CN108192910A - 培育降血糖和降血栓的转基因植物 - Google Patents
培育降血糖和降血栓的转基因植物 Download PDFInfo
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Abstract
本申请提供了培育降血糖和降血栓的转基因植物，通过构建编码胰高血糖素样肽‑1的核酸序列和编码蚓激酶或纳豆激酶的核酸序列植物表达载体，并将所构建的表达载体引入植物中，由此获得能够降血糖和降血栓的转基因植物。通过消耗这些植物的可食部分、植物细胞或植物提取物如纯化后的融合蛋白等，即可达到有效地降血糖以及降血栓的目的。
Description
技术领域
本申请属于基因工程领域，涉及降血糖和降血栓的转基因植物的培育， 具体涉及构建植物表达载体并产生转基因植物以及相关的产品、方法和用途。
背景技术
高血糖是通常大家所说“三高”中的一种。空腹血糖正常值在6.1mmol/L 以下，餐后两小时血糖正常值在7.8mmol/L以下，如果高于这一范围，称为 高血糖。正常情况下，人体能够通过激素调节和神经调节这两大调节系统确 保血糖的来源与去路保持平衡，使血糖维持在一定水平。但是在遗传因素(如 糖尿病家族史)与环境因素(如不合理的膳食、肥胖等)的共同作用下，这两大 调节功能发生紊乱，就会出现血糖水平的升高。长期的高血糖会使全身各个 组织器官发生病变，导致多种急慢性并发症的发生，如失水、电解质紊乱、营养缺乏、抵抗力下降、肾功能受损、神经病变、眼底病变、心脑血管疾病、 糖尿病足等。因此，控制高血糖势在必行。
目前，还没有有效的药物来控制高血糖。胰高血糖素样肽-1(glucagon-likepeptide1，GLP-1)是由人胰高血糖素基因编码，并由肠道L细胞分泌的一种肽 类激素。GLP-1具有多效性，如调节葡萄糖依赖的胰岛素分泌，增强胰岛素敏 感性，抑制胰高血糖素的分泌，促进胰腺β细胞增殖，帮助正常β细胞功能的 恢复，限制食物的摄取，抑制胃肠运动，降低餐后血糖。这一作用是葡萄糖 依赖性的，效应的强弱与血糖浓度的高低有关，血糖愈高，作用愈强，血糖 下降时则减弱，这些功能都有利于降低餐后血糖并使血糖维持在恒定水平， 从而维持血糖稳态，避免引起严重低血糖。这些特性使GLP-1成为控制高血糖 病的理想候选药物。不幸的是，GLP-1生理半衰期非常短，小于2分钟。此外， GLP-1很容易被消化道里面的酶降解，很难进入血液循环系统发挥降糖作用， 这使得GLP-1的临床应用非常有限。
血栓性疾病同样是当前严重威胁人类健康的疾病，其发病率高居各种疾 病之首，且近年来还有渐增之势，是当代医学研究的重点和热点之一。血栓 形成是指在一定条件下，血液有形成分在血管(多数为小血管)形成栓子，造成 血管部分或完全堵塞、相应部位血供障碍的病理过程。当血栓由形成部位脱 落，随血流移动的过程中部分或全部堵塞某些血管，导致形成血栓栓塞，可 引起相应组织和(或)器官缺血、缺氧、坏死(动脉血栓)及瘀血、水肿(静脉血栓) 的病理过程。
蚯蚓又名地龙，在中国传统医学中占有重要地位。口服地龙(蚯蚓)粉可以 有效的促进血液循环。纳豆是一种发酵的大豆制品，在日本被用作传统食品 已有数千年历史。食用纳豆可以降低血栓的风险，减少心血管疾病的发生， 从而促进健康。研究证明，从蚯蚓中提取的蚓激酶以及从发酵纳豆中分离出 来的纳豆激酶可以溶解血块、降低全血粘度，减少血小板聚集，降低血压的 治疗前景。口服蚓激酶以及纳豆激酶对神经系统、呼吸系统、心血管血管或 肝肾功能没有任何不良影响。但是，由于蚓激酶以及纳豆激酶提取及纯化工 艺非常复杂，造成最后的产品也可能含有其他的蚯蚓污染物或者大豆残留物， 可引起不良副作用，如胃部不适或呕吐，或者导致豆类残留物过敏现象。
发明内容
一方面，本申请提供了植物表达载体，其包含：i)编码胰高血糖素样肽-1 的核酸序列；和ii)编码蚓激酶或纳豆激酶的核酸序列。
本申请提供的植物表达载体，能够同时表达胰高血糖素样肽-1和蚓激酶。
本申请提供的植物表达载体，能够同时表达胰高血糖素样肽-1和纳豆激 酶。
在一实施方案中，本申请提供的植物表达载体包含如SEQ ID NO.:7或 SEQ IDNO.:10所示的核酸序列。
另一方面，本申请提供了植物表达载体的构建方法，其包括以下步骤：i) 合成编码胰高血糖素样肽-1和蚓激酶的核酸序列(LK-GLP)，或者编码胰高血 糖素样肽-1和纳豆激酶的核酸序列(NK-GLP)；ii)将所合成的核酸序列插入至 克隆载体pUC57中，获得克隆载体pUC57-LK-GLP或者pUC57-NK-GLP； 以及iii)双酶切所获得的克隆载体，将所获得的酶切片段克隆至植物表达载体 pRD140中，获得植物表达载体pRD-LK-GLP或者pRD-NK-GLP。
在一实施方案中，本申请所提供的植物表达载体的构建策略如图1A或图 1B所示。
在具体实施方案中，本申请所提供的植物表达载体的构建方法中，所述 编码胰高血糖素样肽-1和蚓激酶的核酸序列(LK-GLP)如SEQ ID NO.:7所示。 在另一具体实施方案中，编码胰高血糖素样肽-1和纳豆激酶的核酸序列 (NK-GLP)如SEQ ID NO.:10所示。
又一方面，本申请提供了融合蛋白，其由上述的植物表达载体表达。
本申请提供的融合蛋白，包含胰高血糖素样肽-1和蚓激酶(LK-GLP)，其 氨基酸序列如SEQ ID NO.:6所示。
本申请提供的融合蛋白，包含胰高血糖素样肽-1和纳豆激酶(NK-GLP)， 其氨基酸序列如SEQ ID NO.:9所示。
此外，本申请还提供了所述的融合蛋白在制备用于降血糖和降血栓的药 物或保健品中的用途。
还一方面，本申请提供了产生转基因植物的方法，其包括将上述的植物 表达载体导入植物的基因组中。在一实施方案中，所述植物选自蔬菜或水果， 例如，黄瓜、番茄、生菜、大豆、苹果和香蕉等。
