酵母来源血管紧张素转移酶抑制多肽的制备及其抑制机理的研究
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摘要
天然来源的生物活性多肽因其具有明显的生理功能和很好的生物相容性而被广泛应用于医药、保健、食品、化妆品等行业；血管紧张素转移酶（ACE）抑制多肽是降血压药物及保健品潜在的代替品之一。
本论文应用多酶复合水解、膜分离和层析分离获得了具有单一组成的ACE抑制六肽，并获得了六肽的氨基酸序列，探讨了其热稳定性和抗消化性能；进一步应用酶动力学、分子模拟、化学定点改性、结构生物学等技术手段阐述了抑制多肽与ACE的相互作用的分子机制，构建了六肽抑制ACE活性的机理模型，取得主要研究内容和结果如下：
（1）酶解法制备酵母来源ACE抑制多肽。采用酵母水解酶提取并水解酵母蛋白质，当料液比为1:10（w/v）、加酶量为1%（w/w）时，在40℃提取2h的条件下，酵母蛋白质的提取效率达到最高，为81.32%±1.27%，此时，酵母蛋白质的水解度为23.38±1.26%；在酵母水解液中添加4倍乙醇可以较好地去除其中大分子杂质，核酸和多糖的去除率分别为87.9±1.74%和64.2±2.15%，蛋白质的损失率仅为6.88±1.28%；进一步超滤分级分离发现透过截留分子量为10kDa的超滤膜的组分活性最高，对该组分依次采用凝胶柱层析和阴离子交换柱层析后获得了一种ACE抑制活性较高的多肽组分AP1。
（2）ACE抑制多肽的结构鉴定和性能测试。基质辅助激光解吸电离飞行时间质谱分析（MALDI-TOF-MS）和氨基酸N端测序结果表明，AP1是计算分子量660Da的单一组成多肽，其氨基酸组成为Thr-Pro-Thr-Gln-Gln-Ser；AP1对ACE的半抑制浓度（IC_50）为0.11μmol/mL，与已知的食源性ACE抑制多肽相比，AP1具有更高的ACE抑制活性；酶抑制动力学和等温滴定量热分析表明，AP1对ACE的抑制为非竞争性抑制，AP1不能改变ACE催化反应的米氏常数Km值，但可以改变酶反应的最大反应速率Vmax；采用本文建立的反相-高效液相色谱法（RP-HPLC）探讨了AP1的的热稳定性及抗消化性能，发现RP-HPLC法定量分析AP1具有较好的准确度和精确度，AP1的水溶液在37℃-60℃具有良好的热稳定性，能够抵抗人工胃液和人工肠液的消化。
（3）AP1对ACE非竞争性抑制机理的研究。应用分子对接技术建立了AP1与ACE的分子对接结构模型，根据AP1与ACE活性中心间的相互作用确定了影响AP1活性的关键氨基酸残基，采用化学定点改性AP1的方法获得残基性质不同或肽链长度不同的改性多肽，并考察改性对多肽ACE抑制活性的影响规律，结果表明AP1的C-末端的Ser6与其抑制ACE活性有直接关系，而N-端的Thr1、Thr3、Gln4则是AP1作为ACE非竞争性抑制剂的结构基础，在解析AP1抑制ACE活性的分子机制的基础上构建了相关的机理模型，AP1的N-端的Thr1、Thr3和Gln4将其锚定在ACE亚结构域Ⅰ的盖子结构上，C-末端的Ser6则吸引ACE活性中心的Zn~(2+)使其位置发生偏离，因此，结合了AP1的ACE虽然能继续与底物HHL结合，但是由于催化过程缺少Zn~(2+)的参与而不能将HHL催化生成HA。
Bioactivity peptide has been widely applied to industries such as medicine, health care,food and makeup, because of its extensive physiological and medical functions.Angiotensin-converting enzyme (ACE)-inhibitory peptide has become potential alternative tohealth care products and hypotension drugs for its natural attribute.
