海地瓜蛋白水解物中ACE抑制肽的分离纯化及合成
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摘要
本文研究内容主要有:ACE抑制活性体外检测方法的建立;海地瓜蛋白酶解工艺的确定及酶解液的慢性降压效果研究;海地瓜ACE抑制肽的分离纯化及结构鉴定;ACE抑制肽的设计合成及特性研究。
本文建立了适用于检测食源性ACE抑制肽体外活性的RP-HPLC法。该方法操作简便,重复性好,准确性高。应用该方法对马尿酸浓度与峰面积的相关性进行分析,结果表明马尿酸浓度在0～200μg/mL和200～800μg/mL范围内与峰面积呈现良好的相关性。马尿酸浓度小于200μg/mL时,其重复性最好。经卡托普利、牡蛎酶解液、鳀鱼酶解液验证,表明该方法适用于食源性ACE抑制肽体外活性的测定和化学合成的降压药物。
本文研究了海地瓜蛋白的定向复合酶解工艺。以海地瓜蛋白为原料,选用胰蛋白酶、木瓜蛋白酶、菠萝蛋白酶、3942中性蛋白酶、Ⅰ型胶原酶、alcalase蛋白酶对其进行水解。以单酶水解产物的IC50值为评价指标,确定了菠萝蛋白酶、alcalase蛋白酶、Ⅰ型胶原酶作为目标酶。通过正交实验,确定了这三种单酶的最适水解条件。结果表明:菠萝蛋白酶最适水解条件为:45℃,pH 7.0,底物浓度1.0%,2000 U,4 h;alcalase蛋白酶最适水解条件为:55℃,pH 7.4,底物浓度1.5%,2000 U,2 h;Ⅰ型胶原酶最适水解条件为:37℃,pH 7.4,底物浓度1.0%,1500 U,4 h。在单酶和正交实验的基础上,采用复合酶进行水解实验,得到了最适复合酶水解工艺条件:先采用菠萝蛋白酶进行水解,再用alcalase蛋白酶水解。复合酶水解液分别经过10 KDa、5 KDa、2 KDa的膜超滤,得到了具有更高抑制活性的ACE组分,优化了复合酶解工艺,其水解液的IC50值为0.62 mg/mL。
本文采用两肾一夹型造模手术,成功得到了肾性高血压大鼠。通过长期给药的试验表明,分子量小于2 KDa的海地瓜蛋白水解产物可以显著降低肾性高压大鼠的动脉血压,具有较好的降压效果,且呈剂量依赖性,其中120 mg/kg剂量水解产物的降压效果与卡托普利10 mg/kg相当。
本文利用Sephadex G-25凝胶柱层析、SP Sephadex C-25阳离子交换层析、反相高效液相色谱层析对海地瓜复合酶水解产物进行分离纯化,得到两种高活性的ACE抑制肽-P1(IC50, 0.0496 mg/mL)和P2(IC50, 0.0165 mg/mL),它们的活性分别为复合酶水解液的12.5倍和37.6倍。用反相高效液相色谱C18分析柱鉴定活性肽P1和P2的纯度,按照峰面积计算,活性肽P1的纯度为98.6%,活性肽P2的纯度为100%。应用纳升电喷雾—四极杆—飞行时间串联质谱(Nano-ESI-Ms/Ms)技术,对活性肽P1、P2进行结构鉴定。P1的精确分子量为1629.7 Da,氨基酸序列为YYLEMDFLLFNY,IC50值为30.4μM;P2的精确分子量为1034.5 Da,氨基酸序列为MEGAQEAQGD,IC50值为15.9μM。
本文采用逐步缩合和片断缩合相结合的方法对海地瓜ACE抑制肽MEGAQEAQGD进行了设计合成。首先合成了该十肽的三个片段QGD、QEA、MEGA,然后按照(3+3+4)片段缩合策略最终合成出了MEGAQEAQGD。该十肽的纯度为99.72%,收率为68.2%,分子量与序列结构均与理论值相符。
本文研究了海地瓜ACE抑制肽MEGAQEAQGD的特性。研究发现,ACE酶不会影响抑制肽的稳定性。但是,抑制肽与胃蛋白酶和糜蛋白酶水解反应后,活性却增强了3.5倍,这说明抑制肽属于前体药物型的ACE抑制剂。动物实验表明,灌胃抑制肽(3μM/kg)3个小时后,降压效果最好,自发性高压大鼠的收缩压从192±1.7 mmHg下降到173±2.9 mmHg,并且该活性能持续5个小时。卡托普利组(3μM/kg)只在1-4小时内有明显的降压效果。口服给药4个小时后,抑制肽的降压效果明显好于卡托普利(P < 0.01)。
Establishment of an analysis method for food-derived ACE inhibitory peptides, confirmation of Acaudina molpadioidea protein hydrolytic technics, an antihypertensive effect of hydrolysate by oral administration, purification and structure identification of Acaudina molpadioidea ACE inhibitory peptides and synthesis of ACE inhibitory peptide were studied in this paper.
