CN109206483A - 一种贻贝来源的ace抑制及抗肿瘤活性肽 - Google Patents
一种贻贝来源的ace抑制及抗肿瘤活性肽 Download PDFInfo
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Abstract
本发明属于海洋生物小分子活性肽领域,具体涉及一种贻贝来源的小分子ACE抑制及抗肿瘤活性肽,其氨基酸序列为Arg‑Tyr‑Pro‑Asp‑Pro‑Leu。本发明先采用高效液相色谱‑串联质谱进行紫贻贝酶解低聚肽产品进行分析鉴定及高效率的活性筛选,获得具有潜在降压及抗肝癌活性的小分子肽,通过SephadexLH‑20葡聚糖凝胶柱色谱及高效液相色谱分离纯化获得。该新型的小分子活性肽具有很强的ACE抑制活性及抗肝癌活性,属于食源性活性肽,可用于心脑血管疾病及肝癌相关疾病的治疗,尤其是高血压疾病的保健及治疗,可用于食品、保健品及生物医药制品的开发,具有广阔的应用前景。
Description
技术领域
本发明属于海洋生物小分子活性肽领域,具体涉及一种贻贝来源的小分子ACE抑制及抗肿瘤活性肽。
背景技术
血管紧张素转化酶(ACE)可以将血管紧张素Ⅰ水解成血管紧张素Ⅱ,促使血管进一步收缩,导致血压升高,ACE 也可通过作用于肾上腺皮质而促进醛固酮的分泌,ACE 还可以催化具有降压作用的缓激肽水解而使其失去活性。因此,抑制体内ACE 活性就可以达到降低或者控制血压的目的。血管紧张素转化酶抑制剂是临床上常用的抗高血压药物,如卡托普利、阿拉普利(Alacepril)、赖诺普利等,但是此类化学合成药物在临床应用中出现较多副作用,因此食源性的ACE抑制肽就由于其生理活性高和毒副作用小等优势而成为研究的热点。
贻贝,学名Mytilus edulis,也叫青口,鲜活贻贝是大众化的海鲜品,味道鲜美,营养价值高,贻贝肉除含有蛋白质及多糖外,还含有多种维生素及人体必需的锰、锌、硒、碘等多种微量元素,素有“海中鸡蛋”之称,其蛋白质含有人体需要的缬氨酸、亮氨酸等8 种必需氨基酸,且含量远高于鸡蛋、鸡、鸭、鱼、虾和肉类。除食用外,贻贝还有很高的药用价值,中医学认为贻贝具有滋阴补血, 益精补肾、养血调精等作用,现代研究表明贻贝提取物具有抗肿瘤、抗病毒和增强机体免疫力、降血脂等功效,具有极大的开发利用价值。
干制贻贝肉蛋白质含量高达59.3%,目前已有众多专利对贻贝酶解蛋白生产低聚肽的制备工艺进行了研究,其中一些专利报道了单体活性肽,如201510771143.7 报道的抗氧化肽,201710903341.3和201710677507 .4报道的调脂肽,专利201510177322.8、201710813434.7中报道的降压肽等,相当对紫贻贝中含有的大量肽段来说,分离获得的活性肽仍是少数。
发明内容
本发明针对上述存在问题、现状及发展前景,提供一种贻贝来源的ACE抑制及抗肿瘤活性肽,该活性肽具有ACE抑制活性及抗肝癌活性,分子量小,活性高、易于分离纯化,制备工艺简单,可用于高血压及肝癌等相关疾病的保健及治疗,在食品、保健品及医药生物领域有广阔的应用前景。
本发明为实现上述目的所采取的技术方案为:一种贻贝来源的ACE抑制及抗肿瘤活性肽,其特征在于,所述活性肽其氨基酸序列为Arg-Tyr-Pro-Asp-Pro-Leu。
以所述活性肽序列为核心,任何对其进行的相应的调整或修饰。
所述对其进行相应的调整或修饰后的应用包括对活性肽进行进一步的降压药物设计:
第四位的氨基酸Asp可被其他任一氨基酸所替代,替代后的小分子肽均具有潜在的降压作用。
所述活性肽具有ACE抑制活性及抗肝癌细胞增殖的活性,可应用于制备具有调节血压及抗肝癌作用的功能性食品、保健品及药物方面。
