CN117126234A - 一类天然ace抑制肽及其应用 - Google Patents
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Abstract
本发明公开了一类天然ACE抑制肽及其应用,属于生物医学技术领域。其中,所述天然ACE抑制肽来源于刺参内脏,由6‑13个氨基酸组成,氨基酸序列如SEQ ID NO.1‑12所示。本发明的有益之处在于:本发明提供的ACE抑制肽更安全、更易被人体吸收、具有良好的ACE抑制效果,可应用于抗高血压药物或组合物、抗高血压食品领域。
Description
技术领域
本发明涉及ACE抑制肽及其应用,具体涉及一类来源于刺参内脏的天然ACE抑制肽及其应用,属于生物医学技术领域。
背景技术
高血压(hypertension)是一种以动脉血压升高为特征,伴有心脏、血管、脑和肾脏等器官功能性或器质性改变的全身性疾病,是威胁人类健康的主要疾病之一。现代医学证明,持续的高血压可诱发一系列心血管疾病,如动脉粥样化、脑中风、冠心病、心肌梗塞、肾衰竭等。最近的流行病学研究表明,高血压的发病人群呈年轻化趋势,高血压己经成为亟需解决的世界性健康问题。对高血压疾病预防及治疗药物的研究一直是医学研究领域的热门,据现有医疗方案,高血压患者需要终身服药。当前治疗效果显著的降压药物当属人工合成的血管紧张素转化酶抑制剂:卡托普利,但停药后易出现血压反弹并伴有咳嗽、味觉功能紊乱、肾功能损害等副作用,情节严重时可致人死亡,而赖诺普利、依那普利、福辛普利等合成类降压药具有干咳、血管性水肿、皮疹等副作用。相比之下,天然食源性的血管紧张素转化酶抑制肽则更安全,也更易被人体吸收,可作为人工合成的血压调节剂的替代。
ACE抑制肽(ACE Inhibitory Peptide,ACEIP)是一类特殊的蛋白质片段,长度约为2-20个氨基酸的短序列,相对分子质量介于150-4000Da之间。出于对降压作用和安全性考虑,迄今为止,已经从食品蛋白来源的酶水解物中筛选出了许多ACE抑制肽,包括鱼类、贝类和大型藻类等,在抗高血压肽数据库中已经报道了超过5978种ACEIP,其中一些已被证实在自发性高血压大鼠(SHRs)和患有高血压的人类志愿者中具有明确的降压作用。海洋生物因其富含独特的生物活性化合物,使人们对从海洋生物中分离生物活性化合物以开发新药或保健品的研究备受关注。
发明内容
为解决现有人工合成的血压调节剂的不足,本发明的目的在于提供一类更安全,也更易被人体吸收的天然ACE抑制肽及其应用。
为了实现上述目标,本发明采用如下的技术方案:
一类天然ACE抑制肽,来源于刺参内脏,由6-13个氨基酸组成,氨基酸序列如SEQID NO.1-12所示:
SEQ ID NO.1:SGIQVR,分子量为330.195Da,等电点为10.11,所有氨基酸均为L-型;
SEQ ID NO.2:TIQFGGK,分子量为375.711Da,等电点为9.11,所有氨基酸均为L-型;
SEQ ID NO.3:VEWGLDRIDQR,分子量为462.911Da,等电点为4.56,所有氨基酸均为L-型;
SEQ ID NO.4:PPPVFDAK,分子量为435.742Da,等电点为6.19,所有氨基酸均为L-型;
SEQ ID NO.5:TTENKKPVVVR,分子量为424.254Da,等电点为10.01,所有氨基酸均为L-型;
SEQ ID NO.6:AAGMDGATGPR,分子量为502.235Da,等电点为6.19,所有氨基酸均为L-型;
SEQ ID NO.7:GPAGPQGSR,分子量为413.712Da,等电点为9.10,所有氨基酸均为L-型;
SEQ ID NO.8:GAAGGPGVPGNR,分子量为505.262Da,等电点为10.11,所有氨基酸均为L-型;
SEQ ID NO.9:FVHTGTSGGR,分子量为509.757Da,等电点为10.11,所有氨基酸均为L-型;
SEQ ID NO.10:GPSEGELFGK,分子量为510.755Da,等电点为4.54,所有氨基酸均为L-型;
SEQ ID NO.11:GYQGPAGPQGSR,分子量为587.785Da,等电点为9.10,所有氨基酸均为L-型;
