千日红酪氨酸酶抑制剂的分离纯化及其抑制机理研究
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摘要
酪氨酸酶是一种广泛存在于生物体内的、催化黑色素合成的关键限速酶，与生物体的重要生理过程密切关系，其活性的异常过量表达既可导致人体的色素沉着性疾病产生，也是导致果蔬褐变的主要原因。本文从千日红中提取和分离酪氨酸酶活性抑制成分并对其抑制机理展开深入探讨，获得了千日红具有美白祛斑作用的分子基础，而且揭示了千日红来源酪氨酸酶抑制剂的抑制作用的分子机制，为天然植物源酪氨酸酶抑制剂的开发提供基础数据和理论依据。主要内容及结果如下：
一、植物源酪氨酸酶抑制剂的提取和分离
在单因素实验研究的基础上，采用用响应曲面法（RSM）优化千日红的乙醇浸提条件，获得了优化的提取条件：提取温度为80℃、提取时间为3h，液料比为60mL/g(v/m)，乙醇浓度为50%(v/v)，在此条件下，千日红乙醇粗提物对酪氨酸酶的抑制率为（53.86±2.11）%。
通过追踪分离产物的酪氨酸酶抑制活性，应用溶剂萃取、柱层析、制备色谱等分离到七种单一化合物，并采用核磁共振、质谱和单晶X-射线衍射等鉴定这些化合物的分子结构；分析千日红来源的化合物的酪氨酸酶抑制活性发现，香草酸、麦黄酮、对羟基肉桂酸和对甲氧基肉桂酸对酪氨酸酶的半抑制浓度（IC50）分别为510.01μg/mL、454.86μg/mL、15.82μg/mL和20.37μg/mL。
二、植物源酪氨酸酶抑制剂的分子作用抑制机理研究
应用酶动力学、紫外-可见光光谱分析、荧光光谱分析等探讨了千日红中分离纯化获得的香草酸、麦黄酮和两种肉桂酸衍生物对酪氨酸酶的抑制机理，构建了抑制剂与酪氨酸酶相互作用的分子对接结构模型。香草酸与氨基酸残基发生分子间相互作用酪氨酸酶结合在活性中心，与酪氨酸酶形成的复合体比酪氨酸酶单酚底物（L-酪氨酸）和二酚底物（L-多巴）与酶形成的复合体更加稳定，通过混合型抑制机理延长了酪氨酸酶催化单酚底物的迟滞时间，降低了酪氨酸酶催化单酚底物和二酚底物的反应初速度。
麦黄酮对酪氨酸酶的荧光猝灭为静态猝灭，其通过与酪氨酸酶的氨基酸残基形成氢键和疏水作用在活性中心形成热力学稳定的麦黄酮-酪氨酸酶复合体结构，使酶催化反应的迟滞时间延长并降低酶催化反应初速度，对酪氨酸酶表现出以非竞争性抑制占主导地位的混合型抑制机理。
对羟基肉桂酸和对甲氧基肉桂酸可以通过氢键和疏水作用竞争性地占据L-酪氨酸在酪氨酸酶活性中心的结合位置，而且，对羟基肉桂酸上的-OH既能螯合Cu~(2+)又能与关键氨基酸His-57形成氢键，而对甲氧基肉桂酸的-OCH_3上则不能，因此，对羟基肉桂酸可以抑制酪氨酸酶单酚催化活性和二酚催化活性，对甲氧基肉桂酸则只能抑制单酚催化活性，而且，酪氨酸酶可以催化对羟基肉桂酸生成具有荧光行为的醌类物质。
Tyrosinase is a rate-limiting oxidoreductase and widely exists in biosystem. It plays asignificant role in physiological functions. The excessive expression of tyrosinase may causehyperpigmentation diseases in body and unfavorable browning in food products. In thepresent study, the tyrosinase inhibitors were extracted from Gomphrena globosa (GG) and themechanism of tyrosinase inhibition was further discussed, which could reveal thedehyperpigmentation function of GG. In addition, the obtained results would provide newevidence to elucidate the unique molecular mechanism of GG and provide basic informationand theoretical basis for the exploration of tyrosinase inhibitors from natural plants. Asfollows, it is most content in this paper:
The extraction and separation of tyrosinase inhibitors from natural plants
Based on the results of single factor experiment, the extraction conditions was optimizedby the response surface methodology (RSM). The best extraction condition was80℃,withdraws for3hours, ratio of liquid to material60:1(v/m), as well as the concentration ofethanol50%. Under the above conditions, the inhibition rate of tyrosinase by the crudeextract of GG was (53.86±2.11)%.