所述活性肽的分离纯化方法,包括以下步骤:
S1、贻贝酶解低聚肽的制备
贻贝样品处理后,加入15~20倍质量体积的水制成匀浆液置于酶解罐中,然后加入贻贝质量的2~5%的复合蛋白酶,在40~50℃下酶解4小时,酶反应pH 值控制在8.0~9.0,酶解结束后升温至80~90℃灭酶10分钟,得到贻贝蛋白酶解液,将蛋白酶解液8000转/分钟离心10分钟,去除颗粒状物质,然后采用膜分离技术进行分离,截留分子量为3000 Da,过膜液喷雾干燥得贻贝小分子肽粉;
S2、小分子活性肽的分离纯化
将S1中的小分子活性肽粗品加水溶解,配制成浓度为100 mg/mL的溶液,采用葡聚糖凝胶Sephadex LH-20柱色谱分进行分离纯化,流动相为30%甲醇,流速为0.3 ~0.5 mL/min,洗脱液280 nm或220 nm测定吸光度,根据吸光度值收集所需峰;
采用高效液相色谱进一步纯化,色谱条件如下:C18色谱柱,流动相A为含体积百分数0.05~0.1%三氟乙酸水,流动相B为乙腈,梯度洗脱条件为:0~15 min,3%B,15~20 min,3%~10%B,20~30 min,10%B~20%B,30~40 min,20%B~35%B,流速为1.0 mL/min,检测波长为220或280 nm,收集保留时间在30分钟的色谱峰,浓缩后冷冻干燥得小分子活性肽;
S3、纯度及氨基酸序列测定
收集的小分子肽经液相色谱检测为单一峰,利用高效液相色谱-质谱测定结构,其氨基酸序列为:Arg-Tyr-Pro-Asp-Pro-Leu,其分子量为760.39 Da。
所述步骤S1中的复合蛋白酶的质量配比为:中性蛋白酶:木瓜蛋白酶:风味蛋白酶=(2~4):(3~5):(3~5)。
所述步骤S3中的葡聚糖凝胶Sephadex LH-20柱内径为3.0 cm,柱长100 cm。
所述C18色谱柱内径为4.6 mm,柱长250 mm,粒度5µm。
本发明的有益效果:
(1)本发明在前期对贻贝低聚肽中肽段分析鉴定和活性筛选的基础,对高活性肽段利用Sephadex LH-20凝胶柱色谱及高效液相色谱等手段进行分离纯化,验证其活性,最终获得一个高活性ACE抑制及抗肿瘤活性肽,经质谱鉴定氨基酸序列为:Arg-Tyr-Pro-Asp-Pro-Leu,经在线数据库BIOPEP及EROP-Moscow检索,所述序列为新的小分子活性肽。
(2)该活性肽的分子量小,活性高,分离纯化步骤简单,易于获得,属于食源性的A活性肽,长期食用达到预防、控制、缓解和辅助治疗高血压的目的,可用于开发治疗高血压的相关保健品或者药物,该小分子肽抗肝癌活性,可应用于肝癌相关疾病的保健、治疗及相关产品的开发,在食品、保健品及医药领域等有广阔的应用前景。
(3)在此基础上,对该活性肽进行计算机辅助药物设计,发现其他众多具有潜在活性的降压肽,后续可进行活性验证及相关产品研究开发。
附图说明
图1 为本发明小分子活性肽的ACE抑制活性图。
图2 为本发明小分子活性肽对人肝癌细胞增值的抑制活性图。
具体实施方式
下面结合附图与实施例对本发明进一步说明,但本发明不局限于具体实施例。
实施例1
一种贻贝来源的ACE抑制及抗肿瘤活性肽,所述活性肽其氨基酸序列为Arg-Tyr-Pro-Asp-Pro-Leu。
以所述活性肽序列为核心,任何对其进行的相应的调整或修饰。
所述对其进行相应的调整或修饰后的应用包括对活性肽进行进一步的降压药物设计:
第四位的氨基酸Asp可被其他任一氨基酸所替代,替代后的小分子肽均具有潜在的降压作用。
所述活性肽具有ACE抑制活性及抗肝癌细胞增殖的活性,可应用于制备具有调节血压及抗肝癌作用的功能性食品、保健品及药物方面。
实施例2
实施例1中所述贻贝来源的ACE抑制及抗肿瘤活性肽的分离纯化方法,包括以下步骤:
S1、贻贝酶解小分子肽粉的制备:
紫贻贝干500 g加入适量水浸泡,浸泡后清洗脱盐分, 将脱盐后的贻贝干加水匀浆制成匀浆液置于酶解罐中,紫贻贝干与水的质量体积比为1:15,加入15g的复合蛋白酶制剂,该蛋白酶配比为:中性蛋白酶:木瓜蛋白酶:风味蛋白酶=2:3:3,在40℃下酶解4小时,酶反应pH 值控制在8.5,酶解结束后升温至80℃灭酶10分钟,得到紫贻贝蛋白酶解液,将蛋白酶解液8000转/分钟离心10分钟,去除颗粒状物质,然后采用膜分离技术进行分离,截留分子量为3000 Da,过膜液喷雾干燥得紫贻贝小分子肽粉。
S2、小分子活性肽的分离纯化:
将S1中的紫贻贝小分子活性肽粗品加水溶解,配制成100 mg/mL,采用葡聚糖凝胶Sephadex LH-20柱色谱(3.0×100 cm)分进行分离纯化,流动相为30%甲醇,流速为0.3 mL/min,洗脱液280 nm测定吸光度,根据吸光度值收集所需峰。
采用高效液相色谱进一步纯化,色谱条件如下:依利特C18色谱柱(4.6 mm× 250mm,5µm),流动相A为0.1%三氟乙酸水(v/v),流动相B为乙腈,梯度洗脱条件为:0~15 min,3%B,15~20 min,3%~10%B,20~30 min,10%B~20%B,30~40 min,20%B~35%B,流速为1.0mL/min,检测波长为280 nm,收集保留时间在30分钟的色谱峰,浓缩后冷冻干燥得小分子活性肽。
S3、纯度及结构测定:收集的小分子肽经液相色谱检测为单一峰,利用高效液相色谱-质谱测定结构,其氨基酸序列为:Arg-Tyr-Pro-Asp-Pro-Leu,其分子量为760.39 Da。
ACE抑制活性测定:
预先把冷冻干燥后的小分子活性肽用蒸馏水配制成浓度为5 mg/mL的溶液,依次稀释成浓度为 2mg/mL、1mg/mL、0.5 mg/mL、0.2 mg/mL溶液。水浴锅温度调至37 ℃,在0.5 mLEP管中加入5μL小分子活性肽溶液和15μL ACE(60 mU/mL),同时用超纯水做空白,保温5min后,加入25μL HHL(7.6 mmol/L),反应25 min,最后加10μL 10%三氟乙酸水溶液(v/v)用来终止反应,反应液用高效液相色谱进行检测,
色谱检测条件如下:
色谱柱:大连依利特Hypersil BDS C18色谱柱,检测波长为228 nm,进样量30 μL,流速1 mL /min;流动相为30 %甲醇(含 0.1%三氟乙酸TFA 和0.05%冰醋酸,pH为 3-3.3) ,柱温:25 ℃。
ACE活性的抑制率计算公式是:
ACE抑制率/% =(空白峰面积-样品峰面积)/空白峰面积×100
实验结果见图1,通过计算得到该小分子活性肽的IC50为0.39 mg/mL,表明具有较强的ACE抑制活性。
抗肿瘤活性测定:
采用人肝癌细胞Bel-7402 细胞株中进行MTT 实验,筛选活性肽的抗癌效果。
具体实验过程如下:取对数生长期Bel-7402细胞,以每孔1000-10000个接种于 96孔培养板中, 每孔100μL,在 37℃、5% CO2条件下继续培养,至细胞单层铺满96孔平底板,然后加入不同浓度的小分子肽作用于细胞,每孔100μL,每个浓度设5个复孔,对照组不加药物,5% CO2,37℃孵育24-48 小时,每孔加入20μL浓度为5mg/mL的 MTT 溶液,继续培养4h,4h后终止培养,小心吸去上清液,每孔加入150μL二甲基亚砜,置摇床上低速振荡10 min,使结晶物充分溶解。在酶联免疫检测仪在570 nm 处测量各孔的吸光度值,计算不同浓度小分子肽对细胞的生长抑制率。
细胞抑制率=(对照组A570-实验组A570)/对照组A570×100%
