CN108840906A - 两种具有ace抑制活性的弹涂鱼源活性肽 - Google Patents
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Abstract
本发明提供了两种具有ACE抑制活性的弹涂鱼源活性肽，其氨基酸序列分别IDF和EGF；本发明借助体内消化酶模拟体系并以特定靶点为导向，获得ACE抑制三肽序列，该方法具有特征性强，灵敏度高等优点；还涉及这两种肽与血管紧张素转换酶结合并抑制其活性的作用位点。对开发具有抗高血压的海洋资源食品、保健品及药物提供了新方法。
Description
技术领域
本发明属于生物技术领域，主要涉及两种具有ACE抑制活性的弹涂鱼源活性肽。
背景技术
生物活性肽是特异性的蛋白质片断，通过有效促进机体功能或状态来改善人类的健康。这些生物活性肽在母蛋白中没有活性，但却能通过蛋白水解或发酵释放出来而产生活性。在体内，这些生物活性肽能够发挥多种不同的活性，不仅可改善养分的利用，还可影响心血管、内分泌、免疫以及神经系统。血管紧张素转化酶(ACE)抑制肽通常是一类具有抑制ACE活性的小肽物质，往往与ACE通过不同方式结合后，抑制了ACE催化无活性的血管紧张素I水解为血管紧张素II的作用，进而起到降低血压的目的。
我国海洋资源丰富，种类繁多，海洋生物是新化合物的巨大来源，也是生物活性肽的巨大储存库，开发前景广阔。大弹涂鱼(Boleophthalmus pectinirostris)是系沿岸暖水广温广盐性两栖鱼类。大弹涂鱼具有食物链短，鱼病少，易于养活，耐长途运输等特点，是一种有前途的滩涂养殖鱼类。通过酶解大弹涂鱼蛋白质获得的ACE抑制肽安全性高、毒副作用小、容易吸收，可长期服用，作为降压药物或保健食品有着良好的应用前景。但是基于传统的生物酶解、色谱多维分离及结构鉴定，不仅增加成本而且费时费力，同时会造成一些高活性肽片段的筛选遗漏。因此成为制约鉴定具有ACE抑制活性的肽的高效筛选。
本发明利用在线酶解方法可以定向的针对ACE抑制肽特异性进行筛选并获得氨基酸序列，节省时间并且提高经济效益，为抗高血压活性肽功能性产品及药物研究提供基础，将海洋蛋白作为制备活性肽的良好来源，在预防疾病、保障人体健康方面发挥重要的作用，进而推动人类对于海洋蛋白资源深加工。
发明内容
本发明的目的在于提供：一种分离的生物活性三肽IDF，其包括(a)由Ile-Asp-Phe所示的氨基酸组成的三肽；(b)或在Ile-Asp-Phe所示的氨基酸序列中经取代、缺失或添加一个或几个氨基酸且具有同等活性的由(a)衍生的多肽；
一种分离的生物活性三肽EGF，其包括(c)由Glu-Gly-Phe所示的氨基酸组成的三肽；(d)或在Glu-Gly-Phe所示的氨基酸序列中经取代、缺失或添加一个或几个氨基酸且具有同等活性的由(c)衍生的多肽；
所述生物活性三肽的来源于弹涂鱼肌动蛋白。所述三肽的衍生物，是指在三肽的氨基酸侧链基团上、氨基端或羧基端进行羟基化、羧基化、羰基化、甲基化、乙酰化、磷酸化、酯化或糖基化等修饰，得到的多肽衍生物。
本发明通过利用生物信息学的方法，借助在线活性肽数据库，通过虚拟酶解弹涂鱼肌动蛋白，并利用活性肽的分子量、生物活性评分、水溶性、ADMET等性质进行多轮筛选，结合分子对接实验得到与ACE稳定结合的两种生物活性肽，并通过高效液相色谱法验证体外ACE抑制活性，其三肽序列为IDF和EGF，IC50值分别为423.00μM和451.21μM。最后利用分子对接软件，阐明IDF和EGF分别与ACE相互作用催化位点的氨基酸残基。
本发明ACE抑制肽的有益效果为：本发明的弹涂鱼源ACE抑制肽具有体外ACE抑制活性；两种ACE抑制肽在通常的动物体内消化条件下稳定，能够通过胃肠道直接吸收利用发挥其具有的生物活性功能；本发明获得活性肽序列未经报道，为功能食品开发提供了新的资源。
附图说明
本发明附图2幅，其中：
图1ACE与IDF相互作用；
图2ACE与EGF相互作用；
具体实施方式
本发明采用的实验步骤，具体如下：
实施例1原料的筛选
本发明从NCBI(https：//www.ncbi.nlm.nih.gov/protein/XP_020776504)数据库中搜寻海洋蛋白源相关的蛋白质序列进行分析，选定大弹涂鱼肌动蛋白作为ACE抑制肽的原料蛋白。accession号为XP_020776504，含有6578个氨基酸。
实施例2三肽IDF和EGF的筛选
