CN115353551B - 一种燕麦源促glp-1分泌寡肽及其制备方法和应用 - Google Patents
一种燕麦源促glp-1分泌寡肽及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一种燕麦源促GLP‑1分泌寡肽及其制备方法和应用。该寡肽为DVNNNANQLEPR,氨基酸序列为:Asp‑Val‑Asn‑Asn‑Asn‑Ala‑Asn‑Gln‑Leu‑Glu‑Pro‑Arg。与现有技术相比,本发明寡肽既能通过酶解燕麦蛋白分离纯化后获得,也可以采用化学固相合成方法人工合成。本发明所述寡肽具有显著促进肠道内分泌细胞分泌GLP‑1的功能,同时具有安全无毒副作用、耐受胃肠道消化酶酶解和易吸收等优点,对开发具有降血糖的保健食品和药品具有十分重要的意义。
Description
技术领域
本发明属于生物小分子寡肽领域,尤其是涉及一种燕麦源促GLP-1分泌寡肽及其制备方法和应用。
背景技术
糖尿病(diabetes)是一种与胰岛素分泌缺陷或其生物作用受损相关、以高血糖症为主要特征的内分泌代谢疾病。长期存在的高血糖导致各种组织,特别是眼、肾、心脏、血管、神经的慢性损害和功能障碍。糖尿病主要包括I型和II型糖尿病,我国糖尿病人群以II型糖尿病为主,占糖尿病患者总数的90%以上。II型糖尿病是一种缓慢进展性疾病,其发病的中心环节是胰岛素抵抗和胰岛β细胞功能缺陷。鉴于II型糖尿病的患病人数众多且严重危害性,发展II型糖尿病的预防和治疗措施刻不容缓。当前,许多药物包括磺脲类药物、双胍类降糖药、α葡萄糖苷酶抑制剂、胰岛素增敏剂等用于II型糖尿病的治疗。这些抗糖尿病药物虽然疗效明确,但价格昂贵,且易产生诸多副作用及药物抵抗。因此,开发价格低廉、副作用小且具有改善糖尿病活性的功能食品或保健食品具有重要意义。
胰高血糖素样肽-1(Glucagon like peptide-1,GLP-1)是人体小肠内分泌L细胞分泌的帮助机体在进食碳水化合物后产生餐后胰岛素反应的一种胃肠激素。GLP- 1在II型糖尿病的治疗过程中具有重要的应用价值。GLP-1具有促进胰岛素的分泌、胰岛β细胞增殖并抑制其凋亡、抑制餐后胰高血糖素的分泌、减少肝糖元的合成、提高胰岛素的敏感性以及控制食欲等生理功能。因此,GLP-1已经成为糖尿病预防和治疗新策略的研究热点。增加肠道GLP-1的分泌对于预防和治疗II型糖尿病具有重要意义。研究证实GLP-1的分泌受膳食因素调控。因此,可以通过膳食调控肠道GLP-1的分泌进而改善或预防II糖尿病。
食源性生物寡肽是一种常见的膳食因子。作为食品蛋白质的水解产物,食源性生物寡肽具有易被人体消化吸收、食用安全性高等特点。国家高度重视食源性生物寡肽产业的发展,明确指出,要加快发展功能性食品,支持发展生物寡肽等保健和健康食品,并开展应用示范。当前食源性生物寡肽的来源主要包括动物蛋白和植物蛋白,而植物蛋白因环境、经济、可持续性等因素受到越来越多的关注。燕麦 (Avena sativa L)是我国西部、华北地区的主要农作物之一,具有重要食用价值,其蛋白质含量均高于小麦、玉米、水稻等作物。目前对燕麦多糖和油脂的开发利用较多,但对燕麦蛋白却缺乏开发。以燕麦来源的蛋白为原料,开发生物寡肽具有重要的应用价值和开发前景。
发明内容
本发明的目的在于提供一种燕麦源促GLP-1分泌寡肽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,提供一种燕麦源促GLP-1分泌寡肽,该寡肽为 DVNNNANQLEPR,氨基酸序列为: Asp-Val-Asn-Asn-Asn-Ala-Asn-Gln-Leu-Glu-Pro-Arg,如SEQ ID NO.1所示。
燕麦蛋白主要是球蛋白,其中燕麦12S seed storage globulin 1的氨基酸序列如 SEQ ID NO.2所示。可以发现,DVNNNANQLEPR在燕麦蛋白存在。 DVNNNANQLEPR寡肽可以从燕麦蛋白中制备。
本发明提供的寡肽是燕麦来源的具有促进胰高血糖肽-1(GLP-1)分泌功能的寡肽。
本发明第二方面,提供编码所述燕麦源促GLP-1分泌寡肽的多核苷酸。
