南瓜籽蛋白血管紧张素转化酶抑制肽的研究
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摘要
本论文以南瓜籽为原料,系统地研究了南瓜籽蛋白中ACE抑制肽(ACEIP)的酶法提取工艺条件、分离纯化、结构表征及其降压机理。采用六种蛋白酶分别对南瓜籽蛋白进行水解,研究了不同蛋白酶水解产物的ACE抑制能力；筛选出了适于制备南瓜籽蛋白ACE抑制肽的蛋白酶,并采用响应面方法对其工艺条件进行优化；利用凝胶柱层析、RP-HPLC和UHPLC-Q-TOF等技术对得到的ACE抑制肽进行分离纯化和分析鉴定；并通过研究南瓜籽ACE抑制肽对人脐静脉内皮细胞(HUVECs)功能的影响,采用实时荧光定量PCR技术测定相关基因的表达来研究其降血压的效果及其机理。为南瓜籽蛋白ACE抑制肽的研究开发提供了理论依据和技术支撑。主要研究结果如下：
1采用双向电泳技术测定了脱油以后的南瓜籽的蛋白质含量、蛋白质等电点和分子量等,结果表明：脱油后的南瓜籽蛋白含量高达75.63%,其等电点和分子量分别为pH5-7,22KDa-42KDa。采用全自动氨基酸分析仪测定了南瓜籽蛋白质中性蛋白酶酶解液的氨基酸组成,发现其疏水性氨基酸含量为34.40g/100g蛋白、芳香族氨基酸为11.49g/100g蛋白及脯氨酸的含量为6.68g/100g蛋白,支链氨基酸含量为12.29g/100g蛋白,蛋白质的平均疏水性为4.189kJ/mol,得出南瓜籽蛋白及其酶解液中与ACE抑制活性呈正相关的氨基酸含量丰富,组成合理,是一种理想的蛋白源,可以作为酶法生产降血压肽的原料。
2以南瓜籽粕为底物,酶解产物的ACE抑制能力为衡量指标,从胰蛋白酶、水解蛋白酶、木瓜蛋白酶、中性蛋白酶、Protease N和Protease S酶六种蛋白酶中优选出中性蛋白酶为南瓜籽蛋白制备ACE抑制肽的酶制剂。在单因素试验的基础上,采用响应面对中性蛋白酶水解南瓜籽蛋白的试验条件进行优化,结合各因素对响应值的影响顺序以及综合考虑到成本问题,在中性蛋白酶最适作用温度45℃和pH7.0下,选择最佳酶解条件为：酶浓度为4.8%、底物浓度为4.0%、水解时间为320min,在此优化的条件下,得到ACE抑制率为80.56±0.23%。
3利用Sephadex G-75凝胶色谱分离南瓜籽粕蛋白中性蛋白酶酶解物,得到四个组分,分别为Z1(MW>14220Da), Z2(MW14200-8400Da), Z3(MW8400-4000Da), Z4(MW<4000Da),组分Z4的ACE抑制率达到了80.23±0.21%；选择Z4再进行Sephadex G-15凝胶色谱分离,得到三个组分为Z4-1,Z4-2和Z4-3,其中Z4-2ACE抑制率为81.56±0.41%,选择Z4-2进行进一步的分离纯化。利用RP-HPLC纯化组分Z4-2共得到7个组分,分别命名为Rl、R2、R3、R4、R5、R6和R7,经ACE抑制活性测定,组分R4ACE抑制活性最强,达到79.63±0.32%,经二次RP-HPLC鉴定R4为单一组分,经过ESI-MS-MS串联质谱分析鉴定ACE抑制肽R4的相对分子量为905.67Da,氨基酸序列为L(/I)L(/I)L(/I)SHDL(/I)V[Leu (/Ile)-Leu(/Ile)-Leu(/Ile)-Ser-His-Asp-Leu(/Ile)-Val],为一种新的ACE抑制肽。
4南瓜籽ACE抑制肽对脐静脉内皮细胞功能的影响结果表明,PSMP对细胞的抑制效果与其浓度和作用时间成正比,与常用降血压药卡托普利的作用机理类似,将细胞阻滞于S期,从而达到了抑制细胞增殖的作用。在相同的培养时间内,ACE抑制肽能显著降低细胞培养上清液中ET-1的含量,由此可见ACE抑制肽可以通过降低血管中ET-1的含量达到降血压的目的,但如浓度太低,效果不显著。实时荧光定量PCR测定ACE抑制肽对ET-1,ACE和ACE2基因mRNA表达的结果表明,ACE抑制肽和卡托普利都能引起ET1-1mRNA、ACE mRNA表达量的下调,随着剂量的增加,其表达量下调效果越大。试验结果还表明AngII生成量的变化可能受ACE/ACE2mRNA表达变化量的影响。采用邻苯三酚自氧化法检测了PSMP对超氧阴离子清除效果,表明PSMPs具有一定的清除超氧阴离子自由基的能力；采用考马斯亮蓝法测定血管内皮细胞蛋白质含量,研究PSMPs对内皮细胞抗氧化损伤能力的影响,结果表明PSMPs能降低内皮细胞受损程度,从而降低高血压的发生。综上所述,南瓜籽肽的降血压效果明确,其机制可能与其抑制血管内皮细胞的增殖、清除超氧阴离子自由基、抑制ACE的活性、促进ACE2mRNA的表达量、抑制ACE和ET-1mRNA的表达量,从而降低AngⅡ和ET-1的含量有关。PSMP是一种值得大力研发的降血压天然产品。
This paper studied the collection, isolation, purification of the pumpkin seeds meal peptides (PSMPS) and its cardiovascular functional effects and mechanisms using pumpkin seed meal (PSM) as raw materials. The meal was hydrolyzed by six proteases and those productions inhibiting ability of angiotensin-coverting enzyme (ACE) were analyzed, some proteases PSMPs were screened for making ACEI and their process condition was optimized by Response Surface Analysis. The PSMPs' were collected, isolated, purified and analyzed through many methods including Gel column chromatography, RP-HPLC and UHPLC-Q-TOF technology. The PSMPs' effects on proliferation of human umbilical vein endothelial cells (HUVECs) and expression of some related genes'mRNA were analyzed by Real time fluorescence quantitative PCR technology so as to analyze the PSMPs'cardiovascular functional and mechanisms. The main results are showed as follows:
1. The protein content, isoelectric point and molecular weight of oil removed PSMs were tested by two dimensional electrophoresis technology, the result showed their protein content was75.63%, its isoelectric point was pH5-7and Molecular weight were22KDa-42Kda.The amino acid composition analysis of enzymatic hydrolysate of PSM's neutral protease by automatic amino acid analyzer showed there were34.40g hydrophobic amino acid,11.49g aromatic amino acid,6.68g Proline and12.92g branched chain amino acid in100g protein, its average hydrophobicity was4.189kJ/mol. These results indicated that the protein of PSM and its enzymatic hydrolysate had great amino acid positive related to ACEI activity, its composition was good for producing antihypertensive peptides through enzyme method.
2.Six Protease including Trypsin, Hydrolysis protease, Papain, Neutral protease, Protease N and Protease S were screened for producing ACEI Peptides according to their ACE Inhibiting ability. The Neutral protease was the best and its hydrolysis reaction factors were optimized using Response Surface Analysis. The results showed its best reaction condition were45℃and pH7.0, the protease content was4.8%, Substrate content was4.0%, Hydrolysis time was320min, the ACE inhibiting percentage could be80.56±0.23%under the condition.
3. four compositions were isolated from enzymatic hydrolysates of PSM using Sephadex G-75Gel chromatography, they were Z1(MW>14220Da), Z2(MW14200 -8400Da), Z3(MW8400-4000Da), Z4(MW<4000Da), respectively, the Z4had80.23±0.21%inhibitory percentage. The Z4was isolated by Sephadex G-15Gel chromatography,3compositions were isolated and named Z4-1, Z4-2和Z4-3, the Z4-2had81.56±0.41%inhibitory percentage so it was isolated and purified by RP-HPLC method.7compositions were isolated from Z4-2and named R、R2、R3、 R4、R5、R6and R7, respectively, R4had the highest inhibitory percentage(79.63±0.32%). R4was tested to be Single component through RP-HPLC method again, its Relative molecular weight was905.67Da and Amino acid sequence was L(/I)L(/I)L(/I)SHDL(/I)V[Leu (/Ile)-Leu (/Ile)-Leu (/Ile)-Ser-His-Asp-Leu (/Ile)-Val]. R4was a novel ACEI peptide.
4. PSMPs'effects on HUVEC experiment indicated the effects were Proportional to the PSMPs'concentration and reaction time, the PSMP might have similar mechanism with Captopril, it inhibited cell's proliferation through blocking the cell at S stage. The ACEI could lower the blood pressure through reduce the ET-l's concentration of cell's supernatant, but which need enough content.
The mRNA expression of ET-1, ACE and ACE2genes were tested by Real-time fluorescence quantitative PCR. The results showed both the PSMP and Captopril could reduce the3genes' expressions, the PSMPs' concentration higher, the expressions reduce more. The results also indicated the Generation of Angll were influenced by expression of ACE/ACE2mRNA. The termination agent method showed PSMP could clear02-at some degree, which eases endothelial cell's injury so as to reduce blood pressure.
