560
gctgaagggc ttgctgactg ggtgaaagag cagaaatccg tacttctgac cgatacaacg 1620
ttcagggatg cccatcagtc cctgcttgca acccggatca gatccaatga cttgaaaaaa 1680
atcgcaaacc ctacggctgc tctgtggcct gaactgttca gccttgaaat gtggggtggg 1740
gcgacatttg atgtagcgta ccgtttctta aaggaagatc cttggaaacg ccttgaagat 1800
ctccgcaagg aagtgccgaa cacattgttc cagatgctgc ttcgttcatc aaatgccgtc 1860
ggctatacaa actatccgga caatgtcatt caaaaatttg tccggcagtc agcagcatca 1920
ggtattgacg tattccggat ctttgacagc ctgaactggg tgaaagggat gacgctggcc 1980
atcgatgccg tccgtgaaac cggaaaagtg gcggaggctg cgatttgtta tacgggagat 2040
attcttgata agagccggac gaagtatgat ctgaaatact atctttctat ggcaaaagag 2100
cttgaggcat cgggagcgca tattctcggc attaaagaca tggccggtct tttgaaacct 2160
caagccgcat acgaacttgt ctcagcgctg aaggaaacga ttgatattcc cgttcatctt 2220
cacacgcatg atacgagcgg caacggcgtc tttctctatg ccaaagccgt tgaagcgggt 2280
gtggatatcg tagatgtcgc cgtcagctca atggcgggtc tgacttcaca gccgagtgca 2340
agcggatttt atcatgcgct tgaaggaaac agccgccgtc ctgaaatgga tgtccggcag 2400
gttgaaagac tgtcacaata ttgggaatcc gtccgtcaat attacagtga atttgaaagc 2460
gggatgaagt ctccgcatac tgagatttat aatcacgaaa tgccgggcgg acagtacagc 2520
aatctgcagc agcaggcaaa aggagtcggc ctcggcgacc gctggaatga agtgaaagac 2580
atgtacagcg tcgtcaaccg catgttcggc gacgtcgtta aagtaacgcc ttcttccaaa 2640
gtcgtcggag atatggcgct ttacatggtg caaaacaatt taacggaaca agatgtttat 2700
gataaaggcg aaactcttga ttttccggat tctgttgttg agctctttaa aggacagatc 2760
ggccagccgc acggcggatt tccggaaaaa ctgcaaaagc tcgttctaaa aggacagacg 2820
ccgattaagg taagaccggg tgaactgctt gaaccggtat cttttgaagg catcaaagaa 2880
gaatggaaag aaactcatca gatggaattg agtgatcagg acgcaatcgc gtatgctctt 2940
tatccgaagg tattcactga atacgttaaa acggctgaac gcttcggtga tatttccgta 3000
ttggacacac cgactttctt ctacggcatg aggctcggtg aagaaatcga agtggaaatc 3060
gagcgaggaa aaacgctgat cgtaaagctt gtgtctatcg gtgaaccgca gcctgatgcg 3120
acacgtgtcg tttattttga gttgaacggc cagcctcgtg aggtggtcat taaagatgaa 3180
agcattaaat catccgtaca ggaaaaatta aaggccgatc ggacaaaccc aagccacatc 3240
gcagcatcaa tgccgggaac cgttattaaa ttgttaacgc aaaccggtgc gaaggtgaac 3300
aaaggggatc atctgatgat taatgaagcg atgaaaatgg agacgacggt gcaggcgccg 3360
ttctccggga cgattcagca gattcatgtg aaaaacggtg aaccgattca gacaggcgat 3420
ttactgattg agattgaaaa agcgtag 3447
<210> 9
<211> 1467
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 9
atgtgggaaa gtaaattttc aaaagaaggc ttaacgttcg atgatgtact gctcgtacca 60
