CN112625112B - 一种生物活性多肽paapaqlpkki及其制备方法和应用 - Google Patents
一种生物活性多肽paapaqlpkki及其制备方法和应用 Download PDFInfo
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- CN112625112B CN112625112B CN202011481243.3A CN202011481243A CN112625112B CN 112625112 B CN112625112 B CN 112625112B CN 202011481243 A CN202011481243 A CN 202011481243A CN 112625112 B CN112625112 B CN 112625112B
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Abstract
本发明涉及蛋白领域，具体涉及一种生物活性多肽PAAPAQLPKKI及其制备方法和应用，生物活性多肽PAAPAQLPKKI的氨基酸序列为Pro‑Ala‑Ala‑Pro‑Ala‑Gln‑Leu‑Pro‑Lys‑Lys‑Ile。经过体外免疫功能调节实验，验证了多肽PAAPAQLPKKI具有较好的免疫调节功能。本发明的生物活性肽PAAPAQLPKKI能够促进巨噬细胞的增殖并在炎症情况下促进其吞噬中性红能力，提高机体免疫力，降低机体发病率，提高生命的质量，对开发具有免疫调节功能的食品、保健品和药物具有十分重要的意义。
Description
技术领域
本发明涉及蛋白领域，尤其是涉及一种生物活性多肽PAAPAQLPKKI及其制备方法和应用。
背景技术
近年来，生物活性肽已经成为人们耳熟能详的一个词语。因其具有很多潜在的生物功能，所以引起人们越来越多的关注，成为科学研究的热点之一。目前很多生物活性肽的有益效果也已经得到了很好的证明，如抗癌、降血压、抗菌、降胆固醇、抗糖尿病等等特性。当前最权威的生物活性肽数据库BIOPEP-UMW中已报告了3000多个不同的生物活性肽。
目前对于生物活性肽的研究多集中于食物衍生多肽，对非食物衍生多肽研究和报道较少。且已经有研究结果证实，与食物衍生的生物活性肽相比，非食物衍生的生物活性肽具有更高的亲和力并能有效发挥其生物活性功能。
免疫调节肽是继阿片肽发现后首次从乳中获得并证明其生理活性的一类生物活性多肽。1981年Jolles等人首次发现，利用胰蛋白酶水解人乳蛋白，可以得到一个氨基酸序列为Val-Glu-Pro-Ile-Pro-Tyr的六肽，体外实验证明该肽能够增强小鼠腹腔巨噬细胞对绵羊红细胞的吞噬作用。Migliore-Samour等人发现来自酪蛋白的六肽Thr-Thr-Met-Pro-Leu-Trp能够刺激绵羊血红细胞对小鼠腹膜巨噬细胞的吞噬作用以及增强对于肺炎克雷伯菌的抵抗，具有抗炎功能。李素萍等人用合成的小鼠骨髓巨噬细胞来与源肽（PGPIPN）饲喂大鼠发现大鼠腹腔巨噬细胞的吞噬作用和红细胞相关的抗炎功能有显著的增强。Bowdis等人在研究来源于牛中性粒细胞的13氨基酸肽indolicidin的免疫功能时发现，多肽indolicidin在巨噬细胞样细胞系中抑制LPS诱导的TNF-α产量。
免疫调节肽一般是指具有免疫调节活性的分子量相对较小的小肽。现在公开的免疫调节肽一般是从蛋白质中酶解分离得到或化学方法合成得到的具有特定免疫调节活性的小肽。但是当这些小肽未从蛋白质中酶解分离时，这些蛋白质本身往往是不具备免疫调节活性的。如何从已知氨基酸序列的种类繁多的蛋白质中寻找具有特定功能的生物活性肽，并研究这些多肽的功能是蛋白领域研究的方向之一。
Hematopoietic lineage cell-specific蛋白的氨基酸序列如SEQ ID NO：2所示。目前，现有技术中并没有关于Hematopoietic lineage cell-specific蛋白多肽片段相关功能的研究。
发明内容
本发明的目的在于提供一种生物活性多肽PAAPAQLPKKI及其制备方法和应用。
本发明的目的可以通过以下技术方案来实现：
