CN113943346A - 螺旋藻降压肽及应用 - Google Patents
螺旋藻降压肽及应用 Download PDFInfo
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- CN113943346A CN113943346A CN202111200168.3A CN202111200168A CN113943346A CN 113943346 A CN113943346 A CN 113943346A CN 202111200168 A CN202111200168 A CN 202111200168A CN 113943346 A CN113943346 A CN 113943346A
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- Peptides Or Proteins (AREA)
Abstract
本发明属于生物技术领域,涉及螺旋藻降压活性肽的制备方法及其在功能性食品、保健品或药物中的应用。本发明以螺旋藻为原料,使用蛋白酶K对螺旋藻蛋白进行酶解,酶解后的多肽经凝胶层析和反相色谱分离获得序列为TVFNHEGR和LQAGGLF的螺旋藻低聚肽。实验表明,分离得到的多肽具有显著的血管紧张素转化酶(ACE)抑制活性,IC50分别为198μM和60.01μM。本发明提供了一种制备螺旋藻降压肽的方法,并成功鉴定到两个降压活性较好且序列新颖的的螺旋藻低聚肽,为充分利用螺旋藻蛋白资源提供了参考,具有良好的开发利用前景。
Description
技术领域
本发明属于生物活性肽技术领域,涉及螺旋藻多肽在研发血管紧张素转化酶(ACE)抑制剂,或高血压治疗相关的食品、药品或保健品中的应用。
背景技术
生物活性肽(Bioactive peptides),是由2-20个氨基酸单位组成的具有一定生物活性的肽段。从大豆、谷蛋白、酪蛋白、水产品蛋白中都已分离得到了具有抗肿瘤、抗菌、抗炎、降糖、抗病毒及降血压等活性的多肽。截至2021年9月,BIOPEP数据库收录的具有各种生物活性的多肽多达4300余个,其中具有ACE抑制活性的多肽有1046个,数量最多。与大分子的蛋白相比,生物活性肽具有分子量小,易于吸收,抗原性低等特点,基于此,生物活性肽被广泛应用于食品、保健品、化妆品和药物等领域。
高血压是指在未使用降压药的情况下收缩压(SBP)>140mmHg和(或)舒张压(DBP)>90mmHg,并根据血压升高水平将高血压分为1级,2级,3级。作为一种慢性多发疾病对广大患者的身体健康和日常生活造成困扰,研究证明血压水平和心血管疾病风险呈现直接关系。此外,长期高血压还会对心脏、大血管、肾脏、眼、脑等靶脏器造成损伤。我国成年人高血压患病率为23.2%且仍然呈现上升趋势,因此有效的高血压治疗药物及保健食品十分具有研究价值。
在血压调节过程中,肾素-血管紧张素***(Renin-Angiotensin System,RAS)和激肽-缓激肽***(Kinin-Bradykinin System,KKS)发挥着至关重要的作用。在RAS***中,血管紧张素原经肾素水解产生血管紧张素I,进一步地,通过血管紧张素转化酶(ACE)催化水解后,产生血管紧张素II,血管紧张素II作用于相应受体后引起血管收缩进而引起血压上升。此外,ACE也可以催化缓激肽的降解并通过一系列级联反应降低NO和***素的分泌,进而减轻一氧化氮和***素引起的血压升高的效应。综上,ACE在血压调节过程中起着至关重要的作用,对其活性的调控对于血压的控制至关重要。因而ACE抑制剂的开发工作在高血压防治过程中举足轻重。