本发明第三方面,提供所述燕麦源促GLP-1分泌寡肽的制备方法,通过基因工程的方法人工合成,或从燕麦蛋白中通过分离纯化的方法直接获得,或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燕麦源促GLP-1分泌寡肽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。
关于从燕麦蛋白中通过分离纯化的方法直接获得的方式可以为:基于给定的燕麦源促GLP-1分泌寡肽的氨基酸序列,采用生物学技术上常规的酶解、分离、纯化方法从燕麦获取燕麦源促GLP-1分泌寡肽。
通过化学合成制备的方法为采用传统的固相合成法合成上述寡肽。
本发明第四方面,提供含有所述燕麦源促GLP-1分泌寡肽的酶解产物的制备方法,包括以下步骤:用胃蛋白酶和胰蛋白酶依次酶解燕麦蛋白,得到燕麦蛋白酶解产物,即为含有所述燕麦源促GLP-1分泌寡肽的酶解产物。
在本发明的一个实施方式中,所述用胃蛋白酶和胰蛋白酶依次酶解燕麦蛋白的方法,包括如下步骤:
1)从燕麦中提取燕麦蛋白;
2)用所述胃蛋白酶酶解所述燕麦蛋白,得到第一次酶解产物;
3)用所述胰蛋白酶酶解所述第一次酶解产物,得到燕麦蛋白酶解产物。
在本发明的一个实施方式中,从燕麦中提取燕麦蛋白的方法包括以下步骤:
将燕麦磨粉、脱脂,然后加入蒸馏水中,将pH调到4-6,用纤维素酶预先处理0.5-2h;然后将pH调至10-12进行蛋白提取,结束后离心取上清液,将上清液 pH调至4.5左右,例如4.4-4.6,静置后离心,水洗;最后干燥得到燕麦蛋白。
在本发明的一个实施方式中,所述胃蛋白酶或胰蛋白酶与所述燕麦蛋白的质量比为1:10-80。
在本发明的一个实施方式中,所述胃蛋白酶或胰蛋白酶的酶解条件为37℃酶解1-5h。
在本发明的一个实施方式中,步骤3)得到燕麦蛋白酶解产物后,还包括以下步骤:
将所述燕麦蛋白酶解产物利用Toyopearl HW-40F尺寸排阻色谱柱进行分离,以去离子水作为洗脱剂,流速0.05柱体积/min进行层析纯化,收集不同组分;然后检测不同组分对肠内分泌细胞GLP-1分泌的影响,选取促进GLP-1分泌最高活性的组分为目的组分,即为含有所述燕麦源促GLP-1分泌寡肽的酶解产物。
本发明第五方面,提供基于上述制备方法制备的含有所述燕麦源促GLP-1分泌寡肽的酶解产物。
本发明第六方面,提供所述燕麦源促GLP-1分泌寡肽、所述含有所述燕麦源促GLP-1分泌寡肽的酶解产物在制备预防糖尿病或辅助降血糖的保健品或药品中的应用。
所述燕麦源促GLP-1分泌寡肽、所述含有所述燕麦源促GLP-1分泌寡肽的酶解产物具有促进GLP-1分泌功能,能够预防或辅助治疗糖尿病或辅助降血糖。
本发明第七方面,提供一种产品,其中包含所述燕麦源促GLP-1分泌寡肽,或所述含有所述燕麦源促GLP-1分泌寡肽的酶解产物,所述产品具有预防糖尿病或辅助降血糖的功能。
与现有技术相比,本发明的优点及有益效果体现在以下方面:
本发明筛选出了具有促进肠道GLP-1分泌的寡肽,该寡肽具有新型肽序列结构,迄今尚未见其他相关报道;本发明所述寡肽可由食品蛋白质燕麦蛋白制备得到,具有安全无毒副作用的优点;所述DVNNNANQLEPR肽能够耐受胃肠道中胃蛋白酶和胰酶的消化,具有较好的稳定性,从而最大限度的发挥促GLP-1分泌活性;本发明所述DVNNNANQLEPR肽分子量小于1500Da,分子量小,除了能够促进 GLP-1分泌外,还容易被机体吸收,从而具有很好的营养功能;本发明提供的 DVNNNANQLEPR寡肽或含DVNNNANQLEPR肽的酶解物的制备方法简单、易于操作,便于工业化大规模生产,具有广阔的应用前景。
附图说明
图1为DVNNNANQLEPR寡肽人工合成后的液相图和质谱图;
图2为DVNNNANQLEPR寡肽对STC-1细胞活力的影响;
图3为DVNNNANQLEPR寡肽对STC-1细胞分泌GLP-1的影响;
图4为不同浓度燕麦蛋白酶解物对STC-1细胞分泌GLP-1的影响;
图5为燕麦蛋白酶解物对小鼠肠内分泌细胞分泌GLP-1的影响;
图6为燕麦蛋白酶解物经HW-40F尺寸排阻色谱柱分离的图谱;
图7为分离组分对STC-1细胞分泌GLP-1的影响;
图8为分离组分F1中DVNNNANQLEPR肽的MS/MS图谱及其序列解析。
具体实施方式
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
DVNNNANQLEPR寡肽的人工合成与促GLP-1分泌活性评价