The above results indicated the PSMP had determined reduce blood pressure function, its mechanism might be associated with inhibiting the HUVEC's Proliferation, clearing the O2-, reducing the activity of ACE and expression of mRNA of ACE and ET-1genes, Promoting expression of mRNA of ACE2. all those factors could reduce the content of Angll and ET-1. PSMP is Worthy of research and development as reduce blood pressure natural products.
1采用双向电泳技术测定了脱油以后的南瓜籽的蛋白质含量、蛋白质等电点和分子量等,结果表明：脱油后的南瓜籽蛋白含量高达75.63%,其等电点和分子量分别为pH5-7,22KDa-42KDa。采用全自动氨基酸分析仪测定了南瓜籽蛋白质中性蛋白酶酶解液的氨基酸组成,发现其疏水性氨基酸含量为34.40g/100g蛋白、芳香族氨基酸为11.49g/100g蛋白及脯氨酸的含量为6.68g/100g蛋白,支链氨基酸含量为12.29g/100g蛋白,蛋白质的平均疏水性为4.189kJ/mol,得出南瓜籽蛋白及其酶解液中与ACE抑制活性呈正相关的氨基酸含量丰富,组成合理,是一种理想的蛋白源,可以作为酶法生产降血压肽的原料。
2以南瓜籽粕为底物,酶解产物的ACE抑制能力为衡量指标,从胰蛋白酶、水解蛋白酶、木瓜蛋白酶、中性蛋白酶、Protease N和Protease S酶六种蛋白酶中优选出中性蛋白酶为南瓜籽蛋白制备ACE抑制肽的酶制剂。在单因素试验的基础上,采用响应面对中性蛋白酶水解南瓜籽蛋白的试验条件进行优化,结合各因素对响应值的影响顺序以及综合考虑到成本问题,在中性蛋白酶最适作用温度45℃和pH7.0下,选择最佳酶解条件为：酶浓度为4.8%、底物浓度为4.0%、水解时间为320min,在此优化的条件下,得到ACE抑制率为80.56±0.23%。
3利用Sephadex G-75凝胶色谱分离南瓜籽粕蛋白中性蛋白酶酶解物,得到四个组分,分别为Z1(MW>14220Da), Z2(MW14200-8400Da), Z3(MW8400-4000Da), Z4(MW<4000Da),组分Z4的ACE抑制率达到了80.23±0.21%；选择Z4再进行Sephadex G-15凝胶色谱分离,得到三个组分为Z4-1,Z4-2和Z4-3,其中Z4-2ACE抑制率为81.56±0.41%,选择Z4-2进行进一步的分离纯化。利用RP-HPLC纯化组分Z4-2共得到7个组分,分别命名为Rl、R2、R3、R4、R5、R6和R7,经ACE抑制活性测定,组分R4ACE抑制活性最强,达到79.63±0.32%,经二次RP-HPLC鉴定R4为单一组分,经过ESI-MS-MS串联质谱分析鉴定ACE抑制肽R4的相对分子量为905.67Da,氨基酸序列为L(/I)L(/I)L(/I)SHDL(/I)V[Leu (/Ile)-Leu(/Ile)-Leu(/Ile)-Ser-His-Asp-Leu(/Ile)-Val],为一种新的ACE抑制肽。
4南瓜籽ACE抑制肽对脐静脉内皮细胞功能的影响结果表明,PSMP对细胞的抑制效果与其浓度和作用时间成正比,与常用降血压药卡托普利的作用机理类似,将细胞阻滞于S期,从而达到了抑制细胞增殖的作用。在相同的培养时间内,ACE抑制肽能显著降低细胞培养上清液中ET-1的含量,由此可见ACE抑制肽可以通过降低血管中ET-1的含量达到降血压的目的,但如浓度太低,效果不显著。实时荧光定量PCR测定ACE抑制肽对ET-1,ACE和ACE2基因mRNA表达的结果表明,ACE抑制肽和卡托普利都能引起ET1-1mRNA、ACE mRNA表达量的下调,随着剂量的增加,其表达量下调效果越大。试验结果还表明AngII生成量的变化可能受ACE/ACE2mRNA表达变化量的影响。采用邻苯三酚自氧化法检测了PSMP对超氧阴离子清除效果,表明PSMPs具有一定的清除超氧阴离子自由基的能力；采用考马斯亮蓝法测定血管内皮细胞蛋白质含量,研究PSMPs对内皮细胞抗氧化损伤能力的影响,结果表明PSMPs能降低内皮细胞受损程度,从而降低高血压的发生。综上所述,南瓜籽肽的降血压效果明确,其机制可能与其抑制血管内皮细胞的增殖、清除超氧阴离子自由基、抑制ACE的活性、促进ACE2mRNA的表达量、抑制ACE和ET-1mRNA的表达量,从而降低AngⅡ和ET-1的含量有关。PSMP是一种值得大力研发的降血压天然产品。
This paper studied the collection, isolation, purification of the pumpkin seeds meal peptides (PSMPS) and its cardiovascular functional effects and mechanisms using pumpkin seed meal (PSM) as raw materials. The meal was hydrolyzed by six proteases and those productions inhibiting ability of angiotensin-coverting enzyme (ACE) were analyzed, some proteases PSMPs were screened for making ACEI and their process condition was optimized by Response Surface Analysis. The PSMPs' were collected, isolated, purified and analyzed through many methods including Gel column chromatography, RP-HPLC and UHPLC-Q-TOF technology. The PSMPs' effects on proliferation of human umbilical vein endothelial cells (HUVECs) and expression of some related genes'mRNA were analyzed by Real time fluorescence quantitative PCR technology so as to analyze the PSMPs'cardiovascular functional and mechanisms. The main results are showed as follows:
1. The protein content, isoelectric point and molecular weight of oil removed PSMs were tested by two dimensional electrophoresis technology, the result showed their protein content was75.63%, its isoelectric point was pH5-7and Molecular weight were22KDa-42Kda.The amino acid composition analysis of enzymatic hydrolysate of PSM's neutral protease by automatic amino acid analyzer showed there were34.40g hydrophobic amino acid,11.49g aromatic amino acid,6.68g Proline and12.92g branched chain amino acid in100g protein, its average hydrophobicity was4.189kJ/mol. These results indicated that the protein of PSM and its enzymatic hydrolysate had great amino acid positive related to ACEI activity, its composition was good for producing antihypertensive peptides through enzyme method.
2.Six Protease including Trypsin, Hydrolysis protease, Papain, Neutral protease, Protease N and Protease S were screened for producing ACEI Peptides according to their ACE Inhibiting ability. The Neutral protease was the best and its hydrolysis reaction factors were optimized using Response Surface Analysis. The results showed its best reaction condition were45℃and pH7.0, the protease content was4.8%, Substrate content was4.0%, Hydrolysis time was320min, the ACE inhibiting percentage could be80.56±0.23%under the condition.
3. four compositions were isolated from enzymatic hydrolysates of PSM using Sephadex G-75Gel chromatography, they were Z1(MW>14220Da), Z2(MW14200 -8400Da), Z3(MW8400-4000Da), Z4(MW<4000Da), respectively, the Z4had80.23±0.21%inhibitory percentage. The Z4was isolated by Sephadex G-15Gel chromatography,3compositions were isolated and named Z4-1, Z4-2和Z4-3, the Z4-2had81.56±0.41%inhibitory percentage so it was isolated and purified by RP-HPLC method.7compositions were isolated from Z4-2and named R、R2、R3、 R4、R5、R6and R7, respectively, R4had the highest inhibitory percentage(79.63±0.32%). R4was tested to be Single component through RP-HPLC method again, its Relative molecular weight was905.67Da and Amino acid sequence was L(/I)L(/I)L(/I)SHDL(/I)V[Leu (/Ile)-Leu (/Ile)-Leu (/Ile)-Ser-His-Asp-Leu (/Ile)-Val]. R4was a novel ACEI peptide.
4. PSMPs'effects on HUVEC experiment indicated the effects were Proportional to the PSMPs'concentration and reaction time, the PSMP might have similar mechanism with Captopril, it inhibited cell's proliferation through blocking the cell at S stage. The ACEI could lower the blood pressure through reduce the ET-l's concentration of cell's supernatant, but which need enough content.
The mRNA expression of ET-1, ACE and ACE2genes were tested by Real-time fluorescence quantitative PCR. The results showed both the PSMP and Captopril could reduce the3genes' expressions, the PSMPs' concentration higher, the expressions reduce more. The results also indicated the Generation of Angll were influenced by expression of ACE/ACE2mRNA. The termination agent method showed PSMP could clear02-at some degree, which eases endothelial cell's injury so as to reduce blood pressure.
The above results indicated the PSMP had determined reduce blood pressure function, its mechanism might be associated with inhibiting the HUVEC's Proliferation, clearing the O2-, reducing the activity of ACE and expression of mRNA of ACE and ET-1genes, Promoting expression of mRNA of ACE2. all those factors could reduce the content of Angll and ET-1. PSMP is Worthy of research and development as reduce blood pressure natural products.
引文
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