泥鳅蛋白源ACE抑制肽的酶法制备及其降压活性研究
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摘要
论文以泥鳅蛋白为原料,运用可控酶解技术,制备高活性降血压肽。经过超滤、凝胶过滤、反相高效液相色谱层析及质谱测序等技术分离、纯化并鉴定泥鳅降血压肽,通过体外、体内活性试验确定降血压肽的降压活性。采用z-scales;描述符构建了ACE抑制四肽的定量构效关系模型,为指导和设计新化合物提供理论依据。
首先分析了泥鳅的基本营养成分,从氨基酸组成的角度评估其营养价值。泥鳅的蛋白含量17.4%,脂肪含量仅1.5%,灰分1.3%,水分77.2%,是一种典型的高蛋白低脂肪食品。除蛋氨酸外,蛋白质中的必需氨基酸含量都高于FAO/WHO模式。泥鳅蛋白的必需氨基酸总含量达到42.52%,高于WHO衡量理想蛋白资源推荐的比值36%。蛋氨酸和半胱氨酸是泥鳅蛋白的第一限制性氨基酸。功效比值PER Ⅰ值为2.9,PERⅡ值为2.9,PERⅢ值为2.3,氨基酸组成平衡性很好。高含量的疏水性氨基酸(47.9%)、芳香族氨基酸(13.3%)以及支链氨基酸(17.7%)是酶法生产ACE抑制肽的优良物质基础。
广泛选取植物来源、动物来源及微生物来源的木瓜蛋白酶、菠萝蛋白酶、胰凝乳蛋白酶、中性蛋白酶、胃蛋白酶、酸性蛋白酶、复合蛋白酶、碱性蛋白酶和胰蛋白酶水解泥鳅蛋白,通过比较9种不同蛋白酶水解产物的半抑制浓度IC50,得到酶解泥鳅蛋白的最适用酶为菠萝蛋白酶。通过单因素和响应面法优化酶解工艺,得到高活性ACE抑制肽的最佳制备工艺：[E]/[S]4.9‰,底物浓度30%,pH6.5,温度54.4℃,酶解时间5.9h。泥鳅蛋白降血压肽的ACE抑制率(Y)对[E]/[S](A)、温度(B)和酶解时间(C)的二次多项回归方程：Y=82.17+4.81A+5.57B+3.86C-4.1682-3.97AB+4.27AC。在最佳酶解条件下,菠萝蛋白酶水解泥鳅蛋白的酶解产物中疏水性氨基酸、芳香族氨基酸和支链氨基酸的含量显著增加,泥鳅多肽的ACE抑制率为88.9%。
论文使用超滤、Sephadex G-15凝胶柱层析、AKTA半制备反相高效液相色谱和分析型反相高效液相色谱等多级分离技术,根据酶解产物中肽的分子量大小及疏水性差异逐级纯化,得到目标肽段的IC50值为18.2士0.9μg/mL,纯化倍数33.7,蛋白回收率5.2%。通过TOF-MS/MS质谱技术鉴定目标肽段的氨基酸序列为Ala-His-Leu-Leu,相对分子质量452.2Da。经肽谱库和文摘检索,该肽段为首次发现的ACE抑制四肽。
泥鳅多肽在较宽的pH值(3-9)范围内具有优良的溶解性能,氮溶解指数均在70%以上。溶液pH7.0时,泥鳅多肽具有较好的乳化能力(60.8%)和乳化稳定性(68.6%)。泥鳅蛋白水解后,起泡性及起泡稳定性分别降低15.8%和15.5%；DPPH-清除率和ABTS·+清除率分别提高6.1倍和2.7倍,抗氧化能力显著增强(P<0.05)。温度≤80℃的中性条件下加热2h,泥鳅降血压肽的ACE抑制率没有显著变化(P>0.05)；100℃下加热2h,泥鳅降血压肽的ACE抑制率仍保持80%左右。在酸性至中性范围内,泥鳅降血压肽的ACE抑制活性变化不显著；当pH≥8时,其降压活性与pH值呈现负相关性。与喷雾干燥相比,冷冻干燥后所得产品的颗粒较大、复溶速度较快、降压活力的损失较低。室温下,泥鳅多肽溶液中添加5mmol/L金属离子静置2h,Mg2+对降压活性起到促进作用,Zn2+和Mn2+抑制了多肽的降压活性。泥鳅多肽溶液中添加食品配料,在121℃加热反应20min,结果显示：随着葡萄糖浓度的升高,泥鳅多肽的ACE抑制活性逐渐降低,褐变程度加深；氯化钠在低浓度范围内,对降压活性的影响显著,当浓度≥9%时,其降压活性与氯化钠浓度呈现负相关性。