本发明第一方面，提供一种生物活性多肽PAAPAQLPKKI，其氨基酸序列为Pro-Ala-Ala-Pro-Ala-Gln-Leu-Pro-Lys-Lys-Ile，如SEQ ID NO：1所示。
较优的，所述生物活性多肽为小鼠脾脏来源淋巴细胞肽。具体来源于Hematopoietic lineage cell-specific蛋白，并且为Hematopoietic lineage cell-specific 蛋白第288～298位的氨基酸残基。Hematopoietic lineage cell-specific 蛋白氨基酸序列如SEQ ID NO：2所示。
Hematopoietic lineage cell-specific 蛋白的氨基酸序列以及对应的核苷酸序列为既有技术，编码Hematopoietic lineage cell-specific 蛋白第288～298位氨基酸残基的核苷酸片段能编码成熟的生物活性多肽PAAPAQLPKKI。
较优的，所述生物活性多肽具有抗炎功能和免疫调节功能。
本发明还提供编码所述生物活性肽PAAPAQLPKKI的多核苷酸。
本发明第二方面，提供了所述生物活性多肽PAAPAQLPKKI的制备方法，可以通过基因工程的方法人工合成，可以从细胞中通过分离纯化的方法直接获得，可以直接通过化学合成制备。
通过基因工程的方法人工合成所述生物活性肽PAAPAQLPKKI是本领域技术人员能够实现的技术方案，例如可以是以DNA重组技术为基础，通过合适的DNA模板来控制多肽的序列合成。
关于从细胞中通过分离纯化的方法直接获得的方式可以为：基于给定的生物活性肽PAAPAQLPKKI的氨基酸序列，采用生物学技术上常规的酶解、纯化方法从小鼠脾脏来源淋巴细胞获得所述生物活性肽PAAPAQLPKKI。
本发明第三方面，提供了所述生物活性多肽PAAPAQLPKKI在制备具有抗炎功能的食品、保健品、药物或化妆品中的应用。
进一步地，所述生物活性肽PAAPAQLPKKI在制备有炎症发生的情况下提升体外巨噬细胞吞噬中性红能力的药物中的应用。
本发明第四方面，提供了所述生物活性肽PAAPAQLPKKI在制备具有免疫调节功能的食物或药物中的应用。
进一步地，所述生物活性肽PAAPAQLPKKI在制备促进巨噬细胞增殖的食物或药物中的应用。
本发明第五方面，提供了一种抗炎产品，包括所述生物活性多肽PAAPAQLPKKI或所述生物活性多肽PAAPAQLPKKI的衍生物；所述的抗炎产品包括抗炎食品、抗炎保健品、抗炎药物或抗炎化妆品。
本发明第六方面，提供了一种具有免疫调节功能的产品，包括所述生物活性肽PAAPAQLPKKI或所述生物活性肽PAAPAQLPKKI的衍生物；所述具有免疫调节功能的产品包括具有免疫调节功能的食品或具有免疫调节功能的药物。
所述生物活性肽PAAPAQLPKKI的衍生物是指具有与所述生物活性肽PAAPAQLPKKI相同的活性或更优的活性。
所述生物活性多肽PAAPAQLPKKI的衍生物，是指在生物活性多肽PAAPAQLPKKI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。
本发明生物活性多肽PAAPAQLPKKI的有益效果为：本发明的生物活性多肽PAAPAQLPKKI具有较好的抗炎活性；本发明的生物活性肽PAAPAQLPKKI能够促进巨噬细胞的增殖并在炎症情况下促进其吞噬中性红能力，提高机体免疫力，降低机体发病率，提高生命的质量，对开发具有免疫调节功能的食品、保健品和药物具有十分重要的意义。
附图说明
图1：质荷比为378.5733的片段的一级质谱图（m/z= 378.5733）；
图2：质荷比为378.5733的片段的二级质谱图和多肽az、by断裂情况；
具体实施方式
在进一步描述本发明具体实施方案之前，应理解，本发明的保护范围不局限于下述特定的具体实施方案；还应当理解，本发明实施例中使用的术语是为了描述特定的具体实施方案，而不是为了限制本发明的保护范围。
当实施例给出数值范围时，应理解，除非本发明另有说明，每个数值范围的两个端点以及两个端点之间任何一个数值均可选用。除非另外定义，本发明中使用的所有技术和科学术语与本技术领域技术人员通常理解的意义相同。除实施例中使用的具体方法、设备、材料外，根据本技术领域的技术人员对现有技术的掌握及本发明的记载，还可以使用与本发明实施例中所述的方法、设备、材料相似或等同的现有技术的任何方法、设备和材料来实现本发明。