此外，本申请还提供了由上述方法获得的植物部分、植物细胞或植物提 取物，所述的植物部分、植物细胞或植物提取物在制备用于降血糖和降血栓 的植物制品中的用途，以及包含所述的植物部分、植物细胞或植物提取物的 植物制品。在一实施方案中，所述植物制品为保健品或药物。
可见，本申请利用遗传工程技术，构建了表达蚓激酶(LK)和胰高血糖素 样肽-1(GLP-1)的植物表达载体，以及表达纳豆激酶(NK)和胰高血糖素样肽 -1(GLP-1)的植物表达载体。将所构建的表达载分别体导入植物，如蔬菜或水 果中，获得具有降血糖和降血栓的转基因植物。由于植物本身的特质，如细 胞壁可以保护GLP-1顺利通过消化道系统，然后进入血液系统从而降低血糖。 通过消耗这些植物的可食部分、植物细胞或植物提取物如纯化后的融合蛋白 等，即口服LK-GLP以及NK-GLP，从而达到降血糖以及降血栓的目的。
由于蔬菜或水果的可生食性和高产量的特点，通过利用基因工程的方法 所获得的蔬菜或水果，可实现利用蚓激酶(LK)或纳豆激酶(NK)降血栓，同时 利用胰高血糖素样肽-1(GLP-1)降血糖的功效。也就是说，本申请生产了有活 性、安全、廉价并可以直接食用的植物，这些富含LK-GLP或NK-GLP的蔬 菜水果可以直接为人们食用，既保留了LK-GLP或NK-GLP的降血糖以及降 血栓活性，又可延迟LK-GLP或NK-GLP在消化道系统中被消化液降解，使 其在体内更有效地发挥降血糖以及降血栓的功效。
附图说明
图1A为植物表达载体pRD-LK-GLP的构建策略。
图1B为植物表达载体pRD-NK-GLP的构建策略。
图2为鉴定重组融合蛋白的SDS-PAGE电泳结果。
图3为LK-GLP、NK-GLP及普通黄瓜的Western印迹图。
图4为LK-GLP、NK-GLP及-CK的降解纤维蛋白对比试验示意图。
图5为LK-GLP、NK-GLP、LK、NK、GLP及普通对照组的降解纤维蛋 白对比试验结果。
图6为LK-GLP、NK-GLP及-CK的溶栓溶血对比试验示意图。
图7为LK-GLP、NK-GLP、LK、NK、GLP及普通对照组的溶栓溶血对 比试验结果。
图8为LK-GLP、NK-GLP、GLP及普通对照组的口服葡萄糖耐量试验对 比结果。
具体实施方式
为了使本发明所解决的技术问题、技术方案及有益效果更加清楚明白， 以下对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅 用以解释本发明，并不用于限定本发明。
若未特别指明，实施例中所用的化学试剂均为常规市售试剂，实施例中 所用的技术手段为本领域技术人员所熟知的常规手段。
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。
实施例
实施例1 表达载体的构建
根据基因文库中胰高血糖素样肽-1(GLP-1，Genbank ID：NP_002045.1) 的氨基酸序列(SEQ ID NO.:1)，利用逆转录软件，导出GLP-1基因序列(SEQ ID NO.:2)。
根据基因文库中蚓激酶(LK，Genbank ID：AF433650.1)和纳豆激酶(NK， GenbankID:S51909.1)的基因序列(SEQ ID NO.:3和SEQ ID NO.:4)，将各自 的终止子去掉，然后在3’端分别连接上GLP-1基因序列，得到LK-GLP(SEQ ID NO.:5)以及NK-GLP(SEQ ID NO.:8)。
为了提高融合蛋白在黄瓜中的表达含量，利用GeneArtTM GeneOptimizerTM(ThermoFisher)设计，将LK-GLP以及NK-GLP密码子分别 优化为植物偏好的密码子，序列分别如SEQ ID NO.:7和SEQ ID NO.:10所示。
为了方便构建植物表达载体，分别在LK-GLP以及NK-GLP的5’端和3’ 端加上BamHI与EcoR1酶切位点序列，委托南京金斯瑞公司进行全基因合成。
将所合成的全基因片段分别插入至克隆载体pUC57中，获得克隆载体 pUC57-LK-GLP以及pUC57-NK-GLP。由BamHI/EcoR1双酶切克隆载体 pUC57-LK-GLP和pUC57-NK-GLP，所获得的酶切片段分别插入至植物表达 载体pRD140中，得到植物表达载体pRD-LK-GLP以及pRD-NK-GLP。具体 的构建策略见图1A和图1B。
利用广谱烟草花叶病毒35S启动子激活LK-GLP以及NK-GLP在黄瓜中 的蛋白表达。植物表达载体抗性基因为nptII，对卡那霉素具有抗性。构建好 的植物表达载体通过限制性内切酶酶切鉴定表明其正确性。
实施例2 黄瓜的遗传转化
利用电击法，将实施例1中所构建的植物表达载体导入农杆菌 (A.tumefaciens)LBA4404菌株中。
利用农杆菌介导的转化方法分别将实施例1所构建的植物表达载体 pRD-LK-GLP以及pRD-NK-GLP转入黄瓜当中。
分别得到25株具有卡那霉素抗性的LK-GLP以及NK-GLP黄瓜植株。 通过CTAB的方法提取植物基因组总DNA。
利用地高辛标记的黄瓜基因基因探针DNA杂交技术(Southern Blot)确定 得到T0代转基因黄瓜。
将所获得的T0代转基因黄瓜植株在温室内培养6个月后，得到转基因黄 瓜果实以及T1代转基因黄瓜种子。
实施例3 融合蛋白的鉴定
转基因黄瓜果实样品用搅拌器搅拌，并用体积比为1:1比例的提取缓冲液 (100mMKPi，pH7.8；5mM EDTA；10m Mβ-巯基乙醇)搅拌机中高速匀浆 1～2min。将匀浆物调节至pH为8.0，用纱布过滤，过滤物在4℃以10，000g 离心15min以除去细胞碎片。收集上清液，与硫酸铵(50％)混合，并在冰上摇 动孵育60分钟。通过离心机(10，000g)在4℃下再次分离15min。将得到的上 清液进行第二轮硫酸铵(70％)沉淀，冰上摇动悬浮60min，再次在4℃下以10，000g离心15min。然后，弃去上清液，将处理样品沉淀蛋白质溶于5mL缓冲 液(20mMKPi，pH 7.8；2mM EDTA；10mMβ-巯基乙醇)中，并在4℃下储存。