泥鳅降压肤的抑制类型为竞争性抑制,泥鳅多肽与底物竞争性结合ACE的活性结合部位,从而起到抑制ACE活性的作用。在模拟胃肠道消化体系中,胃蛋白酶的消化作用显著提高了产物的降压活性。但是经过胰蛋白酶消化后,泥鳅多肽的ACE抑制活性显著下降(P<0.05)。泥鳅多肽属于底物型ACE抑制肽。
以原发性高血压大鼠(SHR)为动物模型,采用尾脉搏法测定大鼠的收缩压,从急性和长期实验评价泥鳅多肽的体内降压效果。急性降压试验中,一次性灌胃14h,收缩压达到最低值,血压降低29mmHg,之后血压出现回升。SHR灌胃泥鳅多肽2个月,大鼠心率无显著变化；SHR大鼠的体重显著低于空白对照组(P<0.05)。在灌胃泥鳅多肽的8周期间,SHR高剂量组0周的平均收缩压为195.0mmHg,4周降到最低点165.1mmHg,随后血压值略有升高,8周高剂量组和低剂量组的SBP值分别降低24.3mmHg和10.5mmHg,均表现出良好的降血压效果。与对照组相比,SHR高剂量组大鼠的腹主动脉体重比显著上升(P<0.05),心体重比显著下降(P<0.05),泥鳅多肽起到了一定保护器官的作用。SHR高剂量组大鼠血清中甘油三酯含量显著降低(P<0.05),钠离子浓度显著降低(P<0.05)。8周后大鼠血清与腹组织中的丙二醛含量显著降低(P<0.05),泥鳅多肽对SHR大鼠部分器官和血清的脂质过氧化损伤起到缓解和抑制作用。SHR高剂量组大鼠的血清中总游离氨基酸含量高于空白对照组和阳性对照组,其中His、Ala、Glu、Leu、Ile的含量明显增高(P<0.05)。SHR高剂量组大鼠的腹主动脉ACE酶活性显著降低17.6%(P<0.05),推断泥鳅多肽的作用靶点位于腹主动脉。
泥鳅蛋白酶解物中分离到一种高活性的降血压四肽,论文对四肽的定量构效关系进行深入研究。采用z-scales描述符,对92组ACE抑制四肽进行编码,通过Matlab软件偏最小二乘法对多元数据进行回归分析,得到ACE抑制四肽的QSAR模型：y=2.1519+0.0704x1+0.0443x2+0.0166x3+0.0302x4-0.0758x5-0.0084x6-0.031x7+0.1372x8-0.0629x9+0.0256x10+0.0396x11+0.035x12。模型的相关系数R为0.7489,交叉验证相关系数Rcv2为0.5956,预测能力和拟合度较强。泥鳅蛋白源的ACE抑制四肽AHLL对QSAR;模型进行检验,模型的预测结果准确性高。
ACE inhibitory peptides were prepared from loach protein through controlled enzymatic technology. Separation and isolation of the activity peptides from the loach protein hydrolysate(LPH) by a series of purification technology, including ultrafiltration, gel filtration chromatograghy and reversed-phase high performance chromatography. The sequence of the active peptide was identified by mass spectrum technology. The antihypertensive effect of LPH were evaluated in vitro and in vivo. It provided a theoretical basis of functional food development. Model of QSAR was proposed for tetra-peptide inhibitors of ACE based on z-scales. It provided a theoretical basis of new compounds design.