An analysis method of food-derived ACE inhibitory peptides activity in vitro was established in the paper. In the method, the relationship between hippuric acid concentration and peak area exhibited a good linearity in the concentration ranges of 0～200μg/mL and 200～800μg/mL. The analysis method was further validated by captopril, the oyster hydrolysate and the anchovy hydrolysate, and the results indicate that the method is convenient, accurate and suitable for the analysis of food-derived ACE inhibitory peptides activity in vitro.
The optimal combined-enzymic hydrolytic conditions of Acaudina molpadioidea protein were confirmed in the paper. The IC50 values of the single enzymic hydrolysates were regarded as evaluative index, and bromelain and alcalase were selected as combined-enzyme. Based on the single enzyme and orthogonal tests, the optimal combined-enzymic hydrolytic conditions of Acaudina molpadioidea protein were confirmed. The combined-enzymic hydrolysate was fractionated into two ranges of molecular weight (﹥2 kDa;﹤2 kDa) using an ultrafiltration membrane bioreactor system. The fraction (﹤2 kDa) brought about a high angiotensin-I-converting enzyme (ACE) inhibitory activity, with IC50 value of 0.62 mg/mL. The fraction (﹤2 kDa) was used as drinks administered to renal hypertensive rats (RHR) for 1 month. The systolic blood pressure and diastolic blood pressure of the RHR were significantly reduced, which indicates an antihypertensive effect by oral administration.
Two ACE inhibitory peptides were isolated from the Acaudina molpadioidea combined-enzymic hydrolysate (﹤2 kDa), using the chromatographic methods including gel filtration, ion-exchange chromatography and reversed phase high-performance liquid chromatography. The purified ACE inhibitory peptides were two novel peptides, showing very low similarity to other ACE inhibitory peptide sequences, and were sequenced as MEGAQEAQGD (IC50 value, 15.9μM) and YYLEMDFLLFNY (IC50 value, 30.4μM).
The Acaudina molpadioidea ACE inhibitory peptide (MEGAQEAQGD) was synthesized by a method of gradual condensation and fragmental condensation. The purity of the decapeptide was 99.72%, and the yield was as high as 68.2%. The molecular weight and sequence structure of the decapeptide equate with the fact.
The characters of the Acaudina molpadioidea ACE inhibitory peptide (MEGAQEAQGD) were studied in the paper. It was found that pre-incubation did not change the inhibitory activity of the peptide, and IC50 values for the peptide before and after pre-incubation with ACE were the same (15.9μM). The ACE inhibitory activity of the peptide showed a change after in vitro incubation with gastrointestinal proteases. It was found that the inhibitory activity of the peptide was intensified by 3 times from IC50 15.9μM to IC50 5.3μM after pepsin digestion. The inhibitory activity of the peptide was increased by a factor of 3.5 from IC50 15.9μM to IC50 4.5μM following further chymotrypsin digestion. Therefore, the peptide from Acaudina molpadioidea can be considered pro-drug type ACE inhibitor.
Antihypertensive effect of the decapeptide was evaluated by measuring changes in systolic blood pressure (SBP) of SHR at 1-6 h after oral administration. After 3 h of administrating the ACE inhibitory peptide (3μM/kg per rat), the SBP decreased to 173±2.9 mmHg (compared with negative control group, 192±1.7 mmHg), and the activity was maintained for 5 h. Captopril (3μM/kg per rat) only lowered SBP significantly from 1 to 4 h after administration of the drug. After 4 h of administration, the ACE inhibitory peptide showed more powerfully antihypertensive effect than captopril (P < 0.01).