提取出的可溶性蛋白通过聚丙烯酰胺凝胶电泳(SDS-PAGE)的方法来鉴定 重组融合蛋白。SDS-PAGE电泳显示(图2)，转基因黄瓜果实表达的重组融合 蛋白(LK-GLP，泳道1；NK-GLP，泳道2)大约为31kDa，符合最初的设计， 而普通黄瓜提取液中没有蛋白显示(泳道3)。
对于重组融合蛋白的Western Blot蛋白印迹杂交，10μL的样品分别在 4～12％ Bis-Tris Plus聚丙烯酰胺凝胶上分离，并将其电泳转移到聚偏二 氟乙烯(PVDF)膜上，用抗GLP-1的抗体(Abcam)分别进行免疫反应，稀释1： 10000和辣根过氧化物酶(HRP)标记的山羊抗兔IgG(Beyotime)，稀释度分别为 1:20000，并使用ECL plus(AmershamBiosciences)显现，对显示图像进行拍照。
Western印迹分析也检测到大约31kDa的条带(图3)，观察到的蛋白分子 量与SDS-PAGE条带一致，大小符合预期值(31kDa)。同样表明转基因黄瓜成 功的表达出成熟的LK-GLP(泳道1)以及NK-GLP(泳道2)融合蛋白，而普通黄 瓜提取液中没有蛋白印迹反应(泳道3)。
实施例4 融合蛋白的溶栓溶血测试
1.溶栓测试
通过改进的纤维蛋白板方法检测从转基因黄瓜果实样品中纯化的 LK-GLP以及NK-GLP融合蛋白的溶栓活性，具体操作如下。
将0.5％琼脂糖在50mL的PBS缓冲液中煮沸，并在40℃水浴中冷却。 将1mg/mL纤维蛋白原，0.1IU/mL凝血酶和0.1IU/mL纤溶酶原混合其中。 将混合物缓慢倒入培养皿中，静置，直到琼脂糖固化。
在培养板中用无菌打孔器形成孔(3mm直径)。然后将黄瓜果实中纯化的 LK-GLP以及NK-GLP分别以50μg的量加载到每个孔中，并将板在室温下温 育过夜。
结果显示，来自转基因黄瓜果实的重组蛋白均可降解纤维蛋白(如图4所 示)。纯化的重组蛋白(LK-GLP，NK-GLP)在纤维蛋白板上显示出半透明的溶 解区域，表明纤维蛋白已被降解为可溶性肽。相比之下，对照组普通黄瓜蛋 白提取液不显示纤维蛋白切割活性(-CK)。
图5显示PBS以及GLP单独使用时，并不能降解纤维蛋白；与单独使用 的LK以及NK相比，融合蛋白LK-GLP以及NK-GLP降解纤维蛋白的作用 明显增强(P≤0.001)。具体地，LK-GLP，NK-GLP，LK以及NK半透明区域的 直径分别为23.5±0.65厘米，19.5±0.65厘米，10.75±0.63厘米，以及9.5±0.5 厘米(实验数据为：平均值±标准方差(SE，n＝4))。
2.溶血测试
从转基因黄瓜果实样品中纯化的LK-GLP以及NK-GLP融合蛋白的体外 血凝块溶解试验操作如下。
将血凝块(约50毫克/凝块)然后转移到24孔板中，用1XPBS缓冲液冲洗 两次。将纯化的LK-GLP以及NK-GLP融合蛋白溶解于1XPBS中，制备出 浓缩样品(1μg/μL)。取40μL浓缩样品，用1XPBS缓冲液稀释至500μL，然后 加入含有血液凝块的小孔中，在37℃温浴箱中培养过夜。测量血块样品溶 解前后的重量，并按下式计算溶解血块率：
非转染PBS缓冲液和洗脱液被用作阴性对照。
溶血实验表明，由转基因黄瓜纯化的融合蛋白(LK-GLP，NK-GLP)均可以 溶解血块，而对照组普通黄瓜蛋白提取液(-CK)不能溶解血块(图6)。
图7显示与单独使用的LK以及NK相比，融合蛋白LK-GLP以及NK-GLP 溶解血块的作用明显增强(P≤0.01)。具体地，LK-GLP，NK-GLP，LK以及 NK溶解血块率分别为95±1.3％，87±3.1％，49±0.3％，以及48±1.1％，其 中实验数据为平均值±标准方差(SE，n＝3)。
实施例5 口服葡萄糖耐量试验(OGTT)
检测转基因黄瓜的口服葡萄糖耐量，具体操作如下。
8周龄健康雄性小鼠，体重46.06±1.66g，禁食过夜，分为对照组和实验 组(n＝8)。每组均用灌胃针以2克/千克小鼠体重的葡萄糖灌胃。实验组分别 喂食适量的GLP，LK-GLP以及NK-GLP黄瓜切片，对照组同时口服普通黄 瓜切片，喂食摄入黄瓜切片量均为5克。取各组小鼠尾静脉在0，10，30，60 和120min，用血糖仪测量小鼠血糖水平。
口服葡萄糖耐量试验(OGTT)实验表明，GLP，LK-GLP以及NK-GLP黄 瓜显著降低血糖水平(图8)。血糖水平在口服灌胃后30分钟达到高峰。对照 组小鼠血糖峰值浓度为14.1±0.6mmol/L。而GLP，LK-GLP及NK-GLP在30 分钟的血糖浓度峰值分别为11.1±0.3mmol/L，9.1±0.5mmol/L以及10.06±0.3 mmol/L，与对照组相比，峰值血糖水平均显著降低(P≤0.001)。三组血糖水平 在30分钟后开始下降时，血糖水平的对照组和试验组(GLP，LK-GLP及 NK-GLP)之间的差异仍然存在。在120分钟时，LK-GLP及NK-GLP试验组 的血糖水平恢复正常(4.0±0.50mmol/L)，而GLP组虽然血糖浓度逐渐恢复， 但是血糖浓度仍然为5.0±0.51mmol/L，并没有完全恢复到实验前水平(4.0 mmol/L)。对照组葡萄糖水平仍高达8.01±0.5mmol/L(P≤0.01)。
可见，LK-GLP以及NK-GLP与单独喂食的GLP黄瓜切片组在30分钟和 120分钟时均有明显差异。曲线数据为平均值±标准误差(SE，n＝8)(P≤0.01)。
综上所述，利用基因工程的技术，本申请分别构建了表达胰高血糖素样 肽-1和蚓激酶(LK-GLP)以及胰高血糖素样肽-1和纳豆激酶(NK-GLP)的表达 载体，并以黄瓜为例，将该表达载体成功地转入黄瓜中，由此获得的转基因 黄瓜在降解纤维蛋白以及溶解血块的同时，还能显著降低血糖水平。
以上通过具体的和优选的实施例详细的描述了本发明，但本领域技术人 员应该明白，本发明并不局限于以上所述实施例，凡在本发明的精神和原则 之内，所作的任何修改、等同替换等，均应包含在本发明的保护范围之内。