Following the biological effects to the tyrosinase, seven kinds of constitutes wereobtained by means of solvent extraction, column chromatography and preparativechromatography. The chemical structures were identified to be VA (VA), tricin,p-hydroxy-cinnamic acid (HCA), and p-methoxycinnamic acid (MCA) by modern analysistechniques such as nuclear magnetic resonance, mass spectrometry and X-ray single crystaldiffraction. The IC50values of VA, tricin, HCA and MCA were510.01μg/mL,454.86μg/mL,15.82μg/mL, and20.37μg/mL, respectively.
The inhibitory mechanisms of inhibitors from natural plants on tyrosinase
The molecular mechanisms of inhibitors from Gomphrena globosa (VA, HCA, tricin,and MCA) on tyrosinase were elucidated by means of enzyme kinetics and spectroscopytechniques, and molecular docking was used for interaction model establishment betweeninhibitors and tyrosianse.
VA could interact with residues in the entrance to the dicopper center. VA could form a more stable complex with tyrosinase than the complexes for substrates. Moreover, VA couldprolong the lag time of tyrosinase for oxidation of L-tyrosine and decrease the initial reactionvelocity of monophenolase and diphenolase of tyrosinase by a mixed type of inhibitorymechanism.
Quenching mechanism of tyrosinase by tricin was static mechanism. And tricin couldform complexes with tyrosinase by forming hydrogen bonds with residues near the catalyticcore domain and hydrophobic associations with residues in the hydrophobic pocket oftyrosinase. And these interactions extended the lag time of tyrosinase for oxidation ofL-tyrosine and decreased the initial reaction velocity of monophenolase and diphenolase oftyrosinase. Tricin behaved as a mixed-type inhibitory mechanism, in which thenon-competitive mechanism played the dominant roles.
HCA and MCA could occupy the binding sites of substrates in the active center oftyrosinase by forming hydrogen bonds and hydrophobic force with residues of tyrosinaseactive center. Moreover,-OH of HCA could coordinate to Cu~(2+)and form hydrogen bondswith His-57, whereas-OCH_3of MAC couldn’t. As a result, HCA could inhibit bothmonophenolase and diphenolase activity of tyrosinase, and MCA could only function asmonophenolase inhibitor of tyrosinase. In addition, HCA could be oxidized by tyrosinase tocorresponding quinone slowly.
一、植物源酪氨酸酶抑制剂的提取和分离
在单因素实验研究的基础上，采用用响应曲面法（RSM）优化千日红的乙醇浸提条件，获得了优化的提取条件：提取温度为80℃、提取时间为3h，液料比为60mL/g(v/m)，乙醇浓度为50%(v/v)，在此条件下，千日红乙醇粗提物对酪氨酸酶的抑制率为（53.86±2.11）%。
通过追踪分离产物的酪氨酸酶抑制活性，应用溶剂萃取、柱层析、制备色谱等分离到七种单一化合物，并采用核磁共振、质谱和单晶X-射线衍射等鉴定这些化合物的分子结构；分析千日红来源的化合物的酪氨酸酶抑制活性发现，香草酸、麦黄酮、对羟基肉桂酸和对甲氧基肉桂酸对酪氨酸酶的半抑制浓度（IC50）分别为510.01μg/mL、454.86μg/mL、15.82μg/mL和20.37μg/mL。
二、植物源酪氨酸酶抑制剂的分子作用抑制机理研究
应用酶动力学、紫外-可见光光谱分析、荧光光谱分析等探讨了千日红中分离纯化获得的香草酸、麦黄酮和两种肉桂酸衍生物对酪氨酸酶的抑制机理，构建了抑制剂与酪氨酸酶相互作用的分子对接结构模型。香草酸与氨基酸残基发生分子间相互作用酪氨酸酶结合在活性中心，与酪氨酸酶形成的复合体比酪氨酸酶单酚底物（L-酪氨酸）和二酚底物（L-多巴）与酶形成的复合体更加稳定，通过混合型抑制机理延长了酪氨酸酶催化单酚底物的迟滞时间，降低了酪氨酸酶催化单酚底物和二酚底物的反应初速度。
麦黄酮对酪氨酸酶的荧光猝灭为静态猝灭，其通过与酪氨酸酶的氨基酸残基形成氢键和疏水作用在活性中心形成热力学稳定的麦黄酮-酪氨酸酶复合体结构，使酶催化反应的迟滞时间延长并降低酶催化反应初速度，对酪氨酸酶表现出以非竞争性抑制占主导地位的混合型抑制机理。
对羟基肉桂酸和对甲氧基肉桂酸可以通过氢键和疏水作用竞争性地占据L-酪氨酸在酪氨酸酶活性中心的结合位置，而且，对羟基肉桂酸上的-OH既能螯合Cu~(2+)又能与关键氨基酸His-57形成氢键，而对甲氧基肉桂酸的-OCH_3上则不能，因此，对羟基肉桂酸可以抑制酪氨酸酶单酚催化活性和二酚催化活性，对甲氧基肉桂酸则只能抑制单酚催化活性，而且，酪氨酸酶可以催化对羟基肉桂酸生成具有荧光行为的醌类物质。