gctcaatcag acgtacttcc gcgtgatgtg gatttgtctg ttgaactgac aaaaacgtta 120
aagcttaata ttcctgtcat cagtgcagga atggatacag taacagaatc agcaatggcg 180
attgcgatgg cccgacaagg cggcttgggc attattcata aaaacatgtc catcgaacag 240
caggctgaac atgttgacaa agtcaaacgt tctgaacggg gcgttattac aaatcccttc 300
tttttaacac ctgatcatca agtattcgat gcggagcatt tgatggggaa atacagaatt 360
tccggtgttc cgatcgtaga taataaagac gatcaaaagc tggtcggtat cattacaaac 420
cgcgatcttc gctttatctc tgattattca atgaaaatca gtgatgttat gacaaaagaa 480
gagctggtta cggctcctgt gggaaccaca ttagacgaag cggaaaaaat cttgcagaag 540
cataaaattg aaaaacttcc attagtggat gaccaaaaca aattaaaagg tcttatcacg 600
atcaaagata ttgaaaaggt tatcgaattc ccgaattcat ctaaagatga acacggacgc 660
ctgatcgtcg gcgctgcggt aggcgtgaca ggtgatacaa tgactcgtgt cagcaagctt 720
gttgaagcga atgtcgacgt tatcgtggtt gatacggctc acggacattc cagaggcgta 780
ctgaacacag ttgcgaaaat ccgtgagaca tatcctgaat tgaacattat cgcaggaaat 840
gttgctacgg ctgaagcgac aaaggctttg attgaagccg gagcaaacat tgtaaaagtg 900
ggaatcggac ctggatctat ctgtacgaca cgcgtcgttg caggcgtagg tgtaccgcaa 960
atcactgcga tttatgattg tgccactgaa gcgagaaaac acggcgcaac aattatcgcg 1020
gacggcggta ttaaattctc cggagatatt acgaaagcat tggcatccgg cggacatgct 1080
gtcatgcttg gaagcctgct tgccggtact tcagaaagcc cgggcgaaac tgaaatctat 1140
caaggcagaa gatttaaagt gtatcgcggt atgggttctg tcgctgccat ggaaaaaggc 1200
agtaaagacc gatatttcca agaagaaaat aagaaattcg tccctgaagg tatcgaagga 1260
cggactccgt acaaaggtcc tgtagaagaa acagtgtatc agcttgtcgg cggtcttcgt 1320
tcaggtatgg gatattgcgg ttcaaaagac ttgcgcgctt ttagagaaga agctcaattt 1380
atccgtatga caggagcagg tcttcgcgaa agccatccgc atgatgtcca aatcacgaag 1440
gaatcaccaa actacacaat ctcataa 1467
<210> 10
<211> 931
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
acagaatgct cttgattaaa tccgtatgtt aagttatatt ttttttaatt tttcggattt 60
tgggggtaag ttcatgaagt ttcgtcgcag cggcagattg gtggacttaa caaattattt 120
gttaacccat ccgcatgaat taataccgtt aacgtttttc tcagaacggt atcaatcagc 180
aaagtcatca atcagtgaag atttaacaat tattaaacag accttcgaac agcaaggcat 240
tgggacgctg cttacagtgc cgggagctgc cggaggcgtc aaatatattc cgaaagtaaa 300
acaggctgaa gcagaagcgt ttatacagga gctgggacag tctttagtaa atcctgagcg 360
tatccttccg ggcggttatg tatatttaac ggatatctta ggcaaacctt ctgtcctctc 420
taatgcaggc aggctttttg cttccgtttt tgcggagcgg gagattgatg tggtgatgac 480
cgttgcgaca aaaggaatcc ctcttgctta cgcagcggcc agttatctga acgttccggt 540
tgtcatcgta cgaaaagaca ataaagtgac ggaaggctct acagtgagca tcaattatgt 600
