CN108033995A - 两种来源于大黄鱼肌联蛋白的ace抑制肽 - Google Patents
两种来源于大黄鱼肌联蛋白的ace抑制肽 Download PDFInfo
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Abstract
本发明主要涉及大黄鱼肌联蛋白源ACE抑制肽序列及其应用，两种肽序列分别为WAR和WQR，为高血压的预防和治疗奠定基础。本发明借助不同的在线数据库，多轮筛选后得到具有高效抑制ACE活性的抑制肽。人工合成WAR和WQR，使用高效液相色谱法验证其体外ACE抑制活性。本发明涉及的两种活性肽具有良好的体外ACE抑制活性。本发明所提供的两种肽序列可用于开发具有调节血压作用的保健食品，通过长期服用而达到预防、控制、缓解和辅助治疗高血压的目的。
Description
技术领域
本发明属于生物活性肽领域，主要涉及两种来源于大黄鱼肌联蛋白的ACE抑制肽以及所述肽的应用。
背景技术
高血压是一种慢性动脉高血压症状，并导致心力衰竭，视力丧失和心悸等多种疾病。在人体中，血管紧张素转换酶(angiotensin-I converting enzyme，ACE)将无活性的ACE-I转化为有升压活性的血管收缩剂ACE-II，并使血管舒张激肽失活，导致动脉收缩，血压升高。因此，抑制ACE的活性是治疗高血压疾病的方法之一。化学合成类ACE抑制剂如卡托普利，赖诺普利，依那普利和福辛普利是用于治疗高血压的药物。但是，这些药物会引起某些副作用，包括咳嗽，皮疹和血管性水肿，而来自食物蛋白质的ACE抑制肽会改善这种情况。近些年来，人们对食源性生物活性肽作为候选药物的研究越来越多。每年都有大量相关研究论文发表，发现了各种新的治疗性活性肽及其应用，例如瘤归巢肽，细胞穿透肽，抗微生物剂多肽，抗癌肽等。已经证明，来自各种食物蛋白的生物活性肽可以预防和调节血压升高，且易于吸收，毒副作用小。
近年来，相关研究表明从动植物以及乳制品中分离得到的天然的ACE抑制生物活性肽，可开发具有调节血压作用的保健食品，通过长期服用而达到预防、控制、缓解和辅助治疗高血压的目的。从食物蛋白质制备ACE抑制肽的最常用方法之一是酶水解，分离纯化和结构鉴定。但是它的缺点在于花费时间长且成本高，最终不一定能达到预期效果。随着科学技术的不断发展，结合高性能计算机辅助设计活性肽的研究越来越多，利用在线数据，不仅减少筛选强度、降低筛选人工和缩短研发周期，还提高了筛选成功的机率。利用计算机模拟大黄鱼肌联蛋白的酶水解，并根据在线数据库对当前研究的寡肽进行性质预测，多轮虚拟筛选之后，最终可以筛选到与靶标分子相结合的高效活性肽。目前，在生物活性肽的研发领域，活性肽结构研究比较复杂，借助分子对接技术预测活性肽与靶标分子的结合位点，有助于对活性肽与ACE相互作用与结合机理进行研究。使用分子对接阐明肽与ACE酶上特定的抑制性位点进行分子对接，逐渐成为活性肽研发的热点。
发明内容
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，利用活性肽的分子量、生物活性评分、毒性、水溶性、吸收代谢等性质进行多轮筛选，最终得到与ACE(PDB：1A1B)稳定结合的两种生物活性肽，其寡肽序列为WAR和WQR。人工合成两种寡肽，验证其体外ACE抑制活性，结果表明，两种活性肽具有良好的体外ACE抑制活性。最后利用分子对接软件，将三肽与ACE酶上特定的抑制性位点进行分子对接，阐明ACE抑制活性验证结果与虚拟对接结果之间的相关性。借助本发明获得的寡肽，可用于开发具有调节血压作用的保健食品，通过长期服用而达到预防、控制、缓解和辅助治疗高血压的目的。
本发明的技术方案：
两种来源于大黄鱼肌联蛋白的ACE抑制肽，氨基酸序列分别为WAR和WQR。
所述多肽来自大黄鱼肌联蛋白，包括以所述ACE抑制活性的肽序列为核心，任何对其进行的相应的调整或修饰。
所述三肽WAR与ACE(1O86)催化位点的氨基酸残基分别为ALA354、HIS353、HIS513、TYR523、TYR520和LYS511。WQR与ACE(1O86)的催化位点的氨基酸残基分别为LYS511、TYR520、TYR523、HIS353和HIS513。
所述的ACE抑制肽在开发具有调节血压作用的保健食品和药物中的应用。
利用在线数据库进行多轮筛选，获得ACE抑制肽的方法，包括以下步骤：
(1)从NCBI数据库中搜寻大黄鱼相关的蛋白质序列进行分析，选定依据为大黄鱼肌肉蛋白的重要组分且亲本蛋白质的序列信息的可用性。
(2)使用胃蛋白酶(pH 1.3)和胰蛋白酶通过ExPASy PeptideCutter(http：//web.expasy.org/peptide_cutter/)对肌联蛋白进行虚拟水解，选出所有的三肽，在PeptideRanker(http：//bioware.ucd.ie/～compass/biowareweb/Server_pages/Peptideranker.php)中进行活性评分，选定评分高的部分三肽，使用在线工具Innovagen(http：//www.innovagen.com/proteomics-tools)，ToxinPred(http：//crdd.osdd.net/raghava//toxinpred/)和admetSAR(http：//lmmd.ecust.edu.cn/admetsar1/redict/)分别预测水溶性，毒性和ADMET性质。最终选出所需的肽序列，在SwissDock中与ACE对接，选定对接能量值相对最低的肽序列。进行人工合成后合成，验证体外ACE活性验证。