除非另外说明，本发明中所公开的实验方法、检测方法、制备方法均采用本技术领域常规的分子生物学、生物化学、染色质结构和分析、分析化学、细胞培养、重组DNA技术及相关领域的常规技术。这些技术在现有文献中已有完善说明，具体可参见Sambrook等MOLECULAR CLONING ：A LABORATORY MANUAL，Second edition，Cold Spring HarborLaboratory Press，1989 and Third edition，2001 ；Ausubel 等，CURRENT PROTOCOLS INMOLECULAR BIOLOGY，John Wiley & Sons，New York，1987 and periodic updates ；theseries METHODS IN ENZYMOLOGY，Academic Press，San Diego ；Wolffe，CHROMATINSTRUCTURE AND FUNCTION，Third edition，Academic Press，San Diego，1998 ；METHODSIN ENZYMOLOGY，Vol.304，Chromatin (P.M.Wassarman and A.P.Wolffe，eds.)，AcademicPress，San Diego，1999 ； 和METHODS IN MOLECULAR BIOLOGY，Vol.119，ChromatinProtocols(P.B.Becker，ed.)Humana Press，Totowa，1999等。
下面结合附图和具体实施例对本发明进行详细说明。
实施例1 活性肽PAAPAQLPKKI的人工合成
一、生物活性肽的合成
人工合成生物活性肽PAAPAQLPKKI。
二、生物活性肽的确认
1）UPLC分析
UPLC条件如下：
仪器：Waters ACQUITY UPLC超高效液相、电喷雾、四级杆、飞行时间质谱仪
色谱柱规格：BEH C18 色谱柱
流速：0.4mL/min
温度：50℃
紫外检测波长：210nm
进样量：2μL
梯度条件：A液：含有0.1%甲酸（v/v）的水，B液：含有0.1%甲酸（v/v）的乙腈
Time(min) %A %B
0 95.0 5.0
1.50 80.0 20.0
3.50 60.0 40.0
5.00 40.0 60.0
7.00 15.0 85.0
8.00 0.0 100.0
11.00 0.0 100.0
11.50 95.0 5.0
13.00 95.0 5.0
2）质谱分析
质谱条件如下：
离子方式：ES+
质量范围（m/z）：100、1000
毛细管电压（Capillary）（kV）：3.0
采样锥（V）：35.0
离子源温度（℃）：115
去溶剂温度（℃）：350
去溶剂气流（L/hr）：700.0
碰撞能量（eV）：4.0
扫描时间（sec）：0.25
内扫描时间（sec）：0.02
根据以上分析方法，利用超高效液相、电喷雾、四级杆、飞行时间质谱，对生物活性肽PAAPAQLPKKI进行色谱分析和质谱分析。生物活性肽PAAPAQLPKKI一级质谱图如图1所示，提取峰的二级质谱图和az、by断裂情况如图2所示，可得此峰的多肽质荷比为378.5733，保留时间是20.41 min。
3）结果
由图2可知，根据az、by断裂的情况，经过 Mascot 软件分析计算，得到质荷比378.5733的片段序列为Pro、Ala、Ala、Pro、Ala、Gln、Leu、Pro、Lys、Lys、Ile（PAAPAQLPKKI），记为SEQ ID NO：1。该片段与Hematopoietic lineage cell-specific 蛋白第288～298位的残基序列相对应，Hematopoietic lineage cell-specific 蛋白氨基酸序列见SEQ IDNO：2。
实施例2 生物活性肽的免疫活性实验
一、生物活性多肽PAAPAQLPKKI的促巨噬细胞吞噬中性红能力实验
1. 实验试剂及仪器：