序列表
<110> 陈玉皎
<120> 培育降血糖和降血栓的转基因植物
<141> 2017-12-28
<150> 2017108397323
<151> 2017-09-19
<160> 10
<170> SIPOSequenceListing 1.0
<210> 1
<211> 30
<212> PRT
<213> 智人(Homo sapiens)
<400> 1
His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg
20 25 30
<210> 2
<211> 90
<212> DNA
<213> 智人(Homo sapiens)
<400> 2
catgcggaag gcacctttac cagcgatgtg agcagctatc tggaaggcca ggcggcgaaa 60
gaatttattg cgtggctggt gaaaggccgc 90
<210> 3
<211> 852
<212> DNA
<213> 蚯蚓(Pheretima)
<400> 3
atgttacttc tcgctcttgc atcgttggta gcggtgggct ttgcgcaacc accagtctgg 60
taccccggtg gtcaatgcgg tgtcagccag tactcagatg ctggtgacat ggaacttcct 120
cccggaacaa aaattgtcgg aggaattgaa gccagaccat acgagttccc atggcaggtg 180
tccgtccgaa ggaagtcttc cgattcccat ttctgcggag gtagcatcat caacgatcgt 240
tgggttgtct gcgctgctca ctgcatgcag ggagagagcc ctgccctggt ttcattggtc 300
gtcggtgagc acgatagcag cgctgcgagt acagtacgtc agactcatga cgttgacagc 360
atcttcgtcc acgaggacta caacggaaat acctttgaga acgacgtttc tgtcatcaag 420
acagttaacg ccatcgccat cgacatcaac gttgggccaa tctgcgctcc agatccagcc 480
aacgattacg tctaccgtaa gagccagtgc tccggatggg gaactatcaa ctcaggtgga 540
gtctgctgcc ccaacgttct gcgatatgtg acactgaacg tcacaaccaa cgccttctgc 600
gatgatatct acagcccatt atatacaatt accagcgaca tgatctgcgc cacggacaac 660
accggacaga acgagagaga ctcttgccag ggtgactctg gcggccctct gagcgtcaag 720
gatggcagcg gaatcttcag cctcattggt attgtgtctt ggggaatcgg ttgcgcatct 780
ggatatccag gagtctacgc ccgcgtcggg tcccaaactg gatggatcac agacatcatc 840
accaacaact aa 852
<210> 4
<211> 1089
<212> DNA
<213> 纳豆(natto)
<400> 4
atggcgttca gcaacatgtc tgcgcaggct gccggaaaaa gcagtacaga aaagaaatac 60
attgtcggat ttaagcagac aatgagtgcc atgagttccg ccaagaaaaa ggatgttatt 120
tctgaaaaag gcggaaaggt tcaaaagcaa tttaagtatg ttaacgcggc cgcagcaaca 180
ttggatgaaa aagctgtaaa agaattgaaa aaagatccga gcgttgcata tgtggaagaa 240
gatcatattg cacatgaata tgcgcaatct gttccttatg gcatttctca aattaaagcg 300
ccggctcttc actctcaagg ctacacaggc tctaacgtaa aagtagctgt tatcgacagc 360
ggaattgact cttctcatcc tgacttaaac gtcagaggcg gagcaagctt cgttccttct 420
gaaacaaacc cataccagga cggcagttct cacggtacgc atgtcgccgg tacgattgcc 480
gctcttaata actcaatcgg tgttctgggc gtagcgccaa gcgcatcatt atatgcagta 540
aaagtgcttg attcaacagg aagcggccaa tatagctgga ttattaacgg cattgagtgg 600
gccatttcca acaatatgga tgttatcaac atgagccttg gcggacctac tggttctaca 660
gcgctgaaaa cagtagttga taaagcggtt tccagcggta tcgtcgttgc tgccgcagcc 720
ggaaacgaag gttcatccgg aagcacaagc acagtcggct accctgcaaa atatccttct 780
actattgcag taggtgcggt aaacagcagc aaccaaagag cttcattctc cagcgtaggt 840
tctgagcttg atgtaatggc tcctggcgtg tccatccaaa gcacacttcc tggaggcact 900
