CN113845567B - 一种金枪鱼鱼卵二肽基肽酶ⅳ抑制寡肽 - Google Patents
一种金枪鱼鱼卵二肽基肽酶ⅳ抑制寡肽 Download PDFInfo
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- CN113845567B CN113845567B CN202111323143.2A CN202111323143A CN113845567B CN 113845567 B CN113845567 B CN 113845567B CN 202111323143 A CN202111323143 A CN 202111323143A CN 113845567 B CN113845567 B CN 113845567B
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Abstract
本发明公开了一种金枪鱼鱼卵二肽基肽酶Ⅳ抑制寡肽及其用途，该二肽基肽酶Ⅳ(DPP‑Ⅳ)抑制寡肽的氨基酸序列为Glu‑Ile‑Pro‑Gly‑Thr‑Arg‑Gly‑Pro‑Leu，分子量为939.07Da。本发明制备的金枪鱼鱼卵的二肽基肽酶Ⅳ(DPP‑Ⅳ)抑制寡肽可显著抑制DPP‑Ⅳ活力，降低模型小鼠餐后血糖水平，改善小鼠口服葡萄糖糖耐量和麦芽糖糖耐量，降低模型小鼠的甘油三酯(TG)和胆固醇(TC)的含量，且安全无毒副作用；可应用于制备治疗或者辅助治疗II型糖尿病的特殊医学用途食品、保健产品和药物。
Description
技术领域
本发明涉及多肽技术领域，具体涉及一种源于金枪鱼鱼卵具有治疗II型糖尿病用途的二肽基肽酶Ⅳ(DPP-IV)的抑制寡肽。
背景技术
糖尿病是一种以高血糖为特征的代谢性疾病。高血糖则是由于胰岛素分泌缺陷或其生物作用受损，或两者兼有引起。II型糖尿病(diabetes mellitus type 2，T2DM)，旧称非胰岛素依赖型糖尿病或成人发病型糖尿病，是一种多在35～40岁之后发病的慢性代谢疾病。国家卫计委最新公布数据表明，我国糖尿病人群已达1.14亿人，超过90％是II型糖尿病占患者。
胰高血糖素样肽1(GLP-1)是肠道L细胞分泌的一种由30个氨基酸组成的脑肠肽，具有促进胰岛素分泌、抑制胰高血糖素分泌和刺激胰岛β细胞增殖等生物学作用。GLP-1不仅具有调控血糖和能量代谢的作用，还有保护心肌细胞、改善心脏功能和舒张血管等作用，直接或间接发挥心血管保护效应。但是，GLP-1在体内极易被二肽基肽酶Ⅳ(DPP-Ⅳ)降解，其血浆半衰期很短(1～2min)。因此，基于GLP-1的II型糖尿病药物研发主要有两个方向：可以抵抗DPP-Ⅳ降解的GLP-1受体激动剂和二肽基肽酶Ⅳ(DPP-Ⅳ)抑制剂。
金枪鱼是世界远洋渔业的重要作业鱼种，占公海渔业总产量70％以上。在金枪鱼加工过程中产生约占总重量50％～70％的副产物，这些副产物主要是金枪鱼内脏，碎肉，鱼头、鱼皮和鱼骨等，大量作为饲料原料或初级饲料利用，造成了金枪鱼资源的极大浪费，也给生态环境带来了较大压力。
基于此，申请人选用金枪鱼加工副产物-鱼卵为原料，设计酶解和色谱制备工艺制备二肽基肽酶Ⅳ(DPP-Ⅳ)抑制寡肽，该寡肽活性显著且安全无毒性，可应用于治疗或者辅助治疗II型糖尿病的特殊医学用途食品、保健产品和药物。
发明内容
本发明所要解决的技术问题是针对现有技术的不足，提供了一种金枪鱼鱼卵二肽基肽酶Ⅳ(DPP-IV)抑制寡肽，其可应用于制备治疗或者辅助治疗II型糖尿病的特殊医学用途食品、保健产品和药物。
一种金枪鱼鱼卵的二肽基肽酶Ⅳ(DPP-IV)抑制寡肽，该寡肽为九肽化合物，氨基酸序列为Glu-Ile-Pro-Gly-Thr-Arg-Gly-Pro-Leu(EIPGTRGPL)，ESI-MS测定分子量为939.07Da。