目前已有的血压调节药物有利尿剂类、普利类、地坪类和沙坦类。这些抗高血压药物在调节血压的同时会降低患者机体对药物的依从性从而增加治疗成本和血压控制难度。因此有必要寻找更加多样的ACE抑制剂。过去数十年间,从牛奶、大豆、鱼类蛋白的酶解物中都分离得到了具有降血压、降血糖、抗菌、免疫调节等活性的天然多肽。这些天然来源的ACE抑制肽在有效对ACE的活性产生调节的作用的同时,具有相较化学合成类药物更高的安全性,目前虽然有一部分来源于螺旋藻的ACE抑制肽的报道,但是活性更好,安全性更高的多肽还有待发现。
螺旋藻作为一种营养丰富的藻类具有十分悠久的利用历史,螺旋藻营养丰富,富含蛋白质、维生素、人体必需微量元素等多种营养物质。研究表明螺旋藻具有抗疲劳、降血压、抗菌、抗病毒、抗氧化等作用。螺旋藻蛋白经过酶解有可能释放出活性更好、更容易吸收的小分子活性肽。目前已有一些关于螺旋藻活性肽的专利,这些专利多为活性肽的制备方法,如公布号为CN111154824A、CN107502641A、CN107674905A、CN103981245A、CN107446977A、CN101906135A、CN10126546、CN112646856A等的专利。这些专利报道的多肽的活性集中在抗氧化、抗菌、抗疲劳等方面,除鲁军在公告号为CN101906135A的专利报道了序列为IQP的螺旋藻降压肽之外,便再无序列清晰的螺旋藻降压肽。因此,螺旋藻降压肽依然有待进一步开发研究。
降压肽方面,已经公布的具有确切序列信息的专利和多肽序列如表1所示,而本专利所要求的两个多肽与这些多肽均不相同。
表1为已公开的有关降压肽的专利及多肽序列。
发明内容
本发明的目的是提供一种螺旋藻降压肽及其在食品、药品或保健品中的应用。
为实现上述目的,本发明采用的技术方案为:
所述降压肽以螺旋藻Spirulina platensis或者Spirulina maxima为原料经过酶解和进一步的分离得,所述螺旋藻多肽具有序列表SEQ ID NO.1中所述的氨基酸序列;具体序列为Thr-Val-Phe-Asn-His-Glu-Gly-Arg(简写为TVFNHEGR)。
所述螺旋藻多肽的为序列表SEQ ID NO.2中氨基酸序列;具体序列为Leu-Gln-Ala-Gly-Gly-Leu-Phe((简写为LQAGGLF)。
其中其序列为Thr-Val-Phe-Asn-His-Glu-Gly-Arg(TVFNHEGR)、Leu-Gln-Ala-Gly-Gly-Leu-Phe(LQAGGLF)的分子量分别为959.03Da,704.82Da。通过酶解、分离的方法或者化学合成方法得到的该多肽可以应用在制备降压药物、或药物组合物、或保健品中。
所述螺旋藻降压肽在以马尿酰-组氨酸-亮氨酸为底物的体外实验条件下能显著抑制血管紧张素转化酶(ACE),半数抑制率(IC50)为190.3μM和60.01μM。
所述螺旋藻降压肽的制备方法包括:螺旋藻干粉和水的料液(g:mL)比为1:10~1:20,混悬液-20℃冷冻后20-50℃解冻后以200-800w的功率使用超声细胞破碎仪处理料液,循环(冻融和超声破碎细胞)三次后离心取上清以1%-10%的酶底比加入蛋白酶K,酶解条件为:pH 8-12,25-65℃酶解1-12h后95℃加热15min灭酶。使用Sephadex G-15凝胶柱,以去离子水作为流动相,流速为1mL/min,使用自动馏分收集器收集洗脱峰,冷冻干燥即得螺旋藻降压肽。
以所述螺旋藻多肽为活性成分,与符合药物或食品生产要求的辅料混合后,按照常规制剂制备方法得到的药物、保健品或食品可以实现对高血压的治疗、缓解或预防作用。
所述的螺旋藻多肽的为序列表SEQ ID NO.1或SEQ ID NO.2中的一种或两种螺旋藻降压肽或螺旋藻降压肽提取物配以任何符合食品或药品生产允许的载体或辅料制成。
本发明所具有的优点:
本发明获得的多肽具有优良的体外ACE抑制活性,且在细胞水平实验中无明显细胞毒性。该多肽为六肽,分子量分别为959.03Da和704.82Da,分子量小易于吸收。所述多肽在具有血压调节活性的食品、保健品及药物等领域具有良好的应用前景。
附图说明
图1TVFNHEGR、LQAGGLF质谱图。
图2TVFNHEGR、LQAGGLF纯度鉴定液相色谱图。
图3不同浓度TVFNHEGR、LQAGGLF的ACE抑制率。
图4LQAGGLF双倒数曲线。
表1已公开的有关降压肽的专利及多肽序列。
具体实施方式
下面结合附图和实施例对本发明做进一步的解释说明。本发明的目的是以螺旋藻为原料,经过蛋白酶解,分离并筛选出具有明确序列的,应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解,在阅读了本发明的内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本发明所限定的范围。
实施例1
高效液相色谱法(HPLC)测定多肽的体外ACE抑制活性
实验方法:
本方法的原理为:马尿酰-组胺酰-亮氨酸(Hip-His-Leu,HHL,Sigma-Aldrich)可以作为血管紧张素转化酶(ACE)的底物被分解产生马尿酸,加入不同的ACE抑制剂后,马尿酸的生成量产生相应的下降,通过计算228nm下马尿酸的峰面积,即可评价抑制剂对ACE活性的抑制活性。
实验试剂:
ACE(0.1U/mL)、马尿酰-组氨酸-亮氨酸(HHL)、卡托普利、0.1M硼酸钠溶液(pH8.3,含0.3M氯化钠)
将ACE溶于硼酸钠缓冲液至终浓度0.1U/mL用于测定。将多肽样品溶解在硼酸钠缓冲液中配置成不同浓度的多肽溶液。然后,将20μL一定浓度的多肽溶液与10μL的ACE溶液混合。将混合物在37℃下孵育5min,将50μL的摩尔浓度为5mM的HHL(硼酸钠缓冲液pH8.3,含有0.3M氯化钠)加入上述混合物中开始反应。将反应在37℃保持60min,然后加入150μL的摩尔浓度为1M的HCl以终止反应。溶液透过0.22μm的滤膜得到反应溶液。取20μL反应溶液加载到RP-HPLC中,该HPLC连接Eclipse XDB-C18柱(4.6mm×150mm×5μm),紫外检测马尿酸(HA)的浓度。马尿酸在228nm处检测吸光度。所有检测吸光度测定均重复三次。ACE抑制活性计算如下:
ACE抑制活性(%)=(AControl-AInhibitor)/AControl*100)
其中AInhibitor是ACE和HHL与抑制剂反应得到的马尿酸(HA)峰的相对面积。AControl是无抑制剂的ACE和HHL的反应获得的马尿酸(HA)峰的相对面积。IC50定义为可以抑制一半ACE活性的多肽浓度。
色谱条件:
C18柱(4.6mm x 150mm x 5μm,Agilent),检测波长:228nm;流动相:78%超纯水(含有0.05%TFA)+22%乙腈(含有0.05%TFA);流速:0.8mL/min。
实施例2
(一)螺旋藻降压肽的制备
称取15g螺旋藻干粉以分散于240mL去离子水中,-20℃冷冻4h,37℃解冻后以超声细胞破碎仪破碎螺旋藻混悬液,超声细胞破碎仪参数设置为工作15s,间隔15s,功率550W超声60min。超声时容器置于冰上控制温度在0-4℃,防止液体因超声升温。冻融-超声循环3次后10000RCF,4℃下离心10min取上清。
测蛋白浓度并通过添加去离子水调整蛋白浓度到10mg/mL,加入浓度为0.1M的NaOH溶液调整pH到10后,按照蛋白质量含量的4.5%加入蛋白酶K于57℃反应4h后95℃加热15min灭酶,12000g离心10min取上清冻干得螺旋藻降压肽粗提物。经测定,螺旋藻降压肽在浓度为400μg/mL时ACE抑制率为76.44%。