The basic nutritional components of loach were analyzed first. Its nutritional value was assessed from the point of amino acid analysis. The chemical composition of loach was analyzed as follows:77.2%moisture,1.3%ash,1.5%fat,17.4%protein. It was a typical high protein food. Most of the essential amino acid contents were very close to FAO/WHO mode, except to methionine and cysteine which was the first limiting amino acids. The total content of essential amino acids reached42.5%, higher than the WHO recommended ratio of36%for measuring ideal protein resources. Efficiency ratio was PER I of2.9, PERⅡ of2.9and PER Ⅲ of2.3. The high content of hydrophobic amino acids (47.9%), aromatic amino acids (13.3%) and branched chain amino acids (17.7%) were the excellent material source of ACE inhibitory peptides by enzymolysis.
A wide range of proteases were selected from plant, animal sources to microbial origin including pepsin, acidic protease, α-chymotrypsin, protamex, bromelain, papain, alcalase, trypsin and neutrase.9different proteases were applied to hydrolyze the loach protein, and bromelain was chosen to be the best one for the enzymatic hydrolysis through the comparison of half inhibitory concentration IC50of hydrolysates. On the basis of single-factor test, taking ACE inhibitory rate as response value, the effect of enzymatic temperature, the ratio of enzyme to substrate([E]/[S]) and hydrolysis time were optimized with Box-Behnken design and response surface methodology(RSM). The results showed that the optimum conditions were as follows:[E]/[S]4.9‰, substrate concentration30%, pH6.5, enzymatic temperature at54.4℃for5.9h. The two multiple regression equation for ACE inhibitory rate (Y) were as follows:Y=82.17+4.81A+5.57B+3.86C-4.16B2-3.97AB+4.27AC, where the [E]/[S](A), temperature (B) and hydrolysis time (C) were independent variables. In optimum conditions, hydrophobic amino acids, aromatic amino acids and branched chain amino acids content in hydrolysates were increased significantly, and the ACE inhibitory rate reached88.9%.
Loach peptides were isolated and purified by ultrafiltration, gel filtration chromatography Sephadex G-15and a two-step reverse high-performance liquid chromatography(RP-HPLC) according to the molecular size and hydrophobicity differences step by step. The purified antihypertensive peptide was identified as Ala-His-Leu-Leu (452.2Da) using electrospray ionization(ESI) mass spectrometer. The purified peptide with IC50value of18.2±0.9μ.g/mL showed a33.7-fold higher ACE inhibitory activity compared with the crude loach peptides, and protein recovery was5.2%. The purified peptide is the first tetrapeptide with significant angiotensin-Ⅰ-converting enzyme inhibitory activity to be found.
LPH had nice water-soluble ability with NSIs of70%above over a wide rang of pH(3-9). After the hydrolysis of loach protein, foaming and foam stability were decreased by15.8%and15.5%. Loach peptides exhibited good emulsifying capacity and emulsion stability, which were60.8%and68.6%respectively at pH7.0. The antioxidant ability increases significantly (P<0.05). DPPH·and ABTS·+removal rate of LPH were increased6.1-fold and2.7-fold. The stability experiment showed that ACE inhibitory activity didn't decrease after2h heating below80℃, and it still maintained80%after2h heating at100℃. Loach peptides remained at high active stability from pH2.0to8.0. ACE inhibitory activity of loach peptides decreased with pH rise above8.0. Based on evaluation of ACE inhibitory activity, freeze drying was better than spray drying. Mg2+promoted the angiotensin-Ⅰ-converting enzyme inhibitory activity, while Zn2+and Mn2+inhibited the angiotensin-Ⅰ-converting enzyme inhibitory activity with metal ion concentration of5mmol/L for2h at room temperature. With the increase of glucose concentration, the ACE inhibition activity gradually decreased and browned after the reaction at121℃for20min. Sodium chloride had no significant effect on antihypertensive activity. When its concentration was more than9%, the ACE inhibitory activity and sodium chloride concentrations showed a negative correlation.
Loach peptide exhibited the ACE inhibitory activity because that it competed with the substrate binding ACE enzyme activity sites. Thus, it belonged to competitive inhibition. In simulated gastrointestinal digestion system, peptides hydrolyzed by pepsin exhibited higher angiotensin-I-converting enzyme inhibitory activity than before. But it was lower after further hydrolyzed by trypsin. Loach peptides belonged to the substrate type of ACE inhibitor.