SEQ ID NO.12:TGPAGPQGPAGDR,分子量为590.789Da,等电点为6.19,所有氨基酸均为L-型。
前述的天然ACE抑制肽在制备抗高血压药物或组合物、抗高血压食品中的应用。
本发明的有益之处在于:
(1)本发明提供的ACE抑制肽,来源于刺参内脏,是一类天然ACE抑制肽,对人体更安全;
(2)本发明提供的ACE抑制肽,由6-13个氨基酸组成,分子量较小,更易被人体吸收;
(3)本发明提供的ACE抑制肽,ACE抑制率范围在24.95-70.32%,具有良好的ACE抑制效果,可应用于抗高血压药物或组合物、抗高血压食品领域。
附图说明
图1是合成的12条ACE抑制肽的ACE抑制率计算结果图;
图2是SEQ ID NO.4所示ACE抑制肽的ACE抑制率计算结果图。
具体实施方式
以下结合附图和具体实施例对本发明作具体的介绍。
一、天然ACE抑制肽的发现
将刺参内脏用胰蛋白酶进行酶解,料液比1:1.98,加酶量2.56%,pH=8.5,在37℃酶解1.0h,通过HPLC进行纯化,对氨基酸序列进行测定,通过液质联用(LC-MS/MS)分析得到质谱原始结果文件,与刺参转录组数据集(从NCBI的SRA数据库下载)经过软件Byonic分析比对、匹配数据、确定多肽序列,选择12条在纯化肽中占比相对较高且与ACE抑制肽能量结合值低、无毒、稳定性好的氨基酸序列。
这12条氨基酸序列具体如下:
表1来源于刺参内脏的12条天然ACE抑制肽
注:所有氨基酸均为L-型。
二、天然ACE抑制肽的化学合成方法
用自动多肽合成仪(433A,Applied Biosystems)合成表1所列的12条天然ACE抑制肽的全序列,通过HPLC C18反相柱层析进行脱盐纯化,制成粉末(多肽粉末),备用。
纯化的ACE抑制肽用高效液相色谱(HPLC)法鉴定其纯度>95%,分子量测定采用常规基质辅助激光解析电离飞行时间质谱(MALDI-TOF)法,等电聚焦电泳测定等电点,用自动氨基酸测序仪确定其氨基酸序列结构与表1所列的天然ACE抑制肽一致。
三、天然ACE抑制肽的抑制活性
将前面通过化学方法合成的多肽粉末配成浓度为1mg/mL的肽溶液,测定肽的ACE抑制率。
肽的ACE抑制率的测定方法参照文献(Zhao Y,Li B,Dong S,et al,A novel ACEinhibitory peptide isolated from Acaudina molpadioidea hydrolysate[J],Peptides,2009,30(6):1028-1033。)中记载的方法,略有改动,具体的:
(1)将ACE和HHL分别溶解在pH为8.3、浓度为0.1mol/L的硼酸钠缓冲溶液(含0.3mol/L的NaCl)中,获得酶活力为0.1U/mL的ACE溶液和浓度为5.82mmol/L的HHL溶液;
(2)取前面已经配制完成的浓度为1mg/mL的肽溶液50μL于1.5mL离心管中(对照组为取pH为8.3、浓度为0.1mol/L的硼酸钠缓冲液50μL于1.5mL离心管中),加入浓度为5.82mmol/L的HHL溶液100μL,混匀;
(3)在37℃水浴锅中放置5min,然后加入酶活力为0.1U/mL的ACE溶液10μL,混匀;
(4)在37℃水浴锅中放置30min,然后加入浓度为1mol/L的HCl150μL,混匀至反应终止;
(5)加入1mL乙酸乙酯振荡30s,在4℃、4000r/min条件下离心10min,静置至有机相和水相完全分离;
(6)移取0.8mL上层有机相至2mL离心管中,85℃挥干乙酸乙酯;
(7)加入1mL蒸馏水使残留物充分溶解,测定溶液在228nm处的吸光度值(A228);
(8)按照下列公式计算ACE抑制率:
I(%)=(A0-A1)/A0×100%
式中:I为ACE抑制率;A0为对照组在228nm处的吸光度值;A1为供试品在228nm处的吸光度值。
合成的12条ACE抑制肽(浓度为1mg/mL)对ACE的抑制活性的计算结果见图1。