tacggcgctt ataacggaac gtccatggcg actcctcacg ttgccggagc agcagcgcta 960
attctttcta agcacccgac ttggacaaac gcgcaagtcc gtgatcgttt agaaagcact 1020
gcaacatatc ttggaaactc tttctactat ggaaaagggt taatcaacgt acaagcagct 1080
gcacaataa 1089
<210> 5
<211> 942
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 5
atgttacttc tcgctcttgc atcgttggta gcggtgggct ttgcgcaacc accagtctgg 60
taccccggtg gtcaatgcgg tgtcagccag tactcagatg ctggtgacat ggaacttcct 120
cccggaacaa aaattgtcgg aggaattgaa gccagaccat acgagttccc atggcaggtg 180
tccgtccgaa ggaagtcttc cgattcccat ttctgcggag gtagcatcat caacgatcgt 240
tgggttgtct gcgctgctca ctgcatgcag ggagagagcc ctgccctggt ttcattggtc 300
gtcggtgagc acgatagcag cgctgcgagt acagtacgtc agactcatga cgttgacagc 360
atcttcgtcc acgaggacta caacggaaat acctttgaga acgacgtttc tgtcatcaag 420
acagttaacg ccatcgccat cgacatcaac gttgggccaa tctgcgctcc agatccagcc 480
aacgattacg tctaccgtaa gagccagtgc tccggatggg gaactatcaa ctcaggtgga 540
gtctgctgcc ccaacgttct gcgatatgtg acactgaacg tcacaaccaa cgccttctgc 600
gatgatatct acagcccatt atatacaatt accagcgaca tgatctgcgc cacggacaac 660
accggacaga acgagagaga ctcttgccag ggtgactctg gcggccctct gagcgtcaag 720
gatggcagcg gaatcttcag cctcattggt attgtgtctt ggggaatcgg ttgcgcatct 780
ggatatccag gagtctacgc ccgcgtcggg tcccaaactg gatggatcac agacatcatc 840
accaacaacc atgcggaagg cacctttacc agcgatgtga gcagctatct ggaaggccag 900
gcggcgaaag aatttattgc gtggctggtg aaaggccgct aa 942
<210> 6
<211> 313
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Met Leu Leu Leu Ala Leu Ala Ser Leu Val Ala Val Gly Phe Ala Gln
1 5 10 15
Pro Pro Val Trp Tyr Pro Gly Gly Gln Cys Gly Val Ser Gln Tyr Ser
20 25 30
Asp Ala Gly Asp Met Glu Leu Pro Pro Gly Thr Lys Ile Val Gly Gly
35 40 45
Ile Glu Ala Arg Pro Tyr Glu Phe Pro Trp Gln Val Ser Val Arg Arg
50 55 60
Lys Ser Ser Asp Ser His Phe Cys Gly Gly Ser Ile Ile Asn Asp Arg
65 70 75 80
Trp Val Val Cys Ala Ala His Cys Met Gln Gly Glu Ser Pro Ala Leu
85 90 95
Val Ser Leu Val Val Gly Glu His Asp Ser Ser Ala Ala Ser Thr Val
100 105 110
Arg Gln Thr His Asp Val Asp Ser Ile Phe Val His Glu Asp Tyr Asn
115 120 125
Gly Asn Thr Phe Glu Asn Asp Val Ser Val Ile Lys Thr Val Asn Ala
130 135 140
Ile Ala Ile Asp Ile Asn Val Gly Pro Ile Cys Ala Pro Asp Pro Ala
145 150 155 160
Asn Asp Tyr Val Tyr Arg Lys Ser Gln Cys Ser Gly Trp Gly Thr Ile
165 170 175
Asn Ser Gly Gly Val Cys Cys Pro Asn Val Leu Arg Tyr Val Thr Leu
180 185 190
Asn Val Thr Thr Asn Ala Phe Cys Asp Asp Ile Tyr Ser Pro Leu Tyr
195 200 205
Thr Ile Thr Ser Asp Met Ile Cys Ala Thr Asp Asn Thr Gly Gln Asn