Hypertension animal model SHR was used to evaluate the antihypertensive effect of the peptides, systolic blood pressure (SBP) of the animal were test by a tail cuff blood pressure analyzer through acute and long-term animal studies. In the acute experiment, the maximal decrease of29mmHg in SBP caused by30mg/kg BW of LPH was observed after14h post-administration. In the eight months animal administration of LPH, there was no effect on heart rate. Body weight of SHR was significantly lower than that of control group (P<0.05). After4weeks administration, the SBP of the high doze group showed the maximal reduction from195.0mmHg to165.1mmHg. The reductions of systolic blood pressure(SBP) after8weeks were24.3mmHg and10.5mmHg for high doze group and low doze group respectively. Compared to the model control group, abdomen aorta/body weight ratio increased significantly (P<0.05), heart/body weight ratio decreased significantly (P<0.05), loach peptides played a positive role of organ protection. Serum triglyceride concentration, sodium concentration and MDA concentration in serum and abdomen aorta were reduced significantly(P<0.05) in high doze group after2months administration. Loach peptides contributed to easing lipid peroxidation of some organ or serum. The total free amino acid content in serum of high doze SHR group was higher than that of the blank control group and positive control group, in which His, Ala, Glu, Leu, Ile were significantly increased (P<0.05). LHP exerted its antihypertensive effect on the abdomen aorta, and the activity of the tissue was significantly decreased17.6%(P<0.05).
The traditional model can well explain the ACE inhibition of the di-peptides or the tri-peptides. But the QSAR of tetra-peptides or above still need further research. A tetra-peptide was prepared from loach protein, the QSAR of the tetra-peptides was further explored in this paper. Using z-scales descriptor,92tetra-peptides was encoded. Through partial least squares regression analysis of multivariate data by the Matlab software, the QSAR model of ACE inhibitory tetra-peptides was established as follows:y=2.1519+0.0704x1+0.0443x2+0.0166x3+0.0302x4-0.0758x5-0.0084x6-0.031x7+0.1372x8-0.0629x9+0.0256x10+0.0396x11+0.035x12. The correlation coefficient (R) was0.7489, cross-validation correlation coefficient (Rcv2) was0.5956. The model was validated with tetra-peptide AHLL from loach protein hydrolysates. The results showed that the QSAR model constructed in this paper exhibited a good generalization performance, which could predict the activity of ACE inhibitory tetra-peptide exactly.
首先分析了泥鳅的基本营养成分,从氨基酸组成的角度评估其营养价值。泥鳅的蛋白含量17.4%,脂肪含量仅1.5%,灰分1.3%,水分77.2%,是一种典型的高蛋白低脂肪食品。除蛋氨酸外,蛋白质中的必需氨基酸含量都高于FAO/WHO模式。泥鳅蛋白的必需氨基酸总含量达到42.52%,高于WHO衡量理想蛋白资源推荐的比值36%。蛋氨酸和半胱氨酸是泥鳅蛋白的第一限制性氨基酸。功效比值PER Ⅰ值为2.9,PERⅡ值为2.9,PERⅢ值为2.3,氨基酸组成平衡性很好。高含量的疏水性氨基酸(47.9%)、芳香族氨基酸(13.3%)以及支链氨基酸(17.7%)是酶法生产ACE抑制肽的优良物质基础。