试剂：实验动物 balb/c小鼠（雄性6-8周龄）上海交通大学农业与生物学院动物实验中心；实施例1获得的小鼠脾脏淋巴细胞来源生物活性多肽PAAPAQLPKKI；LPS，购自Sigma公司；中性红染色液，碧云天生物技术研究所生产。
仪器设备：LRH-250F生化培养箱 上海恒科技有限公司；GL-22M高速冷冻离心机上海卢湘仪离心机仪器有限公司； Hera cell 150 CO2 培养箱 Heraeus公司；DragonWellscan MK3酶标仪 Labsystems公司。
2. 实验方法：
加入细胞个数为2×106/ml的细胞悬液100μl/孔，贴壁纯化后加入含活性肽PAAPAQLPKKI（1mg/ml）的RPMI1640完全培养液（10%FBS）200μl/孔为实验组，添加不含活性肽的RPMI1640完全培养液（10%FBS）200μl/孔进行培养的设为空白组；并且实验组和空白组在培养到24h时加入LPS至终浓度10μg/ml；继续培养至48h后，吸弃细胞培养液。PBS清洗孔底后加入37℃的中性红染液80μl/孔，10分钟后吸弃染液，用PBS清洗两次后，每孔加入150μl细胞裂解液（冰醋酸：无水乙醇=1:1， v/v）。4℃隔夜溶解后，在波长540nm下测定吸光度值（OD540）。
3. 实验结果及分析：
表2 生物活性多肽PAAPAQLPKKI促巨噬细胞吞噬中性红能力的测定
| 实验分组 | 炎症组吸光度值（OD540） |
| 空白组 | 0.1010±0.0183 |
| 实验组 | 0.1259±0.0105** |
注：*，与阴性对照比较，有显著性差异(P ＜0.05)
**，与阴性对照组比较，有极显著性差异(P ＜0.01)
实验结果见表2，与细胞空白相比较，添加1mg/ml生物活性多肽PAAPAQLPKKI的炎症组巨噬细胞吞噬中性红能力明显增加，而且与细胞空白组比较，具有极显著性差异(P ＜0.01)。说明生物活性多肽PAAPAQLPKKI在有炎症发生的情况下对体外巨噬细胞吞噬中性红能力具有显著的促进作用。
二、MTT法测定生物活性多肽PAAPAQLPKKI的体外巨噬细胞增殖能力实验
1. 实验试剂及仪器
试剂：实验动物 balb/c小鼠（雄性6-8周龄）上海交通大学农业与生物学院动物实验中心；实施例1获得的小鼠脾脏淋巴细胞来源生物活性肽PAAPAQLPKKI；3-(4，5-二甲基噻唑-2)-2，5-二苯基四氮唑溴盐（MTT）Amresco公司；LPS（脂多糖） Sigma公司；牛血清白蛋白（Bovine Serum Albumin，BSA） Genebase公司；三联溶解液，含10%SDS、5%异丁醇以及0.012mol/L HCl的水溶液。
仪器设备：LRH-250F生化培养箱 上海恒科技有限公司；GL-22M高速冷冻离心机上海卢湘仪离心机仪器有限公司； Hera cell 150 CO2 培养箱 Heraeus公司；DragonWellscan MK3酶标仪 Labsystems公司。
2. 试验方法：
balb/c小鼠腹腔注射2ml的2%（w/w）灭菌淀粉溶液，连续注射三天，最后一次注射24小时后断颈处死。剥去腹部皮肤，用注射器吸取4℃磷酸盐缓冲液（PBS）反复冲洗腹腔，离心管收集冲洗液后，离心（1000rpm，4℃）10分钟后弃上清，用4℃RPMI1640完全培养液（含10%FBS）洗涤两次，0.2%台盼蓝溶液染色做细胞活力检测，确认采集到的有活力巨噬细胞占95%以上。细胞计数板读数后，调整细胞浓度至合适浓度。
将已吹打至完全悬浮的细胞悬液以合适体积加入96孔细胞培养板，37℃、5%CO2环境下培养4小时后，吸弃孔中液体，用37℃ RPMI1640完全培养液小心清洗细胞培养板孔底，洗去未贴壁的细胞和细胞碎片，得到纯化后的贴壁腹腔巨噬细胞。每孔加入0.2mlRPMI1640完全培养基，实验用小肽样品及LPS事先溶解于培养基后加入，开始细胞培养。
得到纯化后的贴壁腹腔巨噬细胞后，实验组每孔加溶解有生物活性多肽PAAPAQLPKKI(1mg/ml)的RPMI1640完全培养液（10%FBS）200μl/孔，连续培养48h；阴性对照组每孔加溶解有BSA（500μg/mL）的RPMI1640完全培养液（10%FBS）200μl/孔；空白组添加RPMI1640完全培养液（10%FBS）200μl/孔，连续培养48h。并且，实验组、阴性对照组和空白组又分别设正常组和炎症组；炎症组在培养到24h时加入LPS至终浓度为100ng/ml；正常组不加LPS；并且正常组和炎症组在44h时加入5% MTT 20μl/孔；细胞培养达到48h后加入100μl/孔的三联溶解液以终止培养，隔夜溶解后，在波长570nm下用酶标仪测各孔的吸光度值（OD570），生长指数（Growth Indices）的计算公式如下：