atcagggtcg tctaaccgca ttcaaacaat gtcgcttgcg aaaagaagtt tggccacggg 660
gtcgaacgtt ttgattattg acgactttat gaaagccggc ggcacaatta acggcatgat 720
cagcctgctt gatgagttta atgcgaacgt cgcgggtata ggcgtcttgg ttgaagctga 780
gggagtgaat gaacggcttg tcgatgaata catgtcgctg cttacccttt caaccatcaa 840
catgaaagac aaaacgattg agattcaaaa cggcaatttt ctgcgatttt ttaaagaaca 900
gcatttaaag aatggggaga cagaaaaatg a 931
<210> 11
<211> 839
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 11
atgttatttt tcattgatac agcaaacatt gacgagatta aagaagctta tgaacttggc 60
gttcttgccg gagttacgac aaaccctagt ttagtggcaa aagaagctga cgtgtctttc 120
catgacagac tgcgtgagat tacggaagtc gtgaaaggat ctgtaagcgc ggaagtcatt 180
tccctgaacg ctgaagaaat gattgaagaa ggtaaagaac ttgcgaaaat cgcgccgaat 240
atcacggtaa aaattccgat gacgtctgaa ggattaaaag ccgtaaaagc gctgagcgac 300
ctgaacatta aaacaaacgt gacgctcatc ttcagcgcca accaggcgct tttggccgcc 360
agagccggag cgacttatgt ttctccgttc ttaggccgtc tggatgatat cggtcataac 420
ggtcttgaac tgatttcaga aataagacag atttttgacc ttcatgacat tgatacacaa 480
atcatcgcag cttccatccg tcatgcgcag cacgtgactg aagccgcttt acgcggtgcc 540
catatcggta cgatgccgct gaaagttatt caccagctga caaagcaccc gttaacggat 600
aaaggcatcg agcaattctt ggcagactgg aataaataag ggcgaaaagg gcggcaaacc 660
ggttgcatcc gtttgccgca cccttatgtt ttcctgtttg acggcgggcc ttcaatatca 720
aagttccccg gaatgtaaac ccggcgggtc tctatgcatc ctatgttaaa aatgccccgc 780
aaagcttcgc tattttcttc ctgttatttt ataatgtcct tgtattcttt ctcttcgaa 839
<210> 12
<211> 585
<212> PRT
<213> 枯草芽孢杆菌(Bacillus subtilis)
<400> 12
Met Arg Lys Thr Lys Ile Val Cys Thr Ile Gly Pro Ala Ser Glu Ser
1 5 10 15
Ile Glu Met Leu Thr Lys Leu Met Glu Ser Gly Met Asn Val Ala Arg
20 25 30
Leu Asn Phe Ser His Gly Asp Phe Glu Glu His Gly Ala Arg Ile Lys
35 40 45
Asn Ile Arg Glu Ala Ser Lys Lys Leu Gly Lys Asn Val Gly Ile Leu
50 55 60
Leu Asp Thr Lys Gly Pro Glu Ile Arg Thr His Thr Met Glu Asn Gly
65 70 75 80
Gly Ile Glu Leu Glu Thr Gly Lys Glu Leu Ile Ile Ser Met Asp Glu
85 90 95
Val Val Gly Thr Thr Asp Lys Ile Ser Val Thr Tyr Glu Gly Leu Val
100 105 110
His Asp Val Glu Gln Gly Ser Thr Ile Leu Leu Asp Asp Gly Leu Ile
115 120 125
Gly Leu Glu Val Leu Asp Val Asp Ala Ala Lys Arg Glu Ile Lys Thr
130 135 140
Lys Val Leu Asn Asn Gly Thr Leu Lys Asn Lys Lys Gly Val Asn Val
145 150 155 160
Pro Gly Val Ser Val Asn Leu Pro Gly Ile Thr Glu Lys Asp Ala Arg
165 170 175
Asp Ile Val Phe Gly Ile Glu Gln Gly Val Asp Phe Ile Ala Pro Ser