一种金枪鱼鱼卵的二肽基肽酶Ⅳ(DPP-IV)抑制寡肽的制备方法，其特征在于包括下述步骤：
1)鱼卵的预处理：金枪鱼鱼卵解冻，去杂，组织捣碎机捣碎，加入丙酮溶液，200W超声15-20min脱脂，重复三次，于4℃、9000rmp离心15～20min，固体沉淀干燥，得脱脂鱼卵；
2)鱼卵的酶解：将上述脱脂鱼卵加入到pH 1.5～2.5缓冲液中，搅匀，溶液调温至37℃，加入脱脂鱼卵重量2.0～2.5％蛋白酶A，酶解3～4h；然后调溶液pH至6.5～7.5，加入脱脂鱼卵重量2.0～2.5％蛋白酶B，酶解4～5h；酶解结束后，溶液冷却至室温，于12000rmp离心10～15min，收集上清液，得金枪鱼鱼卵蛋白酶解液；
3)鱼卵二肽基肽酶Ⅳ(DPP-Ⅳ)抑制寡肽的制备：将上述金枪鱼鱼卵蛋白酶解液经截留分子量为3.0和1.0kDa的超滤膜进行分级，收集分级组分，测定各组分对二肽基肽酶Ⅳ(DPP-Ⅳ)的抑制作用(用半数抑制浓度IC50表示)，选择活性最好的组分依次经凝胶柱层析和反相高效液相色谱(RP-HPLC)纯化，得到二肽基肽酶Ⅳ(DPP-IV)抑制寡肽。
作为优选，所述的步骤1)中的金枪鱼为鲣鱼(Katsuwonus pelamis)。
作为优选，所述步骤1)中的捣碎后的鱼卵与丙酮的重量体积比为1g:8～10mL。
作为优选，所述步骤2)中脱脂脂鱼与缓冲液的重量体积比为1g:10～12mL。
作为优选，所述步骤2)中缓冲液为磷酸盐缓冲液。
作为优选，所述的步骤2)中的蛋白酶A为胃蛋白酶，酶活力≥1.5×104U/g；
作为优选，所述的步骤2)中的蛋白酶B为胰蛋白酶，酶活力≥2.0×104U/g；
作为优选，所述步骤3)中的凝胶柱层析步骤为：
将上述活性最好的超滤酶解物溶于双蒸水配成浓度为35～40mg/mL的溶液，经过Sephadex G-15柱层析分离，用双蒸水进行洗脱，流速0.6mL/min，根据215nm下色谱图收集各色谱峰，测定各个色谱峰的二肽基肽酶Ⅳ(DPP-IV)抑制作用；选择活性最高色谱峰样品，配成浓度为15～20mg/mL的溶液，经过
Peptide 10/300GL分离，用双蒸水进行洗脱，流速0.6mL/min，根据215nm下色谱图收集各色谱峰，测定各个色谱峰的二肽基肽酶Ⅳ(DPP-IV)抑制作用，得凝胶层析酶解物。
作为优选，所述步骤3)中的RP-HPLC纯化步骤为：将上述凝胶层析酶解物用双蒸水配成35～40μg/mL的溶液，利用RP-HPLC进行纯化，根据制备寡肽的活性得1个高二肽基肽酶Ⅳ(DPP-IV)抑制作用的寡肽Glu-Ile-Pro-Gly-Thr-Arg-Gly-Pro-Leu(EIPGTRGPL)，ESI-MS测定分子量为939.07Da。
进一步优选，所述RP-HPLC条件为：进样量10μL；色谱柱Kromasil C-18(250mm×4.6mm，5μm)；流动相：50％乙腈；洗脱速度0.6mL/min；紫外检测波长215nm。
本发明所提供的金枪鱼鱼卵寡肽Glu-Ile-Pro-Gly-Thr-Arg-Gly-Pro-Leu(EIPGTRGPL)可显著抑制DPP-Ⅳ活力，显著降低糖尿病小鼠餐后血糖水平，改善小鼠口服葡萄糖糖耐量和麦芽糖糖耐量，降低甘油三脂和胆固醇的含量。本发明EIPGTRGPL具有安全无毒副作用、降糖活性显著等优点，可应用于制备治疗或者辅助治疗II型糖尿病的特殊医学用途食品、保健产品和药物。
附图说明
图1是本发明实施例中的超滤组分TRH-I的Sephadex G-15柱层析色谱图。
图2是本发明实施例中的Sephadex LH-20柱层析组分TRH-I-2的
Peptide10/300GL分离色谱图。
图3是本发明实施例中的