实验结果见图2,结果表明,该小分子活性肽具有明显的抑制人肝癌细胞增殖的作用,IC50为0.26mg/mL。
实施例3
本实施例中所述的贻贝来源的ACE抑制及抗肿瘤活性肽的分离纯化方法的各步骤均与实施例2中相同,不同点为:
(1)步骤S1中,贻贝干样品处理后,加入17.5倍质量体积的水制成匀浆液置于酶解罐中,然后加入贻贝质量的2%的复合蛋白酶,复合蛋白酶的质量配比为:中性蛋白酶:木瓜蛋白酶:风味蛋白酶=3:4:4,在45℃下酶解4小时,酶反应pH 值控制在8.0,酶解结束后升温至85℃灭酶10分钟,得到贻贝蛋白酶解液;
(2)步骤S2中流动相为30%甲醇,流速为0.4 mL/min;
(3)步骤S2中流动相A为含体积百分数0.75%三氟乙酸水;
(4)步骤S2中检测波长为220 nm。
实施例4
本实施例中所述的贻贝来源的ACE抑制及抗肿瘤活性肽的分离纯化方法的各步骤均与实施例2中相同,不同点为:
(1)步骤S1中,贻贝干样品处理后,加入20倍质量体积的水制成匀浆液置于酶解罐中,然后加入贻贝质量的5%的复合蛋白酶,复合蛋白酶的质量配比为:中性蛋白酶:木瓜蛋白酶:风味蛋白酶=4:5:5,在50℃下酶解4小时,酶反应pH 值控制在9.0,酶解结束后升温至90℃灭酶10分钟,得到贻贝蛋白酶解液;
(2)步骤S2中流动相为30%甲醇,流速为0.5mL/min;
(3)步骤S2中流动相A为含体积百分数0.05%三氟乙酸水。
以上所述,仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明披露的技术范围内,根据本发明的技术方案及其发明构思加以等同替换或改变,都应涵盖在本发明的保护范围之内。
序 列 表
SEQUENCE LISTING
<110> 大连深蓝肽科技研发有限公司
<120> 一种贻贝来源的ACE抑制及抗肿瘤活性肽
<130> 0005S
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 6
<212> PRT
<213> Mytilus Edulis
<400> 1
Arg Tyr Pro Asp Pro Leu
1 5
SEQUENCE LISTING
<110> 大连深蓝肽科技研发有限公司
<120> 一种贻贝来源的ACE抑制及抗肿瘤活性肽
<130> 0005S
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 6
<212> PRT
<213> Mytilus Edulis
<400> 1
Arg Tyr Pro Asp Pro Leu
1 5
Claims (8)
1.一种贻贝来源的ACE抑制及抗肿瘤活性肽,其特征在于,所述活性肽其氨基酸序列为Arg-Tyr-Pro-Asp-Pro-Leu。
2.根据权利要求1所述的一种贻贝来源的ACE抑制及抗肿瘤活性肽,其特征在于,以所述活性肽序列为核心,任何对其进行的相应的调整或修饰。
3.根据权利要求2所述的一种贻贝来源的ACE抑制及抗肿瘤活性肽,其特征在于,所述对其进行相应的调整或修饰后的应用包括对活性肽进行进一步的降压药物设计:
第四位的氨基酸Asp可被其他任一氨基酸所替代,替代后的小分子肽均具有潜在的降压作用。
4.根据权利要求1所述的一种贻贝来源的ACE抑制及抗肿瘤活性肽,其特征在于,所述活性肽具有ACE抑制活性及抗肝癌细胞增殖的活性,可应用于制备具有调节血压及抗肝癌作用的功能性食品、保健品及药物方面。
5.根据权利要求1所述的一种贻贝来源的ACE抑制及抗肿瘤活性肽,其特征在于,所述活性肽的分离纯化方法,包括以下步骤:
S1、贻贝酶解低聚肽的制备