180 185 190
Phe Ile Arg Arg Ser Thr Asp Val Leu Glu Ile Arg Glu Leu Leu Glu
195 200 205
Glu His Asn Ala Gln Asp Ile Gln Ile Ile Pro Lys Ile Glu Asn Gln
210 215 220
Glu Gly Val Asp Asn Ile Asp Ala Ile Leu Glu Val Ser Asp Gly Leu
225 230 235 240
Met Val Ala Arg Gly Asp Leu Gly Val Glu Ile Pro Ala Glu Glu Val
245 250 255
Pro Leu Val Gln Lys Glu Leu Ile Lys Lys Cys Asn Ala Leu Gly Lys
260 265 270
Pro Val Ile Thr Ala Thr Gln Met Leu Asp Ser Met Gln Arg Asn Pro
275 280 285
Arg Pro Thr Arg Ala Glu Ala Ser Asp Val Ala Asn Ala Ile Phe Asp
290 295 300
Gly Thr Asp Ala Ile Met Leu Ser Gly Glu Thr Ala Ala Gly Ser Tyr
305 310 315 320
Pro Val Glu Ala Val Gln Thr Met His Asn Ile Ala Ser Arg Ser Glu
325 330 335
Glu Ala Leu Asn Tyr Lys Glu Ile Leu Ser Lys Arg Arg Asp Gln Val
340 345 350
Gly Met Thr Ile Thr Asp Ala Ile Gly Gln Ser Val Ala His Thr Ala
355 360 365
Ile Asn Leu Asn Ala Ala Ala Ile Val Thr Pro Thr Glu Ser Gly His
370 375 380
Thr Ala Arg Met Ile Ala Lys Tyr Arg Pro Gln Ala Pro Ile Val Ala
385 390 395 400
Val Thr Val Asn Asp Ser Ile Ser Arg Lys Leu Ala Leu Val Ser Gly
405 410 415
Val Phe Ala Glu Ser Gly Gln Asn Ala Ser Ser Thr Asp Glu Met Leu
420 425 430
Glu Asp Ala Val Gln Lys Ser Leu Asn Ser Gly Ile Val Lys His Gly
435 440 445
Asp Leu Ile Val Ile Thr Ala Gly Thr Val Gly Glu Ser Gly Thr Thr
450 455 460
Asn Leu Met Lys Val His Thr Val Gly Asp Ile Ile Ala Lys Gly Gln
465 470 475 480
Gly Ile Gly Arg Lys Ser Ala Tyr Gly Pro Val Val Val Ala Gln Asn
485 490 495
Ala Lys Glu Ala Glu Gln Lys Met Thr Asp Gly Ala Val Leu Val Thr
500 505 510
Lys Ser Thr Asp Arg Asp Met Ile Ala Ser Leu Glu Lys Ala Ser Ala
515 520 525
Leu Ile Thr Glu Glu Gly Gly Leu Thr Ser His Ala Ala Val Val Gly
530 535 540
Leu Ser Leu Gly Ile Pro Val Ile Val Gly Leu Glu Asn Ala Thr Ser
545 550 555 560
Ile Leu Thr Asp Gly Gln Asp Ile Thr Val Asp Ala Ser Arg Gly Ala
565 570 575
Val Tyr Gln Gly Arg Ala Ser Val Leu
580 585
<210> 13
<211> 527
<212> PRT
<213> 芽孢杆菌(Bacillus)
<400> 13
Met Asn Ser Val Asp Leu Thr Ala Asp Leu Gln Ala Leu Leu Thr Cys
1 5 10 15
Pro Asn Val Arg His Asn Leu Ser Ala Ala Gln Leu Thr Glu Lys Val
20 25 30
Leu Ser Arg Asn Glu Gly Ile Leu Thr Ser Thr Gly Ala Val Arg Ala
35 40 45
Thr Thr Gly Ala Tyr Thr Gly Arg Ser Pro Lys Asp Lys Phe Ile Val
50 55 60
Glu Glu Glu Ser Thr Lys Asn Lys Ile Asp Trp Gly Pro Val Asn Gln
65 70 75 80
Pro Ile Ser Glu Glu Ala Phe Glu Arg Leu Tyr Thr Lys Val Val Ser
85 90 95