210 215 220
Glu Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro Leu Ser Val Lys
225 230 235 240
Asp Gly Ser Gly Ile Phe Ser Leu Ile Gly Ile Val Ser Trp Gly Ile
245 250 255
Gly Cys Ala Ser Gly Tyr Pro Gly Val Tyr Ala Arg Val Gly Ser Gln
260 265 270
Thr Gly Trp Ile Thr Asp Ile Ile Thr Asn Asn His Ala Glu Gly Thr
275 280 285
Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu
290 295 300
Phe Ile Ala Trp Leu Val Lys Gly Arg
305 310
<210> 7
<211> 954
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 7
ggatccatgc ttctgcttgc tcttgcttct cttgtggctg ttggttttgc tcagcctcct 60
gtttggtatc ctggtggtca atgtggtgtg agccagtact ctgatgctgg cgatatggaa 120
ttgcctcctg gcactaagat cgttggtggt attgaggcta ggccttacga gttcccttgg 180
caggtttcag ttcggaggaa gtcctctgat tctcacttct gcggtggcag catcatcaac 240
gatagatggg ttgtgtgtgc tgcccactgt atgcaaggtg aaagtcctgc tcttgtgtct 300
ttggtggtgg gtgagcatga tagctctgct gcttctactg tgaggcagac tcacgatgtg 360
gactctatct tcgtgcatga ggactacaac ggcaacacct tcgagaacga tgtgagcgtg 420
atcaagaccg tgaacgctat cgctatcgat atcaacgtgg gtcctatctg cgctcctgat 480
cctgctaatg attacgtgta ccggaagtcc cagtgttctg gttggggaac cattaactct 540
ggtggtgtct gctgccctaa cgtgttgaga tacgtgaccc ttaacgtgac cactaacgct 600
ttctgcgacg acatctacag cccgctttac accatcacca gcgatatgat ttgcgccacc 660
gataacactg gtcagaacga gagggattct tgccagggtg atagtggtgg tcctctgtct 720
gttaaggatg gcagcggtat cttcagcctg atcggtattg tgtcttgggg tatcggttgc 780
gcttctggtt accctggtgt ttacgctaga gtgggttctc agactggttg gatcaccgac 840
atcatcacca acaatcatgc cgagggaacc tttaccagcg acgtgtcatc ttaccttgaa 900
ggccaagctg ccaaagagtt cattgcttgg cttgtgaagg gccgttagga attc 954
<210> 8
<211> 1179
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 8
atggcgttca gcaacatgtc tgcgcaggct gccggaaaaa gcagtacaga aaagaaatac 60
attgtcggat ttaagcagac aatgagtgcc atgagttccg ccaagaaaaa ggatgttatt 120
tctgaaaaag gcggaaaggt tcaaaagcaa tttaagtatg ttaacgcggc cgcagcaaca 180
ttggatgaaa aagctgtaaa agaattgaaa aaagatccga gcgttgcata tgtggaagaa 240
gatcatattg cacatgaata tgcgcaatct gttccttatg gcatttctca aattaaagcg 300
ccggctcttc actctcaagg ctacacaggc tctaacgtaa aagtagctgt tatcgacagc 360
ggaattgact cttctcatcc tgacttaaac gtcagaggcg gagcaagctt cgttccttct 420
gaaacaaacc cataccagga cggcagttct cacggtacgc atgtcgccgg tacgattgcc 480
gctcttaata actcaatcgg tgttctgggc gtagcgccaa gcgcatcatt atatgcagta 540
aaagtgcttg attcaacagg aagcggccaa tatagctgga ttattaacgg cattgagtgg 600
gccatttcca acaatatgga tgttatcaac atgagccttg gcggacctac tggttctaca 660
gcgctgaaaa cagtagttga taaagcggtt tccagcggta tcgtcgttgc tgccgcagcc 720