贻贝样品处理后,加入15~20倍质量体积的水制成匀浆液置于酶解罐中,然后加入贻贝质量的2~5%的复合蛋白酶,在40~50℃下酶解4小时,酶反应pH 值控制在8.0~9.0,酶解结束后升温至80~90℃灭酶10分钟,得到贻贝蛋白酶解液,将蛋白酶解液8000转/分钟离心10分钟,去除颗粒状物质,然后采用膜分离技术进行分离,截留分子量为3000 Da,过膜液喷雾干燥得贻贝小分子肽粉;
S2、小分子活性肽的分离纯化
将S1中的小分子活性肽粗品加水溶解,配制成浓度为100 mg/mL的溶液,采用葡聚糖凝胶Sephadex LH-20柱色谱分进行分离纯化,流动相为30%甲醇,流速为0.3 ~0.5 mL/min,洗脱液280 nm或220 nm测定吸光度,根据吸光度值收集所需峰;
采用高效液相色谱进一步纯化,色谱条件如下:C18色谱柱,流动相A为含体积百分数0.05~0.1%三氟乙酸水,流动相B为乙腈,梯度洗脱条件为:0~15 min,3%B,15~20 min,3%~10%B,20~30 min,10%B~20%B,30~40 min,20%B~35%B,流速为1.0 mL/min,检测波长为220或280 nm,收集保留时间在30分钟的色谱峰,浓缩后冷冻干燥得小分子活性肽;
S3、纯度及氨基酸序列测定
收集的小分子肽经液相色谱检测为单一峰,利用高效液相色谱-质谱测定结构,其氨基酸序列为:Arg-Tyr-Pro-Asp-Pro-Leu,其分子量为760.39 Da。
6.根据权利要求5所述的一种贻贝来源的ACE抑制及抗肿瘤活性肽,其特征在于,所述步骤S1中的复合蛋白酶的质量配比为:中性蛋白酶:木瓜蛋白酶:风味蛋白酶=(2~4):(3~5):(3~5)。
7.根据权利要求5所述的一种贻贝来源的ACE抑制及抗肿瘤活性肽,其特征在于,所述步骤S3中的葡聚糖凝胶Sephadex LH-20柱内径为3.0 cm,柱长100 cm。
8.根据权利要求5所述的一种贻贝来源的ACE抑制及抗肿瘤活性肽,其特征在于,所述C18色谱柱内径为4.6 mm,柱长250 mm,粒度5µm。
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Cited By (6)
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CN112063606A (zh) * | 2020-08-25 | 2020-12-11 | 山东省科学院生物研究所 | 一种快速提取贝类消化内源酶的方法 |
US12102661B2 (en) | 2020-11-23 | 2024-10-01 | Northeast Agricultural University | ACE inhibitory peptide composition derived from ginkgo protein and preparation method and application thereof |
CN114044807A (zh) * | 2021-11-19 | 2022-02-15 | 浙江海洋大学 | 一种治疗高脂血症的贻贝降血脂寡肽 |
CN114044807B (zh) * | 2021-11-19 | 2023-08-22 | 浙江海洋大学 | 一种治疗高脂血症的贻贝降血脂寡肽 |
CN114031669A (zh) * | 2021-12-01 | 2022-02-11 | 浙江海洋大学 | 厚壳贻贝抗氧化活性肽及其制备和应用 |
CN114031669B (zh) * | 2021-12-01 | 2023-05-02 | 浙江海洋大学 | 厚壳贻贝抗氧化活性肽及其制备和应用 |
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