在ExPASy PeptideCutter(https：//web.expasy.org/peptide_cutter/)中使用Pepsin(pH 1.3)和Trypsin对大弹涂鱼肌动蛋白蛋白(accession：XP_020776504)进行在线水解，水解得到含有不同氨基酸的肽序列，并筛选出所有含有三个氨基酸的肽序列。将这些三肽在PeptideRanker(http：//bioware.ucd.ie/～compass/biowareweb/Server_pages/Peptid eranker.php)中进行活性评分，共筛选出17种活性评分高于0.55的三肽。同时，对这17种肽的水溶性Innovagen(http：//www.innovagen.corn/proteomics-tools)和毒性ToxinPred(http：//crdd.osdd.net/raghava//toxinpred/)分别进行预测，筛选出水溶性好且无毒性的三肽。这17种三肽的肽序列、活性评分、水溶性及其毒性预测结果见表1。使用admetSAR(http：//lmmd.ecust.edu.cn/admetsar1/predict/)对上一步筛选出的三肽进行ADMET预测，测定胃肠吸收良好(good intestinal absorption，HIA+)的三肽，筛选得到了预测结果为HIA+的三肽，分别为IDF，VWR，EGF和GDL。将四种三肽分别与ACE(PDB ID：1O86)进行分子对接作为潜在高效ACE抑制肽候选物。结果表明，有两种活性肽与ACE稳定结合，其CDOCKER值见表2，所选两种活性肽IDF和EGF即为本发明鉴定得到的三肽。
表1选定三肽的活性评分、水溶性及毒性预测结果
表2分子对接中三肽与ACE结合能
实施例3体外活性验证
ACE抑制肽是经过大弹涂鱼伴肌动蛋白的在线筛选和分子对接而得到，为了验证本发明IDF和EGF的ACE抑制活性，采用高效液相色谱法。
1、仪器及化学用品：C18液相色谱柱，岛津LC-2030高效液相色谱仪，马尿酰-组氨酰-亮氨酸(HHL)、马尿酸(HA)、血管紧张素转化酶(ACE)购自Sigma公司，乙腈、甲醇和三氟乙酸(TFA)购自Fisher Scientific公司。所有试剂均为色谱纯。
2、高效液相色谱分析：取HHL底物溶液，加入抑制剂混合均匀，在37℃恒温水浴中预热3～5min，然后加入ACE液充分混合，37℃保温30min后立即进行反应，同时用硼酸缓冲液替代抑制剂溶液作为空白对照组。该反应液直接用HPLC系统进行分析。
色谱条件：柱温25℃，流速0.5mL/min，进样量10μL，流动相乙腈∶水为25∶75等度洗脱，检测波长228nm。
利用下列公式计算不同浓度三肽的抑制率：
ACE抑制活性(％)＝(A-B)/A×100％
其中A是反应空白的峰面积，反应空白混合物含有相同体积的缓冲溶液而不是样品；B是ACE和酶促肽样品存在下反应的峰面积，IC50值定义为在测定条件下抑制50％ACE活性的抑制剂浓度。
ACE活性的定义：ACE活性的一个单位(U)定义为在37℃下每分钟从催化HHL形成1mol的HA所需的酶量。
活性肽对ACE酶活性抑制实验结果显示(见表3)，本发明的两种三肽对ACE具有显著的ACE抑制特性。
表3三肽对ACE酶抑制活性
实施例4活性肽与ACE的虚拟对接分析
使用Discovery Studio 2017软件，在CHARMm力场条件下，将IDF和EGF分别与AEC(PDB ID：1O86)进行对接，图1和图2分别显示三肽IDF和EGF与ACE酶上特定的抑制性位点相互作用形式。
活性肽与ACE之间的相互作用主要包括范德华力、氢键结合作用力、疏水作用和静电相互作用，其中IDF与ACE催化位点的氨基酸残基分别为Val518，Tyr520，Tyr523，His513，Lys511，Gln281，Val380，Val379，Asp425；EGF与ACE催化位点的氨基酸残基分别为Tyr520，Gln281，His513，Lys511，His383，His387，Glu384，Val380，Ala354，His353。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在不脱离本发明的原理和宗旨的情况下在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (2)
1.两种具有ACE抑制活性的弹涂鱼源活性肽，其特征是，所述活性肽的氨基酸序列分别为IDF和EGF。
2.根据利要求1所述的两种具有ACE抑制活性的弹涂鱼源活性肽，其特征是，IDF与ACE(PDB ID：1O86)催化位点的氨基酸残基分别为Val518，Tyr520，Tyr523，His513，Lys511，Gln281，Val380，Val379，Asp425；EGF与ACE(PDB ID：1O86)的催化位点的氨基酸残基分别为Tyr520，Gln281，His513，Lys511，His383，His387，Glu384，Val380，Ala354，His353。
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| CN108033995A (zh) * | 2017-12-19 | 2018-05-15 | 渤海大学 | 两种来源于大黄鱼肌联蛋白的ace抑制肽 |
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