Tyr Leu Lys Glu Arg Asp Glu Leu Phe Val Phe Glu Gly Phe Ala Gly
100 105 110
Ala Asp Glu Lys Tyr Arg Leu Pro Ile Thr Val Val Asn Glu Phe Ala
115 120 125
Trp His Asn Leu Phe Ala Arg Gln Leu Phe Ile Arg Pro Glu Gly Asn
130 135 140
Asp Lys Lys Thr Val Glu Gln Pro Phe Thr Ile Leu Ser Ala Pro His
145 150 155 160
Phe Lys Ala Asp Pro Lys Thr Asp Gly Thr His Ser Glu Thr Phe Ile
165 170 175
Ile Val Ser Phe Glu Lys Arg Thr Ile Leu Ile Gly Gly Thr Glu Tyr
180 185 190
Ala Gly Glu Met Lys Lys Ser Ile Phe Ser Ile Met Asn Phe Leu Leu
195 200 205
Pro Glu Arg Asp Ile Leu Ser Met His Cys Ser Ala Asn Val Gly Glu
210 215 220
Lys Gly Asp Val Ala Leu Phe Phe Gly Leu Ser Gly Thr Gly Lys Thr
225 230 235 240
Thr Leu Ser Ala Asp Ala Asp Arg Lys Leu Ile Gly Asp Asp Glu His
245 250 255
Gly Trp Ser Asp Thr Gly Val Phe Asn Ile Glu Gly Gly Cys Tyr Ala
260 265 270
Lys Cys Ile His Leu Ser Glu Glu Lys Glu Pro Gln Ile Phe Asn Ala
275 280 285
Ile Arg Phe Gly Ser Val Leu Glu Asn Val Val Val Asp Glu Asp Thr
290 295 300
Arg Glu Ala Asn Tyr Asp Asp Ser Phe Tyr Thr Glu Asn Thr Arg Ala
305 310 315 320
Ala Tyr Pro Ile His Met Ile Asn Asn Ile Val Thr Pro Ser Met Ala
325 330 335
Gly His Pro Ser Ala Ile Val Phe Leu Thr Ala Asp Ala Phe Gly Val
340 345 350
Leu Pro Pro Ile Ser Lys Leu Thr Lys Glu Gln Ala Met Tyr His Phe
355 360 365
Leu Ser Gly Tyr Thr Ser Lys Leu Ala Gly Thr Glu Arg Gly Val Thr
370 375 380
Ser Pro Glu Thr Thr Phe Ser Thr Cys Phe Gly Ser Pro Phe Leu Pro
385 390 395 400
Leu Pro Ala His Val Tyr Ala Glu Met Leu Gly Lys Lys Ile Asp Glu
405 410 415
His Gly Ala Asp Val Phe Leu Val Asn Thr Gly Trp Thr Gly Gly Gly
420 425 430
Tyr Gly Thr Gly Glu Arg Met Lys Leu Ser Tyr Thr Arg Ala Met Val
435 440 445
Lys Ala Ala Ile Glu Gly Lys Leu Glu Asp Ala Glu Met Ile Thr Asp
450 455 460
Asp Ile Phe Gly Leu His Ile Pro Ala His Val Pro Gly Val Pro Asp
465 470 475 480
His Ile Leu Gln Pro Glu Asn Thr Trp Thr Asn Lys Glu Glu Tyr Lys
485 490 495
Glu Lys Ala Val Tyr Leu Ala Asn Glu Phe Lys Glu Asn Phe Lys Lys
500 505 510
Phe Ala His Thr Asp Ala Ile Ala Gln Ala Gly Gly Pro Leu Val
515 520 525
<210> 14
<211> 340
<212> PRT
<213> 枯草芽孢杆菌(Bacillus subtilis)
<400> 14
Met Lys Val Lys Val Ala Ile Asn Gly Phe Gly Arg Ile Gly Arg Met
1 5 10 15
Val Phe Arg Lys Ala Met Leu Asp Asp Gln Ile Gln Val Val Ala Ile
20 25 30
Asn Ala Ser Tyr Ser Ala Glu Thr Leu Ala His Leu Ile Lys Tyr Asp
35 40 45
Thr Ile His Gly Arg Tyr Asp Lys Glu Val Val Ala Gly Glu Asp Ser