生长指数GI=(小肽组OD值-空白培养液OD值)/(空白组OD值-空白培养液OD值)
其中，空白培养液为含10%FBS的RPMI1640完全培养液。
3. 实验结果及分析
表1 生物活性多肽PAAPAQLPKKI对体外巨噬细胞增殖的影响
| 实验分组 | 正常组GI | 炎症组GI |
| 阴性对照组 | 1 | 1 |
| PAAPAQLPKKI（1mg/ml） | 1.1503±0.0284** | 1.1392±0.0395** |
注：*表示与阴性对照比较，有显著性差异(P ＜0.05)；**表示与阴性对照组比较，有高度显著性差异(P ＜0.01)
实验结果见表1，由表1可知，在添加1mg/ml 生物活性多肽PAAPAQLPKKI的条件下，正常组和炎症组的巨噬细胞均有增殖。而且与阴性对照组比较，均有显著性差异(P ＜0.01)。说明生物活性多肽PAAPAQLPKKI对体外巨噬细胞具有显著的增殖作用。
上述的对实施例的描述是为便于该技术领域的普通技术人员能理解和使用发明。熟悉本领域技术的人员显然可以容易地对这些实施例做出各种修改，并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此，本发明不限于上述实施例，本领域技术人员根据本发明的揭示，不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。
序列表
<110> 熊猫乳品集团股份有限公司,浙江辉肽生命健康科技有限公司
<120> 一种生物活性多肽PAAPAQLPKKI及其制备方法和应用
<160> 2
<170> SIPOSequenceListing 1.0
<210> 1
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Pro Ala Ala Pro Ala Gln Leu Pro Lys Lys Ile
1 5 10
<210> 2
<211> 486
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Met Trp Lys Ser Val Val Gly His Asp Val Ser Val Ser Val Glu Thr
1 5 10 15
Gln Gly Asp Asp Trp Asp Thr Asp Pro Asp Phe Val Asn Asp Ile Ser
20 25 30
Glu Lys Glu Gln Arg Trp Gly Ala Lys Thr Ile Glu Gly Ser Gly Arg
35 40 45
Thr Glu His Ile Asn Ile His Gln Leu Arg Asn Lys Val Ser Glu Glu
50 55 60
His Asp Ile Leu Lys Lys Lys Glu Leu Glu Ser Gly Pro Lys Ala Ser
65 70 75 80
His Gly Tyr Gly Gly Arg Phe Gly Val Glu Arg Asp Arg Met Asp Lys
85 90 95
Ser Ala Val Gly His Glu Tyr Val Ala Asp Val Glu Lys His Ser Ser
100 105 110
Gln Thr Asp Ala Ala Arg Gly Phe Gly Gly Lys Tyr Gly Val Glu Arg
115 120 125
Asp Arg Ala Asp Lys Ser Ala Val Gly Phe Asp Tyr Lys Gly Glu Val
130 135 140
Glu Lys His Ala Ser Gln Lys Asp Tyr Ser His Gly Phe Gly Gly Arg