本文建立了适用于检测食源性ACE抑制肽体外活性的RP-HPLC法。该方法操作简便,重复性好,准确性高。应用该方法对马尿酸浓度与峰面积的相关性进行分析,结果表明马尿酸浓度在0～200μg/mL和200～800μg/mL范围内与峰面积呈现良好的相关性。马尿酸浓度小于200μg/mL时,其重复性最好。经卡托普利、牡蛎酶解液、鳀鱼酶解液验证,表明该方法适用于食源性ACE抑制肽体外活性的测定和化学合成的降压药物。
本文研究了海地瓜蛋白的定向复合酶解工艺。以海地瓜蛋白为原料,选用胰蛋白酶、木瓜蛋白酶、菠萝蛋白酶、3942中性蛋白酶、Ⅰ型胶原酶、alcalase蛋白酶对其进行水解。以单酶水解产物的IC50值为评价指标,确定了菠萝蛋白酶、alcalase蛋白酶、Ⅰ型胶原酶作为目标酶。通过正交实验,确定了这三种单酶的最适水解条件。结果表明:菠萝蛋白酶最适水解条件为:45℃,pH 7.0,底物浓度1.0%,2000 U,4 h;alcalase蛋白酶最适水解条件为:55℃,pH 7.4,底物浓度1.5%,2000 U,2 h;Ⅰ型胶原酶最适水解条件为:37℃,pH 7.4,底物浓度1.0%,1500 U,4 h。在单酶和正交实验的基础上,采用复合酶进行水解实验,得到了最适复合酶水解工艺条件:先采用菠萝蛋白酶进行水解,再用alcalase蛋白酶水解。复合酶水解液分别经过10 KDa、5 KDa、2 KDa的膜超滤,得到了具有更高抑制活性的ACE组分,优化了复合酶解工艺,其水解液的IC50值为0.62 mg/mL。
本文采用两肾一夹型造模手术,成功得到了肾性高血压大鼠。通过长期给药的试验表明,分子量小于2 KDa的海地瓜蛋白水解产物可以显著降低肾性高压大鼠的动脉血压,具有较好的降压效果,且呈剂量依赖性,其中120 mg/kg剂量水解产物的降压效果与卡托普利10 mg/kg相当。
本文利用Sephadex G-25凝胶柱层析、SP Sephadex C-25阳离子交换层析、反相高效液相色谱层析对海地瓜复合酶水解产物进行分离纯化,得到两种高活性的ACE抑制肽-P1(IC50, 0.0496 mg/mL)和P2(IC50, 0.0165 mg/mL),它们的活性分别为复合酶水解液的12.5倍和37.6倍。用反相高效液相色谱C18分析柱鉴定活性肽P1和P2的纯度,按照峰面积计算,活性肽P1的纯度为98.6%,活性肽P2的纯度为100%。应用纳升电喷雾—四极杆—飞行时间串联质谱(Nano-ESI-Ms/Ms)技术,对活性肽P1、P2进行结构鉴定。P1的精确分子量为1629.7 Da,氨基酸序列为YYLEMDFLLFNY,IC50值为30.4μM;P2的精确分子量为1034.5 Da,氨基酸序列为MEGAQEAQGD,IC50值为15.9μM。
本文采用逐步缩合和片断缩合相结合的方法对海地瓜ACE抑制肽MEGAQEAQGD进行了设计合成。首先合成了该十肽的三个片段QGD、QEA、MEGA,然后按照(3+3+4)片段缩合策略最终合成出了MEGAQEAQGD。该十肽的纯度为99.72%,收率为68.2%,分子量与序列结构均与理论值相符。
本文研究了海地瓜ACE抑制肽MEGAQEAQGD的特性。研究发现,ACE酶不会影响抑制肽的稳定性。但是,抑制肽与胃蛋白酶和糜蛋白酶水解反应后,活性却增强了3.5倍,这说明抑制肽属于前体药物型的ACE抑制剂。动物实验表明,灌胃抑制肽(3μM/kg)3个小时后,降压效果最好,自发性高压大鼠的收缩压从192±1.7 mmHg下降到173±2.9 mmHg,并且该活性能持续5个小时。卡托普利组(3μM/kg)只在1-4小时内有明显的降压效果。口服给药4个小时后,抑制肽的降压效果明显好于卡托普利(P < 0.01)。
Establishment of an analysis method for food-derived ACE inhibitory peptides, confirmation of Acaudina molpadioidea protein hydrolytic technics, an antihypertensive effect of hydrolysate by oral administration, purification and structure identification of Acaudina molpadioidea ACE inhibitory peptides and synthesis of ACE inhibitory peptide were studied in this paper.