(3)采用高效液相色谱法验证活性肽的体外ACE抑制活性。取马尿酰组胺酰亮氨酸(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，再加入的1mol/L HCl终止反应，得到反应液。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，流动相乙腈∶水为25∶75等度洗脱，检测波长228nm。
本发明的两种三肽WAR和WQR对ACE蛋白均有显著抑制作用，其IC50分别为31.17±0.79和23133±0.02μM。因此，所述的ACE抑制肽具有开发调节血压作用的保健食品和药物的前景。
(4)分子对接用于预测ACE与肽相互作用。ACE与肽相互作用的能力可能增强或抑制ACE活性。在本实验中，ACE的晶体结构是从蛋白质数据库(PDB)获得的。我们使用Discovery Studio 2017 R2软件进行ACE与三肽的分子对接，并用于分析结合位点处的肽相互作用。最后的分析是手动完成的。在分析之前，执行了以下步骤：(i)使用CDOCKER对接程序；(ii)选择CHARMm力场；(iii)ACE酶的活性中心是XYZ(40.497，34.883，44.381)。CHARMm力场来用来最小化每个肽的构象。根据所得到的对接数据，计算出的WAR和WQR的CDOCKER能量。
本发明的积极有益效果：
(1)本发明通过计算机辅助设计技术来进行定向结合多肽的虚拟筛选，在节省纯化、鉴定肽序列的时间和成本的前提下，缩小了在生物测定中实际测试的化合物的数量，提高了筛选成功的机率。
(2)经过在线数据库BIOPEP的搜索，本文所述肽序列并未被论文发表，本发明所设计的两种三肽为新的食源性ACE抑制肽序列。
附图说明
本发明附图2幅，其中：
图1 WAR与ACE(PDB：1O86)分子对接图谱；
图2 WQR与ACE(PDB：1O86)分子对接图谱。
具体实施方式
下面以具体实施例的方式对本发明作进一步的阐述。
实施例1原料的筛选
从NCBI数据库中搜寻大黄鱼相关的蛋白质序列进行分析，选定依据为大黄鱼肌肉蛋白的重要组分且亲本蛋白质的序列信息的可用性。最终选定大黄鱼肌联蛋白氨基酸(ACCESSION：KKF25250)，氨基酸数为17943。
实施例2三肽的筛选与活性测定
使用胃蛋白酶(pH 1.3)和胰蛋白酶通过ExPASy PeptideCutter对肌联蛋白进行虚拟水解，选出所有的三肽，在PeptideRanker中进行活性评分，选定评分高的50条三肽。
使用在线工具Innovagen、ToxinPred和admetSAR分别预测水溶性，毒性和ADMET性质。筛选出无毒，水溶性良好的三肽。在ADMET预测中，着重的测定胃肠吸收良好(goodintestinal absorption，HIA+)和可穿透血脑屏障的三肽(could penetrate the Blood-Brain Barrier，BBB+)，作为潜在高效ACE抑制肽候选物。最终选出8条所需的三肽序列，在SwissDock中与ACE(PDB ID：1A1B)对接，选定对接能量值相对最低的两种三肽WAR和WQR，ΔG分别为-10.40和-9.57kcal/mol。最后进行合成，使用高效液相色谱法进行体外ACE活性验证。
ExPASy PeptideCutter和PeptideRanker两轮筛选获得的活性肽信息结果见表1，Innovagen、ToxinPred、admetSAR和SwissDock两轮筛选获得的活性肽信息结果见表2。
表1 高生物活性评分的三肽信息
表2 ADMET与SwissDock对接结果
实施例3体外活性验证
采用高效液相色谱法验证WAR和WQR的ACE抑制活性。取马尿酰组胺酰亮氨酸(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，再加入的1mol/L HCl终止反应，得到反应液。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，流动相乙腈∶水为25∶75等度洗脱，检测波长228nm。
经过实验验证WAR和WQR的体外ACE抑制活性，分别31.17±0.79和231.33±0.02μM。
实施例4三肽与ACE的虚拟对接分析
使用Discovery Studio 2017软件，在CHARMm力场条件下，将WAR、WQR和WYR分别与(PDB ID：1O86)进行对接，图谱显示三肽与ACE酶上特定的抑制性位点相互作用形式。
三肽与1O86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三种形式，其中WAR与1O86催化位点的氨基酸残基分别为ALA354、HIS353、HIS513、TYR523、TYR520和LYS511。WQR与1O86的催化位点的氨基酸残基分别为LYS511、TYR520、TYR523、HIS353和HIS513。WAR与WQR相比，在1O86中具有更大的相互作用。WAR和WQR的抑制效力不同可归因于它们催化1O86不同活性位点的能力。
Claims (4)
1.两种ACE抑制肽，其特征是，所述的两种ACE抑制肽氨基酸序列分别为WAR和WQR。
2.根据权利要求1所述的ACE抑制肽，来自大黄鱼肌联蛋白，包括以所述ACE抑制活性的肽序列为核心，任何对其进行的相应的调整或修饰。
3.如权利要求1所述的ACE抑制肽，其特征是，WAR与ACE(1O86)相互作用涉及的催化位点的氨基酸残基分别为ALA354、HIS353、HIS513、TYR523、TYR520和LYS511；WQR与1O86相互作用涉及的的催化位点的氨基酸残基分别为LYS511、TYR520、TYR523、HIS353和HIS513。
4.权利要求1所述的ACE抑制肽在开发具有调节血压作用的保健食品和药物中的应用。
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