结果表明,合成的12条ACE抑制肽的ACE抑制率范围在24.95-70.32%,肽段VEWGLDRIDQR(SEQ ID NO.3)对ACE活性的抑制率最高,为70.32%,其次是肽段GPSEGELFGK(SEQ ID NO.10)、肽段PPPVFDAK(SEQ ID NO.4)、肽段TGPAGPQGPAGDR(SEQ ID NO.12),它们的ACE抑制率分别为69.68%、67.53%、66.67%,这4条ACE抑制肽均显示出良好的ACE抑制活性。
四、天然ACE抑制肽对ACE的抑制的IC50值
选取SEQ ID NO.4所示的ACE抑制肽(PPPVFDAK),测定其对ACE的抑制的IC50值。
把SEQ ID NO.4所示的ACE抑制肽(PPPVFDAK)配成不同的浓度,分别为:50μM、100μM、200μM、400μM、800μM,进行体外IC50活性测定。
肽对ACE抑制率的大小,一般都通过IC50值(即抑制率达到50%的肽浓度)来比较,IC50值越小,说明抑制活性越大。
以肽段的浓度为横坐标,以ACE抑制率为纵坐标,利用Origin2021软件绘制曲线,通过GraphPad Prism进行数据转化、最小二程法拟合计算IC50。
SEQ ID NO.4所示的ACE抑制肽(PPPVFDAK)的ACE抑制活性的检测结果见图2。
由图2可知,SEQ ID NO.4所示的ACE抑制肽(PPPVFDAK)的ACE抑制率与肽段浓度均呈正相关,其IC50值为54.70μM。
综上,本发明提供的ACE抑制肽来源于刺参内脏,是一类天然ACE抑制肽,更安全;这些ACE抑制肽由6-13个氨基酸组成,分子量较小,更易被人体吸收;并且,经检测,这些ACE抑制肽具有良好的ACE抑制效果,故本发明提供的ACE抑制肽可应用于抗高血压药物或组合物、抗高血压食品领域。
需要说明的是,本发明的上述实施例仅仅是为清楚地说明本发明所作的举例,而并非是对本发明的实施方式的限定。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无法对所有的实施方式予以穷举。凡是属于本发明技术方案所引伸出的显而易见变化或变动仍处于本发明的保护范围之列。
Claims (2)
1.一类天然ACE抑制肽,其特征在于,所述天然ACE抑制肽源于刺参内脏,由6-13个氨基酸组成,氨基酸序列如SEQ ID NO.1-12所示:
SEQ ID NO.1:SGIQVR,分子量为330.195Da,等电点为10.11,所有氨基酸均为L-型;
SEQ ID NO.2:TIQFGGK,分子量为375.711Da,等电点为9.11,所有氨基酸均为L-型;
SEQ ID NO.3:VEWGLDRIDQR,分子量为462.911Da,等电点为4.56,所有氨基酸均为L-型;
SEQ ID NO.4:PPPVFDAK,分子量为435.742Da,等电点为6.19,所有氨基酸均为L-型;
SEQ ID NO.5:TTENKKPVVVR,分子量为424.254Da,等电点为10.01,所有氨基酸均为L-型;
SEQ ID NO.6:AAGMDGATGPR,分子量为502.235Da,等电点为6.19,所有氨基酸均为L-型;
SEQ ID NO.7:GPAGPQGSR,分子量为413.712Da,等电点为9.10,所有氨基酸均为L-型;
SEQ ID NO.8:GAAGGPGVPGNR,分子量为505.262Da,等电点为10.11,所有氨基酸均为L-型;
SEQ ID NO.9:FVHTGTSGGR,分子量为509.757Da,等电点为10.11,所有氨基酸均为L-型;
SEQ ID NO.10:GPSEGELFGK,分子量为510.755Da,等电点为4.54,所有氨基酸均为L-型;
SEQ ID NO.11:GYQGPAGPQGSR,分子量为587.785Da,等电点为9.10,所有氨基酸均为L-型;
SEQ ID NO.12:TGPAGPQGPAGDR,分子量为590.789Da,等电点为6.19,所有氨基酸均为L-型。
2.权利要求1所述的天然ACE抑制肽在制备抗高血压药物或组合物、抗高血压食品中的应用。
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