广泛选取植物来源、动物来源及微生物来源的木瓜蛋白酶、菠萝蛋白酶、胰凝乳蛋白酶、中性蛋白酶、胃蛋白酶、酸性蛋白酶、复合蛋白酶、碱性蛋白酶和胰蛋白酶水解泥鳅蛋白,通过比较9种不同蛋白酶水解产物的半抑制浓度IC50,得到酶解泥鳅蛋白的最适用酶为菠萝蛋白酶。通过单因素和响应面法优化酶解工艺,得到高活性ACE抑制肽的最佳制备工艺：[E]/[S]4.9‰,底物浓度30%,pH6.5,温度54.4℃,酶解时间5.9h。泥鳅蛋白降血压肽的ACE抑制率(Y)对[E]/[S](A)、温度(B)和酶解时间(C)的二次多项回归方程：Y=82.17+4.81A+5.57B+3.86C-4.1682-3.97AB+4.27AC。在最佳酶解条件下,菠萝蛋白酶水解泥鳅蛋白的酶解产物中疏水性氨基酸、芳香族氨基酸和支链氨基酸的含量显著增加,泥鳅多肽的ACE抑制率为88.9%。
论文使用超滤、Sephadex G-15凝胶柱层析、AKTA半制备反相高效液相色谱和分析型反相高效液相色谱等多级分离技术,根据酶解产物中肽的分子量大小及疏水性差异逐级纯化,得到目标肽段的IC50值为18.2士0.9μg/mL,纯化倍数33.7,蛋白回收率5.2%。通过TOF-MS/MS质谱技术鉴定目标肽段的氨基酸序列为Ala-His-Leu-Leu,相对分子质量452.2Da。经肽谱库和文摘检索,该肽段为首次发现的ACE抑制四肽。
泥鳅多肽在较宽的pH值(3-9)范围内具有优良的溶解性能,氮溶解指数均在70%以上。溶液pH7.0时,泥鳅多肽具有较好的乳化能力(60.8%)和乳化稳定性(68.6%)。泥鳅蛋白水解后,起泡性及起泡稳定性分别降低15.8%和15.5%；DPPH-清除率和ABTS·+清除率分别提高6.1倍和2.7倍,抗氧化能力显著增强(P<0.05)。温度≤80℃的中性条件下加热2h,泥鳅降血压肽的ACE抑制率没有显著变化(P>0.05)；100℃下加热2h,泥鳅降血压肽的ACE抑制率仍保持80%左右。在酸性至中性范围内,泥鳅降血压肽的ACE抑制活性变化不显著；当pH≥8时,其降压活性与pH值呈现负相关性。与喷雾干燥相比,冷冻干燥后所得产品的颗粒较大、复溶速度较快、降压活力的损失较低。室温下,泥鳅多肽溶液中添加5mmol/L金属离子静置2h,Mg2+对降压活性起到促进作用,Zn2+和Mn2+抑制了多肽的降压活性。泥鳅多肽溶液中添加食品配料,在121℃加热反应20min,结果显示：随着葡萄糖浓度的升高,泥鳅多肽的ACE抑制活性逐渐降低,褐变程度加深；氯化钠在低浓度范围内,对降压活性的影响显著,当浓度≥9%时,其降压活性与氯化钠浓度呈现负相关性。
泥鳅降压肤的抑制类型为竞争性抑制,泥鳅多肽与底物竞争性结合ACE的活性结合部位,从而起到抑制ACE活性的作用。在模拟胃肠道消化体系中,胃蛋白酶的消化作用显著提高了产物的降压活性。但是经过胰蛋白酶消化后,泥鳅多肽的ACE抑制活性显著下降(P<0.05)。泥鳅多肽属于底物型ACE抑制肽。
以原发性高血压大鼠(SHR)为动物模型,采用尾脉搏法测定大鼠的收缩压,从急性和长期实验评价泥鳅多肽的体内降压效果。急性降压试验中,一次性灌胃14h,收缩压达到最低值,血压降低29mmHg,之后血压出现回升。SHR灌胃泥鳅多肽2个月,大鼠心率无显著变化；SHR大鼠的体重显著低于空白对照组(P<0.05)。在灌胃泥鳅多肽的8周期间,SHR高剂量组0周的平均收缩压为195.0mmHg,4周降到最低点165.1mmHg,随后血压值略有升高,8周高剂量组和低剂量组的SBP值分别降低24.3mmHg和10.5mmHg,均表现出良好的降血压效果。与对照组相比,SHR高剂量组大鼠的腹主动脉体重比显著上升(P<0.05),心体重比显著下降(P<0.05),泥鳅多肽起到了一定保护器官的作用。SHR高剂量组大鼠血清中甘油三酯含量显著降低(P<0.05),钠离子浓度显著降低(P<0.05)。8周后大鼠血清与腹组织中的丙二醛含量显著降低(P<0.05),泥鳅多肽对SHR大鼠部分器官和血清的脂质过氧化损伤起到缓解和抑制作用。SHR高剂量组大鼠的血清中总游离氨基酸含量高于空白对照组和阳性对照组,其中His、Ala、Glu、Leu、Ile的含量明显增高(P<0.05)。SHR高剂量组大鼠的腹主动脉ACE酶活性显著降低17.6%(P<0.05),推断泥鳅多肽的作用靶点位于腹主动脉。
泥鳅蛋白酶解物中分离到一种高活性的降血压四肽,论文对四肽的定量构效关系进行深入研究。采用z-scales描述符,对92组ACE抑制四肽进行编码,通过Matlab软件偏最小二乘法对多元数据进行回归分析,得到ACE抑制四肽的QSAR模型：y=2.1519+0.0704x1+0.0443x2+0.0166x3+0.0302x4-0.0758x5-0.0084x6-0.031x7+0.1372x8-0.0629x9+0.0256x10+0.0396x11+0.035x12。模型的相关系数R为0.7489,交叉验证相关系数Rcv2为0.5956,预测能力和拟合度较强。泥鳅蛋白源的ACE抑制四肽AHLL对QSAR;模型进行检验,模型的预测结果准确性高。
ACE inhibitory peptides were prepared from loach protein through controlled enzymatic technology. Separation and isolation of the activity peptides from the loach protein hydrolysate(LPH) by a series of purification technology, including ultrafiltration, gel filtration chromatograghy and reversed-phase high performance chromatography. The sequence of the active peptide was identified by mass spectrum technology. The antihypertensive effect of LPH were evaluated in vitro and in vivo. It provided a theoretical basis of functional food development. Model of QSAR was proposed for tetra-peptide inhibitors of ACE based on z-scales. It provided a theoretical basis of new compounds design.