ggaaacgaag gttcatccgg aagcacaagc acagtcggct accctgcaaa atatccttct 780
actattgcag taggtgcggt aaacagcagc aaccaaagag cttcattctc cagcgtaggt 840
tctgagcttg atgtaatggc tcctggcgtg tccatccaaa gcacacttcc tggaggcact 900
tacggcgctt ataacggaac gtccatggcg actcctcacg ttgccggagc agcagcgcta 960
attctttcta agcacccgac ttggacaaac gcgcaagtcc gtgatcgttt agaaagcact 1020
gcaacatatc ttggaaactc tttctactat ggaaaagggt taatcaacgt acaagcagct 1080
gcacaacatg cggaaggcac ctttaccagc gatgtgagca gctatctgga aggccaggcg 1140
gcgaaagaat ttattgcgtg gctggtgaaa ggccgctaa 1179
<210> 9
<211> 392
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Met Ala Phe Ser Asn Met Ser Ala Gln Ala Ala Gly Lys Ser Ser Thr
1 5 10 15
Glu Lys Lys Tyr Ile Val Gly Phe Lys Gln Thr Met Ser Ala Met Ser
20 25 30
Ser Ala Lys Lys Lys Asp Val Ile Ser Glu Lys Gly Gly Lys Val Gln
35 40 45
Lys Gln Phe Lys Tyr Val Asn Ala Ala Ala Ala Thr Leu Asp Glu Lys
50 55 60
Ala Val Lys Glu Leu Lys Lys Asp Pro Ser Val Ala Tyr Val Glu Glu
65 70 75 80
Asp His Ile Ala His Glu Tyr Ala Gln Ser Val Pro Tyr Gly Ile Ser
85 90 95
Gln Ile Lys Ala Pro Ala Leu His Ser Gln Gly Tyr Thr Gly Ser Asn
100 105 110
Val Lys Val Ala Val Ile Asp Ser Gly Ile Asp Ser Ser His Pro Asp
115 120 125
Leu Asn Val Arg Gly Gly Ala Ser Phe Val Pro Ser Glu Thr Asn Pro
130 135 140
Tyr Gln Asp Gly Ser Ser His Gly Thr His Val Ala Gly Thr Ile Ala
145 150 155 160
Ala Leu Asn Asn Ser Ile Gly Val Leu Gly Val Ala Pro Ser Ala Ser
165 170 175
Leu Tyr Ala Val Lys Val Leu Asp Ser Thr Gly Ser Gly Gln Tyr Ser
180 185 190
Trp Ile Ile Asn Gly Ile Glu Trp Ala Ile Ser Asn Asn Met Asp Val
195 200 205
Ile Asn Met Ser Leu Gly Gly Pro Thr Gly Ser Thr Ala Leu Lys Thr
210 215 220
Val Val Asp Lys Ala Val Ser Ser Gly Ile Val Val Ala Ala Ala Ala
225 230 235 240
Gly Asn Glu Gly Ser Ser Gly Ser Thr Ser Thr Val Gly Tyr Pro Ala
245 250 255
Lys Tyr Pro Ser Thr Ile Ala Val Gly Ala Val Asn Ser Ser Asn Gln
260 265 270
Arg Ala Ser Phe Ser Ser Val Gly Ser Glu Leu Asp Val Met Ala Pro
275 280 285
Gly Val Ser Ile Gln Ser Thr Leu Pro Gly Gly Thr Tyr Gly Ala Tyr
290 295 300
Asn Gly Thr Ser Met Ala Thr Pro His Val Ala Gly Ala Ala Ala Leu
305 310 315 320
Ile Leu Ser Lys His Pro Thr Trp Thr Asn Ala Gln Val Arg Asp Arg
325 330 335
Leu Glu Ser Thr Ala Thr Tyr Leu Gly Asn Ser Phe Tyr Tyr Gly Lys
340 345 350
Gly Leu Ile Asn Val Gln Ala Ala Ala Gln His Ala Glu Gly Thr Phe
355 360 365
Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe
370 375 380
Ile Ala Trp Leu Val Lys Gly Arg
385 390
<210> 10
<211> 1191
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