一、DVNNNANQLEPR寡肽的合成
Gln-Gly-Asp-Val-Val-Ala-Leu-Pro-Ala(DVNNNANQLEPR)寡肽由“浙江鸿拓科技有限公司”采用肽固相合成法合成,通过高效液相方法和质谱技术验证了合成肽的纯度大于95%,DVNNNANQLEPR的液相图和质谱图1所示。
二、DVNNNANQLEPR对SCT-1细胞活性和PYY分泌的影响
(1)STC-1细胞的培养
STC-1细胞培养在含有10%胎牛血清(FBS),1%非必需氨基酸(NEAA),100 U/mL青霉素和0.1mg/mL链霉素的DMEM培养基中。将细胞在37℃,含有5% CO2的细胞培养箱中孵育,并在达到80-90%密度时,通过胰蛋白酶消化进行传代培养。
(2)细胞活性测定
通过3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化物[3-(4, 5-dimethyl-2-thiazolyl)-2,5-diphenyl]-2H-tetrazoliumbromide,MTT)细胞增殖及细胞毒性测试和评估DVNNNANQLEPR寡肽对STC-1细胞活力的影响。在96孔板处理后的STC-1细胞中加入MTT,代谢活跃的细胞将黄色四唑盐MTT裂解成紫色的甲瓒晶体。将形成的甲瓒溶解,用酶标仪在检测波长为570nm处测量吸光度,结果以对照组的百分比表示。结果如2所示,在不同肽测试浓度下(0,1,2,4mmol/L),相比对照物STC-1细胞活力没有现在变化,说明DVNNNANQLEPR寡肽对细胞无毒性。
(3)STC-1细胞分泌激素含量的测定
将DVNNNANQLEPR寡肽用Hank’s缓冲液配成摩尔浓度分别0.2,2,5mM的肽溶液。在24孔培养板中将STC-1细胞以1.25×105个细胞的密度接种。待细胞达到80%-90%汇合时,将细胞用Hank’s缓冲液洗涤两次,以除去培养基。将7条寡肽溶液加入STC-1细胞中,在培养箱中37℃孵育细胞2h。孵育结束后,1000g 离心20min,取上清液。采用武汉云克隆科技股份有限公司的商用GLP-1试剂盒测定GLP-1含量。
DVNNNANQLEPR寡肽对STC-1细胞分泌GLP-1的影响见图3,可以看到 DVNNNANQLEPR寡肽剂量依赖的增加GLP-1的分泌。大量研究已证实GLP-1具有促进胰岛素的分泌、胰岛β细胞增殖并抑制其凋亡、抑制餐后胰高血糖素的分泌、减少肝糖元的合成、提高胰岛素的敏感性以及控制食欲等生理功能。增加GLP-1 的分泌对于预防和治疗II型糖尿病具有重要意义。本专利所述DVNNNANQLEPR 寡肽能够显著促进肠道内分泌细胞STC-1分泌GLP-1,因此该肽对于预防糖尿病或辅助降血糖具有重要意义。
实施例2制备燕麦蛋白酶解物与活性评价
(1)燕麦蛋白酶解物制备
将燕麦磨粉过80筛,然后用己烷将燕麦粉脱脂。将脱脂燕麦粉用蒸馏水以质量比为12:1于烧杯中浸泡,用1mol/L HCl将pH值调至5.0,在50℃下用纤维素酶处理1h。然后将pH值用1mol/L NaOH调至11.0,在磁力搅拌器作用2h后离心取上清液。用1mol/L HCl将上清液pH值调至其等电点(pH 4.5)静置1h后离心,水洗沉淀至中性,用少量蒸馏水复溶后冷冻干燥得到燕麦蛋白,4℃储藏备用。
将冻干的1g蛋白粉末溶于20mL含25mg新鲜制备的胃蛋白酶的 K2HPO4-KH2PO4磷酸盐缓冲液(0.1mol/L)中,将溶液pH值用HCl(1mol/L)调节至2.0,在37℃下孵育2h。孵育结束,将溶液pH值用NaOH(1mol/L)调至 6.8后,加入50mg胰蛋白酶继续酶解2h。结束后沸水浴灭酶8min,离心取上清液冷冻干燥,得到燕麦蛋白酶解物。
(2)活性评价
将燕麦蛋白酶解物用Hank’s缓冲液配成质量浓度分别为3,4,5mg/mL的溶液, 用上述方法测定酶解物对STC-1细胞分泌GLP-1的影响,结果见图4。由结果可以看到燕麦蛋白酶解物能够显著的刺激STC-1细胞分泌GLP-1。