Peptide 10/300GL制备组分TRH-I-2C的RP-HPLC色谱图。
图4 Glu-Ile-Pro-Gly-Thr-Arg-Gly-Pro-Leu(EIPGTRGPL)的结构。
图5 Glu-Ile-Pro-Gly-Thr-Arg-Gly-Pro-Leu(EIPGTRGPL)的质谱图。
图6为实施例中Glu-Ile-Pro-Gly-Thr-Arg-Gly-Pro-Leu(EIPGTRGPL)对糖尿病小鼠餐后血糖曲线下面积的影响。
图7为实施例中Glu-Ile-Pro-Gly-Thr-Arg-Gly-Pro-Leu(EIPGTRGPL)对糖尿病小鼠口服葡萄糖耐量曲线下面积的影响。
图8实施例中Glu-Ile-Pro-Gly-Thr-Arg-Gly-Pro-Leu(EIPGTRGPL)对糖尿病小鼠口服麦芽糖耐量曲线下面积的影响。
具体实施方式
下列实施例用于进一步解释说明本发明，但是，它们并不构成对本发明范围的限制或限定。
本发明实验所用的金枪鱼为鲣鱼(Katsuwonus pelamis)，由宁波今日食品有限公司提供。
磷酸盐缓冲液(pH2.0)的配置：
甲液：取磷酸16.6ml，加水至1000ml，摇匀。乙液：取磷酸氢二钠71.63g，加水使溶解成1000ml。取上述甲液72.5ml与乙液27.5ml混合，摇匀。
实施例
1)金枪鱼鱼卵的预处理：取鲣鱼鱼卵解冻，去杂，称取1000g，组织捣碎机捣碎，按料液比1g:8mL加入丙酮溶液，200W超声20min脱脂，重复三次，于4℃、9000rmp离心15min，固体沉淀干燥，得脱脂鱼卵；
2)鱼卵的酶解：将上述脱脂鱼卵按照料液比1g:12mL加入到pH 2.0缓冲液中，搅匀，溶液调温至37℃，加入脱脂鱼卵重量2.5％胃蛋白酶(1.5×104U/g)，酶解3.5h；然后调溶液pH至7.0，加入脱脂鱼卵重量2.0％胰蛋白酶(2.0×104U/g)，酶解4h；酶解结束后，溶液冷却至室温，于12000rmp离心10～15min，收集上清液，即鱼卵蛋白酶解液；
3)鱼卵二肽基肽酶Ⅳ(DPP-Ⅳ)抑制寡肽的制备：将上述鱼卵蛋白酶解液经截留分子量为3.0和1.0kDa的超滤膜进行分级，收集分级组分TRH-I(MW<1.0kDa)、TRH-II(1.0<MW<3kDa)和TRH-III(MW>3kDa)，测定各组分对二肽基肽酶Ⅳ(DPP-Ⅳ)的抑制作用(用半数抑制浓度IC50表示)，选择活性最好的组分TRH-I依次经凝胶柱层析和反相高效液相色谱(RP-HPLC)纯化，得到高活性二肽基肽酶Ⅳ(DPP-Ⅳ)抑制寡肽TRP-6，利用氨基酸序列分析仪和质谱测定TRP-6结构，具体过程为：
①凝胶色谱层析：将上述TRH-I溶于双蒸水配成浓度为35mg/mL的溶液，经过0.45μm微孔滤膜除不溶物，利用葡聚糖凝胶Sephadex G-15柱(2.0×100cm)层析分离，用双蒸水进行洗脱，流速0.6mL/min，根据215nm下的吸光度制作凝胶层析色谱图收集各色谱峰TRH-I-1～TRH-I-3(见图1)，测定各色谱峰对二肽基肽酶Ⅳ(DPP-Ⅳ)的抑制作用(见表1)；将TRH-I-2溶于双蒸水，配成浓度为20mg/mL的溶液，经过0.45μm微孔滤膜除不溶物，利用
Peptide 10/300GL分离，用双蒸水进行洗脱，流速0.6mL/min，根据215nm下色谱图收集各色谱峰TRH-I-2A～TRH-I-2D(见图2)，测定各色谱峰的二肽基肽酶Ⅳ(DPP-Ⅳ)抑制作用(IC50)，得凝胶层析酶解物TRH-I-2C。
表1
| 组分 | IC50(mg/mL) | 组分 | IC50(mg/mL) |
| TRH | 2.372 | TRH-I-3 | 2.698 |
| TRH-I | 0.3876 | TRH-I-2A | 3.216 |