The basic nutritional components of loach were analyzed first. Its nutritional value was assessed from the point of amino acid analysis. The chemical composition of loach was analyzed as follows:77.2%moisture,1.3%ash,1.5%fat,17.4%protein. It was a typical high protein food. Most of the essential amino acid contents were very close to FAO/WHO mode, except to methionine and cysteine which was the first limiting amino acids. The total content of essential amino acids reached42.5%, higher than the WHO recommended ratio of36%for measuring ideal protein resources. Efficiency ratio was PER I of2.9, PERⅡ of2.9and PER Ⅲ of2.3. The high content of hydrophobic amino acids (47.9%), aromatic amino acids (13.3%) and branched chain amino acids (17.7%) were the excellent material source of ACE inhibitory peptides by enzymolysis.
A wide range of proteases were selected from plant, animal sources to microbial origin including pepsin, acidic protease, α-chymotrypsin, protamex, bromelain, papain, alcalase, trypsin and neutrase.9different proteases were applied to hydrolyze the loach protein, and bromelain was chosen to be the best one for the enzymatic hydrolysis through the comparison of half inhibitory concentration IC50of hydrolysates. On the basis of single-factor test, taking ACE inhibitory rate as response value, the effect of enzymatic temperature, the ratio of enzyme to substrate([E]/[S]) and hydrolysis time were optimized with Box-Behnken design and response surface methodology(RSM). The results showed that the optimum conditions were as follows:[E]/[S]4.9‰, substrate concentration30%, pH6.5, enzymatic temperature at54.4℃for5.9h. The two multiple regression equation for ACE inhibitory rate (Y) were as follows:Y=82.17+4.81A+5.57B+3.86C-4.16B2-3.97AB+4.27AC, where the [E]/[S](A), temperature (B) and hydrolysis time (C) were independent variables. In optimum conditions, hydrophobic amino acids, aromatic amino acids and branched chain amino acids content in hydrolysates were increased significantly, and the ACE inhibitory rate reached88.9%.
Loach peptides were isolated and purified by ultrafiltration, gel filtration chromatography Sephadex G-15and a two-step reverse high-performance liquid chromatography(RP-HPLC) according to the molecular size and hydrophobicity differences step by step. The purified antihypertensive peptide was identified as Ala-His-Leu-Leu (452.2Da) using electrospray ionization(ESI) mass spectrometer. The purified peptide with IC50value of18.2±0.9μ.g/mL showed a33.7-fold higher ACE inhibitory activity compared with the crude loach peptides, and protein recovery was5.2%. The purified peptide is the first tetrapeptide with significant angiotensin-Ⅰ-converting enzyme inhibitory activity to be found.