50 55 60
Leu Ile Val Asn Gly Lys Lys Val Leu Leu Leu Asn Ser Arg Asp Pro
65 70 75 80
Lys Gln Leu Pro Trp Arg Glu Tyr Asp Ile Asp Ile Val Val Glu Ala
85 90 95
Thr Gly Lys Phe Asn Ala Lys Asp Lys Ala Met Gly His Ile Glu Ala
100 105 110
Gly Ala Lys Lys Val Ile Leu Thr Ala Pro Gly Lys Asn Glu Asp Val
115 120 125
Thr Ile Val Met Gly Val Asn Glu Asp Gln Phe Asp Ala Glu Arg His
130 135 140
Val Ile Ile Ser Asn Ala Ser Cys Thr Thr Asn Cys Leu Ala Pro Val
145 150 155 160
Val Lys Val Leu Asp Glu Glu Phe Gly Ile Glu Ser Gly Leu Met Thr
165 170 175
Thr Val His Ala Tyr Thr Asn Asp Gln Lys Asn Ile Asp Asn Pro His
180 185 190
Lys Asp Leu Arg Arg Ala Arg Ala Cys Gly Glu Ser Ile Ile Pro Thr
195 200 205
Thr Thr Gly Ala Ala Lys Ala Leu Ser Leu Val Leu Pro His Leu Lys
210 215 220
Gly Lys Leu His Gly Leu Ala Leu Arg Val Pro Val Pro Asn Val Ser
225 230 235 240
Leu Val Asp Leu Val Val Asp Leu Lys Thr Asp Val Thr Ala Glu Glu
245 250 255
Val Asn Glu Ala Phe Lys Arg Ala Ala Lys Thr Ser Met Tyr Gly Val
260 265 270
Leu Asp Tyr Ser Asp Glu Pro Leu Val Ser Thr Asp Tyr Asn Thr Asn
275 280 285
Pro His Ser Ala Val Ile Asp Gly Leu Thr Thr Met Val Met Glu Asp
290 295 300
Arg Lys Val Lys Val Leu Ala Trp Tyr Asp Asn Glu Trp Gly Tyr Ser
305 310 315 320
Cys Arg Val Val Asp Leu Ile Arg His Val Ala Ala Arg Met Lys His
325 330 335
Pro Ser Ala Val
340
<210> 15
<211> 340
<212> PRT
<213> 解淀粉芽孢杆菌(Bacillus amyloliquefaciens)
<400> 15
Met Lys Val Lys Val Ala Ile Asn Gly Phe Gly Arg Ile Gly Arg Met
1 5 10 15
Val Phe Arg Lys Ala Met Glu Asp Asp Gln Ile Gln Ile Thr Ala Ile
20 25 30
Asn Ala Ser Tyr Pro Pro Glu Thr Leu Ala His Leu Ile Lys Tyr Asp
35 40 45
Thr Ile His Gly Arg Tyr Asp Gln Glu Val Glu Ala Ala Glu Asp Ser
50 55 60
Leu Ile Val Asn Gly Lys His Ile Met Leu Phe Asn Arg Arg Asp Pro
65 70 75 80
Arg Glu Leu Pro Trp Lys Glu Cys Gly Ile Asp Ile Val Val Glu Ala
85 90 95
Thr Gly Lys Phe Asn Ser Lys Glu Lys Ala Met Ser His Ile Glu Ala
100 105 110
Gly Ala Lys Lys Val Ile Leu Thr Ala Pro Gly Lys Asn Glu Asp Val
115 120 125
Thr Ile Val Met Gly Val Asn Glu Glu Gln Phe Asn Pro Asp Glu His
130 135 140
Val Ile Ile Ser Asn Ala Ser Cys Thr Thr Asn Cys Leu Ala Pro Val
145 150 155 160
Val Lys Val Leu Asp Gln Glu Phe Gly Ile Glu Ser Gly Leu Met Thr
165 170 175
Thr Val His Ala Tyr Thr Asn Asp Gln Lys Asn Ile Asp Asn Pro His
180 185 190
Lys Asp Leu Arg Arg Ala Arg Ala Cys Gly Glu Ser Ile Ile Pro Thr
195 200 205