| TRH-II | 2.109 | TRH-I-2B | 0.978 |
| TRH-III | 6.746 | TRH-I-2C | 0.176 |
| TRH-I-1 | 1.347 | TRH-I-2D | 1.397 |
| TRH-I-2 | 0.269 |
②RP-HPLC精制：将上述TRH-I-2C用双蒸水配成浓度为35μg/mL的溶液，经过0.45μm微孔滤膜除不溶物，利用RP-HPLC进行纯化(进样量10μL；色谱柱Kromasil C-18(250mm×4.6mm，5μm)；流动相50％乙腈；紫外检测波长215nm，根据215nm下的吸光度曲线收集寡肽TRP-1～TRP-9(见图3)，测定9个组分的寡肽对二肽基肽酶Ⅳ(DPP-Ⅳ)抑制作用(见表2)，得高活性二肽基肽酶Ⅳ(DPP-Ⅳ)抑制寡肽TRP-6。
表2
| 组分 | IC50(mg/mL) | 组分 | IC50(mg/mL) |
| TRP-1 | 1.837 | TRP-5 | 1.087 |
| TRP-2 | 0.698 | TRP-6 | 0.093 |
| TRP-3 | 3.574 | TRP-7 | 0.905 |
| TRP-4 | 0.538 | TRP-8 | 2.367 |
| TRP-9 | 1.542 |
③结构检测：收集活性最高的二肽基肽酶Ⅳ(DPP-Ⅳ)抑制寡肽TRP-6，利用蛋白/多肽序列分析仪测定其氨基酸序列为Glu-Ile-Pro-Gly-Thr-Arg-Gly-Pro-Leu(EIPGTRGPL)(见图4)，ESI-MS测定分子量为939.07Da(见图5)。
④功能评价：采用小鼠体内实验评估鱼卵二肽基肽酶Ⅳ(DPP-Ⅳ)抑制寡肽EIPGTRGPL治疗糖尿病的效果，实验方法参照文献[陈明珠.杭白菊中黄酮成分的抗糖尿病活性及其机制研究[D].天津科技大学,2019，P18-19]。采用阿卡波糖为阳性对照，实验结果表明：Glu-Ile-Pro-Gly-Thr-Arg-Gly-Pro-Leu(EIPGTRGPL)能显著降低餐后血糖水平(见图6)，改善小鼠口服葡萄糖糖耐量(见图7)和麦芽糖糖耐量(见图8)，降低甘油三脂(TG)和胆固醇(TC)的含量(见表3)。
表3
--表示未给任何药物，空白组：正常饲养小鼠，模型组：高脂饮食饲养但未给任何药物的小鼠。
综上，Glu-Ile-Pro-Gly-Thr-Arg-Gly-Pro-Leu(EIPGTRGPL)显著抑制二肽基肽酶Ⅳ(DPP-Ⅳ)活力和降低II型糖尿病小鼠的血糖水平，且无显著毒副作用，可应用于治疗或者辅助治疗II型糖尿病的特殊医学用途食品、保健产品和药物。
最后，尚需注意的是，以上列举的仅是本发明的一个具体实施例。显然，本发明不限于以上实施例，还可以有许多变形。本领域的普通技术人员能从本发明公开的内容直接导出或联想到的所有变形，均应认为是本发明的保护范围。
Claims (2)
1.一种金枪鱼鱼卵的二肽基肽酶Ⅳ抑制寡肽，其特征在于所述寡肽为九肽化合物，其氨基酸序列为Glu-Ile-Pro-Gly-Thr-Arg-Gly-Pro-Leu，ESI-MS测定分子量为939.07 Da。
2.如权利要求1所述一种金枪鱼鱼卵的二肽基肽酶Ⅳ抑制寡肽在制备治疗或者辅助治疗II型糖尿病的药物中的用途。
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| 绿鳍马面鲀(Navodon septentrionalis)鱼头酸溶性与酶溶性胶原蛋白的分离纯化及理化性质研究;赵玉勤;《海洋与湖沼》(第3期);237-243 * |
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