(二)螺旋藻降压肽的凝胶层析分离纯化及活性评价
螺旋藻降压肽粗提物以凝胶层析柱(Sephadex G15,1.6×100cm)进行分离纯化,以去离子水作为流动相,流速控制在1mL/min,收集并冻干洗脱时间为80-86min,87-112min,113-138min,139-162min的四个组分,分别命名为SK-G1,SK-G2,SK-G3,SK-G4。
依据实施例1中ACE抑制活性计算方法计算,对4个组分ACE抑制活性进行评估,SK-G4在400μg/mL的浓度下ACE抑制率为86.85%。
(三)螺旋藻降压肽的反向色谱分离纯化及活性评价
SK-G4以安捷伦Zorbax SB-Aq C18柱(4.6×250mm,5μm)对Sephadex G-15分离得到的SK-G4进行分离,洗脱程序为:
1-5min:5%乙腈(v%);5-55min:5%-95%乙腈(v%);55-60min:95%乙腈(v%);流速为0.8mL/min。按下表对应出峰时间收集到12个组分。
表2洗脱时间组分对照表
SK-G4R1 | SK-G4R2 | SK-G4R3 | SK-G4R4 | SK-G4R5 | SK-G4R6 |
4-5min | 6-7min | 8-9min | 10-11min | 12-15min | 16-17min |
SK-G4R7 | SK-G4R8 | SK-G4R9 | SK-G4R10 | SK-G4R11 | SK-G4R12 |
17-18min | 19-20min | 21-22min | 23-25min | 32-33min | 59-60min |
依据实施例1中方法对12个组分ACE抑制活性进行评价,SK-G4R2,SK-G4R3,SK-G4R5三个组分具有比较好的ACE抑制活性。
(四)螺旋藻降压肽序列鉴定
样品溶于适量ddH2O并加入DTT使其终浓度为10mmol/L,56℃水浴1h后加入IAA溶液使其终浓度为50mmol/L,避光反应40min后脱盐,真空挥干溶剂后以0.1%甲酸溶液重新溶解以用于LC-MS/MS分析。
Nano LC-MS/MS:色谱柱填料为ReproSil-Pur C18-AQ(1.9μm,)规格为150μm×150mm。流动相A、B分别为含有0.1%甲酸的水和乙腈,上样5μL后以600nL/min的流速进行梯度洗脱。梯度程序如下表:
表3洗脱梯度表
时间(min) | B相 |
0 | 4% |
2 | 8% |
45 | 28% |
55 | 40% |
56 | 95% |
66 | 95% |
使用Q Exactive Hybrid Quadrupole-Orbitrap-MS/MS(Thermo FisherScirntific,USA)得到的二级质谱数据于Byonic软件自带数据库中比对得到包括序列为TVFNHEGR和LQAGGLF的多肽在内的多个多肽序列。
实施例3
螺旋藻降压肽的虚拟筛选
依据丰度对得到的多肽序列进行第一轮筛选。使用ChemDraw绘制每个多肽的二位和三维结构。多肽结构经过在pH7.0下的质子化和能量最小化后保存与人tACE晶体结构(PDB ID:1O8A)使用Pyrx进行分子对接,对接时以活性中心锌离子为对接盒中心,对接球半径为对接结果显示各多肽与ACE的亲和力,其中TVFNHEGR、LQAGGLF的对接分数为-9.0,亲和力较强。采用如实施例1所述方法测得TVFNHEGR、LQAGGLF在浓度为400μg/mL时,对ACE分别具有68.4%和64.09%的抑制率。
实施例4
TVFNHEGR、LQAGGLF的质谱鉴定
0.1mg样品溶于0.5mL超纯水,样品通过C18柱后以Q-Exactive质谱仪对样品进行分析,上样量为1μL,载气流速为1.5L/min,液相流动相为50%H2O+50%MeOH。