进一步,在动物水平上评价燕麦蛋白酶解物对小鼠肠内分泌细胞分泌激素的影响。经过1周的适应期后,将ICR小鼠随机分为2组(每组28只)。对照组:灌胃生理盐水;燕麦蛋白酶解物组:灌胃燕麦蛋白酶解物(1.0g/kg体重)。灌胃后,分别在0,15min,30min,60min,90min,120min,150min摘眼球取血,放入含有EDTA(最终浓度为1mg/mL)、抑肽酶(最终浓度为0.6TIU/mL)的离心管中,离心取上清液,用ELISA方法血清中GLP-1激素含量。灌胃生理盐水组血清中的GLP-1在这个期间水平维持在20pg/mL左右。灌胃燕麦蛋白酶解物组结果如图5 所示,可以发现燕麦蛋白酶解物极大增加小鼠体内GLP-1水平。
实施例3制备燕麦蛋白促GLP-1分泌的寡肽
取Toyopearl HW-40F填料常规溶胀与装柱(装填缓冲溶液为0.1M NaCl溶于 50mM磷酸盐),柱高10cm,内径2.6cm,任何时刻柱顶需留水层1.5-2cm,柱平衡约3-4个柱体积后即可使用,保留液面2-3mm时开始加样燕麦蛋白酶解物。称取燕麦蛋白酶解物粉末约20mg溶于2mL蒸馏水中,0.45μm微孔滤膜过滤后加入层析柱,洗脱液为蒸馏水,洗脱速度为2mL/min,收集洗脱峰。燕麦蛋白酶解物分离图谱见图6,可以看到HW-40F色谱柱将蛋白酶解物分为4个肽组分。
将4个肽组分用上述方法进行活性评价,结果如图7所示。可以发现在4个肽组分中,F1组分具有最好的刺激STC-1细胞分泌GLP-1的能力。因此,F1组分为高活性的促GLP-1分泌的肽。
实施例4燕麦蛋白含DVNNNANQLEPR寡肽的鉴定
将F1组分中的肽序列采用质谱技术进行鉴定。将样品溶于蒸馏水,制成 1mg/mL样品。使用反相色谱柱(150μm i.d.×150mm,packed with Acclaim PepMap RPLC C18,1.9μm,)进行分离,流动相A为0.1%甲酸水溶液,流动相B为 0.1%甲酸/80%乙腈溶液,在600nL/min流速下梯度洗脱,分离梯度:0-2min,4-8%B;2-45min,8-40%B;45-55min,40-60%B;55-56min,60-95%B;56-66min, 95%B。质谱离子源类型为电喷雾电离源(ESI),正离子扫描模式,喷雾电压2200 V,毛细管温度270℃。一级质谱参数设置:扫描范围100-2000m/z,最大分辨率 70000,自动增益参数3000000。二级质谱参数设置:扫描范围50-2000m/z,最大分辨率17500,自动增益参数100000。
经质谱检测,F1组分中主要出现的离子峰是m/z=692.337,带2个电荷。将该分子离子峰进一步进行二级质谱分析,该分子离子峰的二级质谱图见图8。经数据库匹配,该分子离子峰对应的肽为 Asp-Val-Asn-Asn-Asn-Ala-Asn-Gln-Leu-Glu-Pro-Arg(DVNNNANQLEPR)。
燕麦蛋白主要是球蛋白,其中燕麦12S seed storage globulin 1的氨基酸序列如 SEQ ID NO.2所示。可以发现,DVNNNANQLEPR在燕麦蛋白存在。 DVNNNANQLEPR寡肽可以从燕麦蛋白中制备。
燕麦12S seed storage globulin 1的氨基酸序列具体如下所示:
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> 上海理工大学
<120> 一种燕麦源促GLP-1分泌寡肽及其制备方法和应用
<160> 2
<170> SIPOSequenceListing 1.0
<210> 1
<211> 12
<212> PRT
<213> 燕麦(Avena longiglumis)
<400> 1
Asp Val Asn Asn Asn Ala Asn Gln Leu Glu Pro Arg
1 5 10
<210> 2
<211> 518
<212> PRT
<213> 燕麦(Avena longiglumis)
<400> 2
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Claims (1)
1.燕麦源寡肽或含有所述燕麦源寡肽的酶解产物在制备促进肠道GLP-1分泌的产品中的应用,其特征在于,所述燕麦源寡肽为DVNNNANQLEPR,氨基酸序列为:Asp-Val-Asn-Asn-Asn-Ala-Asn-Gln-Leu-Glu-Pro-Arg。
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