LPH had nice water-soluble ability with NSIs of70%above over a wide rang of pH(3-9). After the hydrolysis of loach protein, foaming and foam stability were decreased by15.8%and15.5%. Loach peptides exhibited good emulsifying capacity and emulsion stability, which were60.8%and68.6%respectively at pH7.0. The antioxidant ability increases significantly (P<0.05). DPPH·and ABTS·+removal rate of LPH were increased6.1-fold and2.7-fold. The stability experiment showed that ACE inhibitory activity didn't decrease after2h heating below80℃, and it still maintained80%after2h heating at100℃. Loach peptides remained at high active stability from pH2.0to8.0. ACE inhibitory activity of loach peptides decreased with pH rise above8.0. Based on evaluation of ACE inhibitory activity, freeze drying was better than spray drying. Mg2+promoted the angiotensin-Ⅰ-converting enzyme inhibitory activity, while Zn2+and Mn2+inhibited the angiotensin-Ⅰ-converting enzyme inhibitory activity with metal ion concentration of5mmol/L for2h at room temperature. With the increase of glucose concentration, the ACE inhibition activity gradually decreased and browned after the reaction at121℃for20min. Sodium chloride had no significant effect on antihypertensive activity. When its concentration was more than9%, the ACE inhibitory activity and sodium chloride concentrations showed a negative correlation.
Loach peptide exhibited the ACE inhibitory activity because that it competed with the substrate binding ACE enzyme activity sites. Thus, it belonged to competitive inhibition. In simulated gastrointestinal digestion system, peptides hydrolyzed by pepsin exhibited higher angiotensin-I-converting enzyme inhibitory activity than before. But it was lower after further hydrolyzed by trypsin. Loach peptides belonged to the substrate type of ACE inhibitor.
Hypertension animal model SHR was used to evaluate the antihypertensive effect of the peptides, systolic blood pressure (SBP) of the animal were test by a tail cuff blood pressure analyzer through acute and long-term animal studies. In the acute experiment, the maximal decrease of29mmHg in SBP caused by30mg/kg BW of LPH was observed after14h post-administration. In the eight months animal administration of LPH, there was no effect on heart rate. Body weight of SHR was significantly lower than that of control group (P<0.05). After4weeks administration, the SBP of the high doze group showed the maximal reduction from195.0mmHg to165.1mmHg. The reductions of systolic blood pressure(SBP) after8weeks were24.3mmHg and10.5mmHg for high doze group and low doze group respectively. Compared to the model control group, abdomen aorta/body weight ratio increased significantly (P<0.05), heart/body weight ratio decreased significantly (P<0.05), loach peptides played a positive role of organ protection. Serum triglyceride concentration, sodium concentration and MDA concentration in serum and abdomen aorta were reduced significantly(P<0.05) in high doze group after2months administration. Loach peptides contributed to easing lipid peroxidation of some organ or serum. The total free amino acid content in serum of high doze SHR group was higher than that of the blank control group and positive control group, in which His, Ala, Glu, Leu, Ile were significantly increased (P<0.05). LHP exerted its antihypertensive effect on the abdomen aorta, and the activity of the tissue was significantly decreased17.6%(P<0.05).
The traditional model can well explain the ACE inhibition of the di-peptides or the tri-peptides. But the QSAR of tetra-peptides or above still need further research. A tetra-peptide was prepared from loach protein, the QSAR of the tetra-peptides was further explored in this paper. Using z-scales descriptor,92tetra-peptides was encoded. Through partial least squares regression analysis of multivariate data by the Matlab software, the QSAR model of ACE inhibitory tetra-peptides was established as follows:y=2.1519+0.0704x1+0.0443x2+0.0166x3+0.0302x4-0.0758x5-0.0084x6-0.031x7+0.1372x8-0.0629x9+0.0256x10+0.0396x11+0.035x12. The correlation coefficient (R) was0.7489, cross-validation correlation coefficient (Rcv2) was0.5956. The model was validated with tetra-peptide AHLL from loach protein hydrolysates. The results showed that the QSAR model constructed in this paper exhibited a good generalization performance, which could predict the activity of ACE inhibitory tetra-peptide exactly.
引文
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