Tyrosinase is a rate-limiting oxidoreductase and widely exists in biosystem. It plays asignificant role in physiological functions. The excessive expression of tyrosinase may causehyperpigmentation diseases in body and unfavorable browning in food products. In thepresent study, the tyrosinase inhibitors were extracted from Gomphrena globosa (GG) and themechanism of tyrosinase inhibition was further discussed, which could reveal thedehyperpigmentation function of GG. In addition, the obtained results would provide newevidence to elucidate the unique molecular mechanism of GG and provide basic informationand theoretical basis for the exploration of tyrosinase inhibitors from natural plants. Asfollows, it is most content in this paper:
The extraction and separation of tyrosinase inhibitors from natural plants
Based on the results of single factor experiment, the extraction conditions was optimizedby the response surface methodology (RSM). The best extraction condition was80℃,withdraws for3hours, ratio of liquid to material60:1(v/m), as well as the concentration ofethanol50%. Under the above conditions, the inhibition rate of tyrosinase by the crudeextract of GG was (53.86±2.11)%.
Following the biological effects to the tyrosinase, seven kinds of constitutes wereobtained by means of solvent extraction, column chromatography and preparativechromatography. The chemical structures were identified to be VA (VA), tricin,p-hydroxy-cinnamic acid (HCA), and p-methoxycinnamic acid (MCA) by modern analysistechniques such as nuclear magnetic resonance, mass spectrometry and X-ray single crystaldiffraction. The IC50values of VA, tricin, HCA and MCA were510.01μg/mL,454.86μg/mL,15.82μg/mL, and20.37μg/mL, respectively.
The inhibitory mechanisms of inhibitors from natural plants on tyrosinase
The molecular mechanisms of inhibitors from Gomphrena globosa (VA, HCA, tricin,and MCA) on tyrosinase were elucidated by means of enzyme kinetics and spectroscopytechniques, and molecular docking was used for interaction model establishment betweeninhibitors and tyrosianse.
VA could interact with residues in the entrance to the dicopper center. VA could form a more stable complex with tyrosinase than the complexes for substrates. Moreover, VA couldprolong the lag time of tyrosinase for oxidation of L-tyrosine and decrease the initial reactionvelocity of monophenolase and diphenolase of tyrosinase by a mixed type of inhibitorymechanism.
Quenching mechanism of tyrosinase by tricin was static mechanism. And tricin couldform complexes with tyrosinase by forming hydrogen bonds with residues near the catalyticcore domain and hydrophobic associations with residues in the hydrophobic pocket oftyrosinase. And these interactions extended the lag time of tyrosinase for oxidation ofL-tyrosine and decreased the initial reaction velocity of monophenolase and diphenolase oftyrosinase. Tricin behaved as a mixed-type inhibitory mechanism, in which thenon-competitive mechanism played the dominant roles.
HCA and MCA could occupy the binding sites of substrates in the active center oftyrosinase by forming hydrogen bonds and hydrophobic force with residues of tyrosinaseactive center. Moreover,-OH of HCA could coordinate to Cu~(2+)and form hydrogen bondswith His-57, whereas-OCH_3of MAC couldn’t. As a result, HCA could inhibit bothmonophenolase and diphenolase activity of tyrosinase, and MCA could only function asmonophenolase inhibitor of tyrosinase. In addition, HCA could be oxidized by tyrosinase tocorresponding quinone slowly.
引文
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