ggatccatgg ccttctctaa catgtctgct caggctgctg gtaagtcctc taccgagaag 60
aagtacatcg tcggcttcaa gcagactatg agcgctatgt ccagcgccaa gaagaaggac 120
gtcatctctg agaaaggtgg caaggtgcaa aagcagttca agtacgttaa cgctgctgct 180
gctaccctgg atgagaaggc tgtgaaagag cttaagaagg acccgtccgt tgcttacgtg 240
gaagaggatc atattgctca cgagtacgct cagtctgtgc cttacggtat ctctcagatt 300
aaggctcctg ctctgcactc tcagggttac actggttcta atgtgaaggt ggccgtgatc 360
gatagcggca tcgattcttc acaccctgat ctgaacgtta gaggcggtgc ttctttcgtg 420
ccttctgaga ctaatcctta ccaggacggt tcttctcacg gaactcatgt ggctggtact 480
atcgctgctc tgaacaactc tattggcgtg ttgggtgttg ctcctagcgc ttcactttac 540
gctgttaagg tgctggatag caccggttct ggtcagtact cttggatcat caacggtatc 600
gagtgggcca tcagcaacaa catggacgtg atcaacatga gccttggtgg tcctactgga 660
agcactgctc ttaagactgt ggtggacaag gctgtgtcct ctggtattgt ggttgctgct 720
gcagctggta acgaaggatc ttctggttct actagcaccg tgggttaccc tgctaagtac 780
ccttctacta ttgctgtggg cgccgtgaac tcttctaatc agagggcttc tttcagcagc 840
gtgggttctg agcttgatgt tatggctcct ggtgtgtcta tccagtctac tcttcctggt 900
ggtacttacg gtgcttacaa cggaacttct atggctactc ctcatgttgc tggggctgct 960
gctcttattc tttctaagca ccctacctgg accaacgctc aggttagaga taggcttgag 1020
tctaccgcta cctacctggg caactctttc tactacggta agggccttat caacgtgcaa 1080
gctgctgcac aacatgctga gggaaccttt acctccgacg tgtcatctta ccttgagggc 1140
caagctgcca aagagttcat tgcttggctt gtgaagggcc gttaggaatt c 1191
Claims (10)
1.植物表达载体，其包含：i)编码胰高血糖素样肽-1的核酸序列；和ii)编码蚓激酶或纳豆激酶的核酸序列。
2.如权利要求1所述的植物表达载体，其包含如SEQ ID NO.:7或SEQ ID NO.:10所示的核酸序列。
3.如权利要求1所述的植物表达载体的构建方法，其包括以下步骤：
i)合成编码胰高血糖素样肽-1和蚓激酶的核酸序列(LK-GLP)，或者编码胰高血糖素样肽-1和纳豆激酶的核酸序列(NK-GLP)；
ii)将所合成的核酸序列插入至克隆载体pUC57中，获得克隆载体pUC57-LK-GLP或者pUC57-NK-GLP；以及
iii)双酶切所获得的克隆载体，将所获得的酶切片段克隆至植物表达载体pRD140中，获得植物表达载体pRD-LK-GLP或者pRD-NK-GLP；
任选地，所述构建方法如图1A或图1B所示。
4.如权利要求3所述的方法，其中所述编码胰高血糖素样肽-1和蚓激酶的核酸序列(LK-GLP)如SEQ ID NO.:7所示；编码胰高血糖素样肽-1和纳豆激酶的核酸序列(NK-GLP)如SEQ ID NO.:10所示。
5.融合蛋白，其由权利要求1或2所述的植物表达载体表达。
6.权利要求5所述的融合蛋白在制备用于降血糖和降血栓的药物或保健品中的用途。
7.产生转基因植物的方法，其包括将权利要求1或2所述的植物表达载体导入植物的基因组中；
任选地，所述植物选自蔬菜或水果，包括黄瓜、番茄、生菜、大豆、苹果和香蕉。
8.由权利要求7所述的方法获得的植物部分、植物细胞或植物提取物。
9.权利要求8所述的植物部分、植物细胞或植物提取物在制备用于降血糖和降血栓的植物制品中的用途，优选地，所述植物制品为保健品或药物。
10.用于降血糖和降血栓的植物制品，其包含权利要求8所述的植物部分、植物细胞或植物提取物；优选地，所述植物制品为保健品或药物。
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110256581A (zh) * | 2019-06-24 | 2019-09-20 | 王跃驹 | 植物生产口服索玛鲁泰（Semaglutide）与蚓激酶的融合蛋白降糖胶囊的应用 |
| CN110256580A (zh) * | 2019-06-24 | 2019-09-20 | 王跃驹 | 植物生产口服杜拉鲁肽与纳豆激酶降糖胶囊的应用 |
| CN110302366A (zh) * | 2019-07-05 | 2019-10-08 | 王跃驹 | 植物源蚓激酶胶囊及其生产方法 |
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