CN108191969B - 两种来源于大西洋鳟鱼胶原蛋白的ace抑制肽 - Google Patents
两种来源于大西洋鳟鱼胶原蛋白的ace抑制肽 Download PDFInfo
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Abstract
本发明公开了两种来源于大西洋鳟鱼胶原蛋白的ACE抑制肽，分别为IGPR和PGAR。ACE抑制肽属于一种有高血压预防、治疗功能的活性肽。本发明主要利用多种在线数据库对已知蛋白序列进行酶解，并对酶解后得到的肽序列进行高活性筛选，得到高效的ACE抑制活性肽序列。对得到的肽序列进行化学合成，使用高效液相色谱法验证其体外ACE抑制活性。本发明所提供的两种肽序列可用于开发具有血压调节作用的食品、保健品。
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西洋鳟鱼胶原蛋白的ACE抑制肽。
背景技术
高血压被认为是引起中风、心脏衰竭、视力丧失和慢性肾脏疾病的主要因素。血管紧张素转换酶(angiotensin-I converting enzyme，ACE)能将不具活性的血管紧张-I(angiotensin-I)转换为能够引起血压上升的血管紧张素-II(angiotensin-II)，而对ACE酶活性的抑制能够有效地降低血压。事实上ACE抑制剂已经广泛用于高血压的治疗之中，如卡托普利、赖诺普利、依那普利和福辛普利。然而这些化学合成的药物普遍具有咳嗽、皮疹和血管性水肿等副作用。从食物中提取的活性肽不仅没有副作用，还有易于吸收的特点。
近年来，相关研究表明各种食物及食品工业生产副产物中分离得到的天然的ACE抑制肽，可开发为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。传统ACE抑制活性肽的研究主要通过从食物原料中酶解后经过分离纯化、结构鉴定并与相应的化学合成肽进行活性对比，整个过程步骤繁杂，耗时耗力。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逐渐发展，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。利用计算机模拟蛋白酶解，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。
本发明主要利用分子模拟及活性预测对大西洋鳟鱼胶原蛋白中潜在的ACE抑制肽进行筛选，并通过分子对接对阐明高活性ACE抑制肽的作用位点，确定其半抑制浓度。
发明内容
本发明主要内容包括：
(1)通过利用在线活性肽数据库得到所选蛋白的序列信息，从NCBI上提取所选大西洋鳟鱼VII型胶原蛋白α-1链的X5亚型(Accession XP-013988307.1)序列信息。
(2)使用在线酶水解模拟软件ExPASy PeptideCutter(http://web.expasy.org/peptide_cutter/)对胶原蛋白进行虚拟水解。选出所有四肽并利用PeptideRanker(http://bioware.ucd.ie/～compass/biowareweb/Server_pages/Peptideranker.php)进行活性肽的生物活性评分，选出较高评分的活性肽分别进行ACE抑制活性测定、水溶性测定、毒性测定。所用工具依次为BIOPEP(http://www.uwm.edu.pl/biochemia/index.php/pl/biopep)、Innovagen(http://www.innovagen.com/proteomics-tools)和ToxinPred(http://crdd.osdd.net/raghava//toxinpred/)。以上选出的肽再经SwissDock(http://www.swissdock.ch/docking)进行最后的筛选。
(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。
(4)应用Discovery Studio 2017 R2软件，将具有高体外活性的ACE抑制肽在与ACE(1O86)进行对接，通过计算-CDOCKER ENERGY、-CDOCKER INTERACTION ENERGY的数值确定其结合程度，并确定了本发明中的活性肽与ACE(1O86)的结合位点。
(5)采用化学合成法合成高活性的ACE抑制肽，并利用(3)中的高效液相色谱法测定ACE抑制肽的活性。
本发明的积极有益效果：
①本发明是对传统复杂的ACE抑制肽筛选方法的革新，采用了一种新型、有效、准确的方法替代了传统方法中的复杂步骤，提高了ACE抑制活性肽筛选的工作效率。
②发现了两种新的能够有效抑制ACE活性的大西洋鳟鱼胶原蛋白生物活性肽，他们具有预防高血压的潜在价值。
附图说明
本发明附图2幅，其中：
图1 IGPR与ACE(PDB：1O86)分子对接图谱；
图2 PGAR与ACE(PDB：1O86)分子对接图谱。
具体实施方式
以下具体实施方式为本发明作进一步的阐述。
实施例1 原料的选择
从NCBI数据库中搜寻大西洋鳟鱼相关蛋白质序列进行分析，选定依据为大西洋鳟鱼生产中的重要组分及其序列分析的可行性。最终选定大西洋鳟鱼VII型胶原蛋白α-1链的X5亚型(Accession XP-013988307.1)。
实施例2 所选蛋白的酶解及活性四肽的筛选
使用胃蛋白酶(pH1.3)和胰蛋白酶通过ExPASy PeptideCutter对胶原蛋白进行虚拟水解，选出所有54条四肽序列，见表1。使用在线工具BIOPEP、PeptideRanker、Innovagen和ToxinPred分别对四肽进行ACE抑制活性预测、肽生物活性评分、水溶性测定和毒性测定，进而筛选出11个具有ACE抑制活性、生物活性评分高、水溶性好并且无毒性的四肽序列。为进一步筛选高效抑制活性肽，11个肽序列在SwissDock中与ACE(1A1B)进行分子模拟对接，结合最稳定的5个活性肽作为潜在活性肽进行化学合成。
表1.筛选的四肽信息
表1中，AHT代表有ACE抑制活性，Non-AHT代表无ACE抑制活性。
表2 11个活性肽与ACE(1A1B)的对接结果
实施例3 活性肽的体外活性的测定
采用高效液相色谱法对五种活性肽的ACE抑制活性进行测定。采用高效液相色谱法测定IGPR和PGAR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/LHCl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。
IGPR和PGAR的IC50测定分别为0.598mM和0.43mM。
实施例4活性肽与ACE分子对接
体外活性最高的两个肽用DS进行分子模拟对接，对其与ACE(1O86)结合形式进行分析得到附图1、2。他们与高血压合成药Lisinopril的-CDOCKER ENERGY、-CDOCKERINTERACTION ENERGY都进行了测量和对比，如表3。
表3 活性肽PGAR和IGPR与ACE(1O86)对接结果
通过分子对接分析，活性肽IGPR与ACE(1O86)相互作用位点所涉及的氨基酸残基分别为GLU162、GLU376、HIS353、ASP377、ALA354、GLN281、LYS511、HIS513、HIS387、TYR523、ZN701、VAL518、GLU384、HIS383。活性肽PGAR与ACE(1O86)相互作用位点所涉及的氨基酸残基分别为ALA356、GLU384、GLA411、HIS387、GLU376、HIS353、TYR523、TYR520、LYS511、ASP453、GLU376。
Claims (1)
1.一种ACE抑制肽，其特征在于，其氨基酸序列为IGPR。
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| CN113880942A (zh) * | 2021-09-30 | 2022-01-04 | 吴伟 | 一种具有抗氧化活性的鸡骨胶原蛋白肽及其应用 |
| CN116589562B (zh) * | 2023-07-11 | 2023-09-05 | 烟台赛春生物科技有限公司 | 一种鱼胶原蛋白肽及其应用 |
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