Ser Thr Gly Ala Ala Lys Ala Leu Ser Leu Val Leu Pro His Leu Lys
210 215 220
Gly Lys Leu His Gly Leu Ala Leu Arg Val Pro Val Pro Asn Val Ser
225 230 235 240
Leu Val Asp Leu Val Cys Asp Leu Lys Thr Asp Val Ser Ala Glu Gln
245 250 255
Val Asn Ala Ala Phe Gln Arg Ala Ala Lys Thr Ser Met Tyr Gly Ile
260 265 270
Leu Asp Tyr Ser Asp Glu Pro Leu Val Ser Ser Asp Tyr Asn Thr Asn
275 280 285
Ser His Ser Ala Ile Ile Asp Gly Leu Thr Thr Met Val Met Glu Asp
290 295 300
Arg Lys Val Lys Val Leu Ala Trp Tyr Asp Asn Glu Trp Gly Tyr Ser
305 310 315 320
Cys Arg Val Val Asp Leu Ile Arg His Val Ala Ala Arg Met Lys His
325 330 335
Pro Ser Ala Val
340
Claims (10)
1.果糖1,6-二磷酸酶II突变体，其特征在于，所述突变体包含果糖1,6-二磷酸酶II第175位氨基酸由R到H或P的突变；
其中，果糖1,6-二磷酸酶II在NCBI上的参考序列编号为NP_391590.1或CBI44672.1。
2.编码权利要求1所述突变体的核酸分子或含有所述核酸分子的生物材料；
所述生物材料为重组DNA、表达盒、转座子、质粒载体、病毒载体或工程菌。
3.权利要求2所述核酸分子或所述生物材料的以下任一应用：
(1)用于核苷的发酵生产；
(2)用于提高核苷的发酵产量；
(3)用于构建产核苷的基因工程菌。
4.核苷生产菌株的构建方法，其特征在于，利用基因工程手段，在具有核苷生产能力的微生物基因组中引入突变，使其编码的果糖1,6-二磷酸酶II包含R175H或R175P突变位点；其中，果糖1,6-二磷酸酶II在NCBI上的参考序列编号为NP_391590.1或CBI44672.1。
5.根据权利要求4所述的方法，其特征在于，所述微生物为芽孢杆菌属(Bacillus)菌种，优选枯草芽孢杆菌(Bacillus subtilis)、解淀粉芽孢杆菌(Bacillusamyloliquefaciens)、短小芽孢杆菌(Bacillus pumilus)。
6.产核苷的工程菌的构建方法，其特征在于，以权利要求4或5所述方法构建得到的核苷生产菌株作为出发菌株，采用如下①～④中的至少一种方法对出发菌株进行基因工程改造：
①利用基因工程手段，在出发菌株中引入突变，使其编码的丙酮酸激酶包含T101K、T101R或T101P突变位点；其中，丙酮酸激酶在NCBI上的参考序列编号为NP_390796.1；
②利用基因工程手段，在出发菌株中引入突变，使其编码丙酮酸羧化酶的pycA基因包含第一个碱基由T到G或A的突变；
③利用基因工程手段，在出发菌株中引入突变，使其编码的磷酸烯醇式丙酮酸羧激酶包含K147R或K147H突变位点；其中，磷酸烯醇式丙酮酸羧激酶在NCBI上的参考序列编号为NP_390934.2；
④利用基因工程手段，在出发菌株中引入突变，使其编码的甘油醛-3-磷酸脱氢酶包含G169D或G169E突变位点；其中，甘油醛-3-磷酸脱氢酶在NCBI上的参考序列编号为NP_390780.1或CBI43831.1；
优选地，采用①～④的组合方法对出发菌株进行基因工程改造。
7.根据权利要求6所述的方法，其特征在于，pycA基因来自枯草芽孢杆菌，其为：
i)SEQ ID NO:7所示的核苷酸序列；
ii)SEQ ID NO:7所示的核苷酸序列经取代、缺失和/或增加一个或多个核苷酸且表达相同功能蛋白质的核苷酸序列；
iii)在严格条件下与SEQ ID NO:7所示序列杂交且表达相同功能蛋白质的核苷酸序列，所述严格条件为在含0.1％SDS的0.1×SSPE或含0.1％SDS的0.1×SSC溶液中，在65℃下杂交，并用该溶液洗膜；
iv)与i)、ii)或iii)的核苷酸序列具有90％以上同源性且表达相同功能蛋白质的核苷酸序列；或者，
pycA基因来自解淀粉芽孢杆菌，其为：
a)SEQ ID NO:8所示的核苷酸序列；
b)SEQ ID NO:8所示的核苷酸序列经取代、缺失和/或增加一个或多个核苷酸且表达相同功能蛋白质的核苷酸序列；
c)在严格条件下与SEQ ID NO:8所示序列杂交且表达相同功能蛋白质的核苷酸序列，所述严格条件为在含0.1％SDS的0.1×SSPE或含0.1％SDS的0.1×SSC溶液中，在65℃下杂交，并用该溶液洗膜；
d)与a)、b)或c)的核苷酸序列具有90％以上同源性且表达相同功能蛋白质的核苷酸序列。
8.按照权利要求5-7任一项所述方法构建得到的核苷生产菌株或工程菌。
9.一种生产核苷的方法，其特征在于，所述方法包括如下步骤：
1)培养权利要求8所述菌株或工程菌，以获得微生物的培养物；
2)从步骤1)中获得的所述培养物中收集所产生的核苷。
10.根据权利要求9所述的方法，其特征在于，所述核苷包括腺苷、肌苷、鸟苷及其对应的核苷衍生物。
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