145 150 155 160
Tyr Gly Val Glu Lys Asp Lys Arg Asp Lys Ala Ala Leu Gly Tyr Asp
165 170 175
Tyr Lys Gly Glu Thr Glu Lys His Glu Ser Gln Arg Asp Tyr Ala Lys
180 185 190
Gly Phe Gly Gly Gln Tyr Gly Ile Gln Lys Asp Arg Val Asp Lys Ser
195 200 205
Ala Val Gly Phe Asn Glu Met Glu Ala Pro Thr Thr Ala Tyr Lys Lys
210 215 220
Thr Thr Pro Ile Glu Ala Ala Ser Ser Gly Ala Arg Gly Leu Lys Ala
225 230 235 240
Lys Phe Glu Ser Leu Ala Glu Glu Lys Arg Lys Arg Glu Glu Glu Glu
245 250 255
Lys Ala Gln Gln Met Ala Arg Gln Gln Gln Glu Arg Lys Ala Val Val
260 265 270
Lys Met Ser Arg Glu Val Gln Gln Pro Ser Met Pro Val Glu Glu Pro
275 280 285
Ala Ala Pro Ala Gln Leu Pro Lys Lys Ile Ser Ser Glu Val Trp Pro
290 295 300
Pro Ala Glu Ser His Leu Pro Pro Glu Ser Gln Pro Val Arg Ser Arg
305 310 315 320
Arg Glu Tyr Pro Val Pro Ser Leu Pro Thr Arg Gln Ser Pro Leu Gln
325 330 335
Asn His Leu Glu Asp Asn Glu Glu Pro Pro Ala Leu Pro Pro Arg Thr
340 345 350
Pro Glu Gly Leu Gln Val Val Glu Glu Pro Val Tyr Glu Ala Ala Pro
355 360 365
Glu Leu Glu Pro Glu Pro Glu Pro Asp Tyr Glu Pro Glu Pro Glu Thr
370 375 380
Glu Pro Asp Tyr Glu Asp Val Gly Glu Leu Asp Arg Gln Asp Glu Asp
385 390 395 400
Ala Glu Gly Asp Tyr Glu Asp Val Leu Glu Pro Glu Asp Thr Pro Ser
405 410 415
Leu Ser Tyr Gln Ala Gly Pro Ser Ala Gly Ala Gly Gly Ala Gly Ile
420 425 430
Ser Ala Ile Ala Leu Tyr Asp Tyr Gln Gly Glu Gly Ser Asp Glu Leu
435 440 445
Ser Phe Asp Pro Asp Asp Ile Ile Thr Asp Ile Glu Met Val Asp Glu
450 455 460
Gly Trp Trp Arg Gly Gln Cys Arg Gly His Phe Gly Leu Phe Pro Ala
465 470 475 480
Asn Tyr Val Lys Leu Leu
485
Claims (3)
1.一种生物活性多肽PAAPAQLPKKI，其特征在于，其氨基酸序列为Pro-Ala-Ala-Pro-Ala-Gln-Leu-Pro-Lys-Lys-Ile。
2.编码权利要求1所述生物活性肽PAAPAQLPKKI的多核苷酸。
3.如权利要求1所述生物活性多肽PAAPAQLPKKI的制备方法，其特征在于，直接通过化学合成制备。
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