In this research, preparation technology of producing ACE from yeast throughmulti-enzyme hydrolysis was studied systematically. Based on these studies, purity, aminoacid sequence and stability of an ACE peptide with high ACE-inhibitory activity weredetermined. On the basis of these studies, the inhibition mechanism and model of reactionsbetween the ACE-inhibitory peptide and ACE were obtained using knowledge on enzymekinetics and thermodynamics, molecular simulation, designated chemical modification,structure biological, etc. The main experimental results are as follows:
1. Preparation of ACE-inhibitory peptide by hydrolysis of yeast hydrolytic enzyme. Thehighest yeast protein extraction efficiency of81.32%±1.27%and the degree of yeast proteinhydrolysis of23.38%±1.26%were obtained when solid-liquid ratio is1:10, enzyme loading is1%(w/w), extraction temperature is40℃and extraction time is2hours. Yeast hydrolysatewas then roughly purified with4times (V/V) ethanol by ethanol precipitation method. Afterremoving impurities, the removal rates of polysaccharide and nucleic acid were64.2±2.15%and87.9±1.74%respectively, and the loss rate of protein was only6.88±1.28%. Furthermore,the component with MWCO-10kDa has the highest ACE-inhibitory activity withultrafiltration separation, and was purified with gel filtration chromatography and anionexchange chromatography. An ACE-inhibitory peptide AP1was purified.
2. Structure identification and performance test of AP1. A hexapeptide,Thr-Pro-Thr-Gln-Gln-Ser, with a calculated molecular weight of660Da, was identified byMALDI-TOF-MS and automated edman degradation. The hexapeptide showed remarkableACE-inhibitory activity, with an IC50of0.11μmol/mL. The level of ACE-inhibitory activityof the hexapeptide is higher than other ACE-inhibitory peptides food-derived. Based on theresearch of enzyme inhibition kinetics and thermodynamics, the type of ACE inhibited by AP1is noncompetitive inhibition, and AP1could not change Kmof ACE, but change VmaxofACE. RP-HPLC determination method of AP1was established, and thermal stability andresistant of digestion were researched. The results showed that AP1demonstrated goodthermal stability at37-60℃, and resistant of digestion was good.
3. ACE-Inhibitory mechanism of AP1. The docking model of AP1and ACE wasestablished. Based on the docking results, the key amino acids which affected the inhibitoryactive of AP1were concerned, and modified peptides with different length and amino acidcomposition were researched. The results showed that the hexapeptide bound to ACE viainteractions of the N-terminal Thr1, Thr3, and Gln4residues with the residues on the lidstructure of ACE, and the C-terminal Ser6attracted the zinc ion, which is vital for ACEcatalysis. The displacement of the zinc ion from the active site resulted in the inhibition ofACE activity. The structural model based on the docking simulation was supported byexperiments in which the peptide was modified. This study provides a new inhibitorymechanism of ACE by a peptide which broads our knowledge for drug designing againstenzyme targets.
本论文应用多酶复合水解、膜分离和层析分离获得了具有单一组成的ACE抑制六肽，并获得了六肽的氨基酸序列，探讨了其热稳定性和抗消化性能；进一步应用酶动力学、分子模拟、化学定点改性、结构生物学等技术手段阐述了抑制多肽与ACE的相互作用的分子机制，构建了六肽抑制ACE活性的机理模型，取得主要研究内容和结果如下：
（1）酶解法制备酵母来源ACE抑制多肽。采用酵母水解酶提取并水解酵母蛋白质，当料液比为1:10（w/v）、加酶量为1%（w/w）时，在40℃提取2h的条件下，酵母蛋白质的提取效率达到最高，为81.32%±1.27%，此时，酵母蛋白质的水解度为23.38±1.26%；在酵母水解液中添加4倍乙醇可以较好地去除其中大分子杂质，核酸和多糖的去除率分别为87.9±1.74%和64.2±2.15%，蛋白质的损失率仅为6.88±1.28%；进一步超滤分级分离发现透过截留分子量为10kDa的超滤膜的组分活性最高，对该组分依次采用凝胶柱层析和阴离子交换柱层析后获得了一种ACE抑制活性较高的多肽组分AP1。
（2）ACE抑制多肽的结构鉴定和性能测试。基质辅助激光解吸电离飞行时间质谱分析（MALDI-TOF-MS）和氨基酸N端测序结果表明，AP1是计算分子量660Da的单一组成多肽，其氨基酸组成为Thr-Pro-Thr-Gln-Gln-Ser；AP1对ACE的半抑制浓度（IC_50）为0.11μmol/mL，与已知的食源性ACE抑制多肽相比，AP1具有更高的ACE抑制活性；酶抑制动力学和等温滴定量热分析表明，AP1对ACE的抑制为非竞争性抑制，AP1不能改变ACE催化反应的米氏常数Km值，但可以改变酶反应的最大反应速率Vmax；采用本文建立的反相-高效液相色谱法（RP-HPLC）探讨了AP1的的热稳定性及抗消化性能，发现RP-HPLC法定量分析AP1具有较好的准确度和精确度，AP1的水溶液在37℃-60℃具有良好的热稳定性，能够抵抗人工胃液和人工肠液的消化。