An analysis method of food-derived ACE inhibitory peptides activity in vitro was established in the paper. In the method, the relationship between hippuric acid concentration and peak area exhibited a good linearity in the concentration ranges of 0～200μg/mL and 200～800μg/mL. The analysis method was further validated by captopril, the oyster hydrolysate and the anchovy hydrolysate, and the results indicate that the method is convenient, accurate and suitable for the analysis of food-derived ACE inhibitory peptides activity in vitro.
The optimal combined-enzymic hydrolytic conditions of Acaudina molpadioidea protein were confirmed in the paper. The IC50 values of the single enzymic hydrolysates were regarded as evaluative index, and bromelain and alcalase were selected as combined-enzyme. Based on the single enzyme and orthogonal tests, the optimal combined-enzymic hydrolytic conditions of Acaudina molpadioidea protein were confirmed. The combined-enzymic hydrolysate was fractionated into two ranges of molecular weight (﹥2 kDa;﹤2 kDa) using an ultrafiltration membrane bioreactor system. The fraction (﹤2 kDa) brought about a high angiotensin-I-converting enzyme (ACE) inhibitory activity, with IC50 value of 0.62 mg/mL. The fraction (﹤2 kDa) was used as drinks administered to renal hypertensive rats (RHR) for 1 month. The systolic blood pressure and diastolic blood pressure of the RHR were significantly reduced, which indicates an antihypertensive effect by oral administration.
Two ACE inhibitory peptides were isolated from the Acaudina molpadioidea combined-enzymic hydrolysate (﹤2 kDa), using the chromatographic methods including gel filtration, ion-exchange chromatography and reversed phase high-performance liquid chromatography. The purified ACE inhibitory peptides were two novel peptides, showing very low similarity to other ACE inhibitory peptide sequences, and were sequenced as MEGAQEAQGD (IC50 value, 15.9μM) and YYLEMDFLLFNY (IC50 value, 30.4μM).
The Acaudina molpadioidea ACE inhibitory peptide (MEGAQEAQGD) was synthesized by a method of gradual condensation and fragmental condensation. The purity of the decapeptide was 99.72%, and the yield was as high as 68.2%. The molecular weight and sequence structure of the decapeptide equate with the fact.
The characters of the Acaudina molpadioidea ACE inhibitory peptide (MEGAQEAQGD) were studied in the paper. It was found that pre-incubation did not change the inhibitory activity of the peptide, and IC50 values for the peptide before and after pre-incubation with ACE were the same (15.9μM). The ACE inhibitory activity of the peptide showed a change after in vitro incubation with gastrointestinal proteases. It was found that the inhibitory activity of the peptide was intensified by 3 times from IC50 15.9μM to IC50 5.3μM after pepsin digestion. The inhibitory activity of the peptide was increased by a factor of 3.5 from IC50 15.9μM to IC50 4.5μM following further chymotrypsin digestion. Therefore, the peptide from Acaudina molpadioidea can be considered pro-drug type ACE inhibitor.
Antihypertensive effect of the decapeptide was evaluated by measuring changes in systolic blood pressure (SBP) of SHR at 1-6 h after oral administration. After 3 h of administrating the ACE inhibitory peptide (3μM/kg per rat), the SBP decreased to 173±2.9 mmHg (compared with negative control group, 192±1.7 mmHg), and the activity was maintained for 5 h. Captopril (3μM/kg per rat) only lowered SBP significantly from 1 to 4 h after administration of the drug. After 4 h of administration, the ACE inhibitory peptide showed more powerfully antihypertensive effect than captopril (P < 0.01).
引文
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