如图1,质谱鉴定两个多肽TVFNHEGR、LQAGGLF的分子量分别依次为959.03Da和704.82Da。
实施例5
TVFNHEGR、LQAGGLF的纯度鉴定
称取0.5mg样品以0.5mL超纯水溶解后以配有NanoChrom Chromcore TM120 C18(4.6×250MM×5μM)色谱柱的高效液相色谱***对样品进行分析。上样量为40μL,流动相分别为含有0.1%三氟乙酸的乙腈和超纯水。流速为1.0mL/min,在214nm下检测出峰情况,色谱图见图2。
以归一化方法对多肽色谱峰进行分析,TVFNHEGR和LQAGGLF多肽的纯度均≥95%。
实施例6
TVFNHEGR、LQAGGLF的IC50测定
在100,50,10,1,0.1,0.01,0.001μg/mL的浓度下按照实施例2所述方法测定TVFNHEGR、LQAGGLF的ACE抑制率,实验设置三个平行,取平均值以浓度的对数对抑制率作图(图3)计算多肽的IC50值。
经测定,螺旋藻降压肽TVFNHEGR、LQAGGLF的IC50值分别为190.3μM和60.01μM。
实施例7
LQAGGLF的抑制模式以硼酸缓冲液配制浓度为4,2,1,0.5,0.25,0.1mM的HHL溶液及浓度为0.5mg/mL和0.1mg/mL的多肽溶液,分别取不同浓度的多肽与不同浓度的HHL溶液进行如实施例2所述的活性评价。以马尿酸生成速度的倒数对底物浓度的倒数作图,双倒数法分析多肽对ACE的抑制模式。
如图4所示,随着多肽浓度的增大,双倒数曲线的斜率变大而纵截距不变,即Vmax不变Km变大,其曲线相交于纵轴,因此认为该多肽的抑制模式为竞争性抑制,这也与虚拟筛选中LQAGGLF与ACE活性中心的作用结果相符。
序列表
<110> 中国科学院海洋研究所
<120> 螺旋藻降压肽及应用
<160> 2
<170> SIPOSequenceListing 1.0
<210> 1
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Thr Val Phe Asn His Glu Gly Arg
1 5
<210> 2
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Leu Gln Ala Gly Gly Leu Phe
1 5
Claims (5)
1.一种螺旋藻降压肽,其特征在于:所述螺旋藻多肽具有序列表SEQ ID NO.1中所述的氨基酸序列;具体序列为Thr-Val-Phe-Asn-His-Glu-Gly-Arg(简写为TVFNHEGR)。
2.一种螺旋藻降压肽,其特征在于:所述螺旋藻多肽的为序列表SEQ ID NO.2中氨基酸序列;具体序列为Leu-Gln-Ala-Gly-Gly-Leu-Phe((简写为LQAGGLF)。
3.一种权利要求1或2所述的螺旋藻降压肽的应用,其特征在于:权利要求1或权利要求2所述螺旋藻降压肽中的一种或两种作为活性成分(它们对血管紧张素转化酶(ACE)有抑制作用)在制备血管紧张素转化酶(ACE)抑制剂或高血压疾病的预防、高血压疾病的缓解或高血压疾病的治疗相关的食品、保健品或药物制剂中的应用。
4.一种血管紧张素转化酶抑制剂或高血压疾病的治疗、高血压疾病的缓解或高血压疾病的预防的制剂,其特征在于:以权利要求1或权利要求2所述的螺旋藻降压肽中的一种或两种为活性成份。
5.按照权利要求4所述的制剂,其特征在于:以权利1和权利2所述的一种或两种螺旋藻降压肽或螺旋藻降压肽提取物配以任何符合食品或药品生产允许的载体或辅料制成。
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