（3）AP1对ACE非竞争性抑制机理的研究。应用分子对接技术建立了AP1与ACE的分子对接结构模型，根据AP1与ACE活性中心间的相互作用确定了影响AP1活性的关键氨基酸残基，采用化学定点改性AP1的方法获得残基性质不同或肽链长度不同的改性多肽，并考察改性对多肽ACE抑制活性的影响规律，结果表明AP1的C-末端的Ser6与其抑制ACE活性有直接关系，而N-端的Thr1、Thr3、Gln4则是AP1作为ACE非竞争性抑制剂的结构基础，在解析AP1抑制ACE活性的分子机制的基础上构建了相关的机理模型，AP1的N-端的Thr1、Thr3和Gln4将其锚定在ACE亚结构域Ⅰ的盖子结构上，C-末端的Ser6则吸引ACE活性中心的Zn~(2+)使其位置发生偏离，因此，结合了AP1的ACE虽然能继续与底物HHL结合，但是由于催化过程缺少Zn~(2+)的参与而不能将HHL催化生成HA。
Bioactivity peptide has been widely applied to industries such as medicine, health care,food and makeup, because of its extensive physiological and medical functions.Angiotensin-converting enzyme (ACE)-inhibitory peptide has become potential alternative tohealth care products and hypotension drugs for its natural attribute.
In this research, preparation technology of producing ACE from yeast throughmulti-enzyme hydrolysis was studied systematically. Based on these studies, purity, aminoacid sequence and stability of an ACE peptide with high ACE-inhibitory activity weredetermined. On the basis of these studies, the inhibition mechanism and model of reactionsbetween the ACE-inhibitory peptide and ACE were obtained using knowledge on enzymekinetics and thermodynamics, molecular simulation, designated chemical modification,structure biological, etc. The main experimental results are as follows:
1. Preparation of ACE-inhibitory peptide by hydrolysis of yeast hydrolytic enzyme. Thehighest yeast protein extraction efficiency of81.32%±1.27%and the degree of yeast proteinhydrolysis of23.38%±1.26%were obtained when solid-liquid ratio is1:10, enzyme loading is1%(w/w), extraction temperature is40℃and extraction time is2hours. Yeast hydrolysatewas then roughly purified with4times (V/V) ethanol by ethanol precipitation method. Afterremoving impurities, the removal rates of polysaccharide and nucleic acid were64.2±2.15%and87.9±1.74%respectively, and the loss rate of protein was only6.88±1.28%. Furthermore,the component with MWCO-10kDa has the highest ACE-inhibitory activity withultrafiltration separation, and was purified with gel filtration chromatography and anionexchange chromatography. An ACE-inhibitory peptide AP1was purified.
2. Structure identification and performance test of AP1. A hexapeptide,Thr-Pro-Thr-Gln-Gln-Ser, with a calculated molecular weight of660Da, was identified byMALDI-TOF-MS and automated edman degradation. The hexapeptide showed remarkableACE-inhibitory activity, with an IC50of0.11μmol/mL. The level of ACE-inhibitory activityof the hexapeptide is higher than other ACE-inhibitory peptides food-derived. Based on theresearch of enzyme inhibition kinetics and thermodynamics, the type of ACE inhibited by AP1is noncompetitive inhibition, and AP1could not change Kmof ACE, but change VmaxofACE. RP-HPLC determination method of AP1was established, and thermal stability andresistant of digestion were researched. The results showed that AP1demonstrated goodthermal stability at37-60℃, and resistant of digestion was good.
3. ACE-Inhibitory mechanism of AP1. The docking model of AP1and ACE wasestablished. Based on the docking results, the key amino acids which affected the inhibitoryactive of AP1were concerned, and modified peptides with different length and amino acidcomposition were researched. The results showed that the hexapeptide bound to ACE viainteractions of the N-terminal Thr1, Thr3, and Gln4residues with the residues on the lidstructure of ACE, and the C-terminal Ser6attracted the zinc ion, which is vital for ACEcatalysis. The displacement of the zinc ion from the active site resulted in the inhibition ofACE activity. The structural model based on the docking simulation was supported byexperiments in which the peptide was modified. This study provides a new inhibitorymechanism of ACE by a peptide which broads our knowledge for drug designing againstenzyme targets.
引文
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