大黄中五种蒽醌类化合物对酪氨酸酶的活性影响及作用机理研究
发布时间：2018-10-08 08:45
【摘要】：酪氨酸酶是黑色素生成的关键限速酶,黑色素的含量与分布决定着人体皮肤和毛发的颜色。在人体中,酪氨酸酶活性增强,使黑色素生成增加,黑色素的过量生成会引起黄褐斑、色斑、老年斑等皮肤病。因此,抑制酪氨酸酶的活性可以有效减少黑色素的生成,从而起到淡化此类斑痕的效果,进而达到美白的作用。目前,已发现一些具有抑制酪氨酸酶活性的药物,然而在实际应用中往往存在一定的毒副作用,如光敏效应、低稳定性等,甚至有些具有致癌的危险。因此,寻找具有低毒、高效的酪氨酸酶抑制剂成为当前美容行业的当务之急。大黄是我国的一种传统中药,具有“泻热通肠、逐瘀通经、凉血解毒”的功效。研究表明,大黄水提取液对酪氨酸酶活性具有良好的抑制作用,然而对其具体作用的物质基础尚不明确,蒽醌类成分是大黄的主要有效成分。因此,本研究以大黄中五种蒽醌类成分(大黄素、大黄素甲醚、芦荟大黄素、大黄酚、大黄酸)为研究对象,采用酶促动力学反应、光谱学及分子模拟等方法探讨五种蒽醌类成分对酪氨酸酶的抑制活性及其抑制机理。研究结果表明,五种蒽醌类化合物均有抑制酪氨酸酶活性的作用,其作用大小为:大黄素甲醚大黄素芦荟大黄素大黄酚大黄酸,其抑制类型均为竞争性抑制。光谱学和分子模拟研究表明,五种蒽醌类化合物直接进入酪氨酸酶的活性中心,主要通过疏水性作用力和静电引力与酪氨酸酶活性中心的氨基酸残基发生相互作用,从而引起了酪氨酸酶二级结构的变化,导致酪氨酸酶内源荧光的静态猝灭。由于蒽醌类成分进入酪氨酸酶的活性位点,阻碍了底物左旋多巴(L-DOPA)进入该活性位点,形成竞争性抑制,这可能是最主要的抑制机理。此外,查阅相关文献,通过分子模拟软件,建立了酪氨酸酶抑制剂的二维定量构效关系(2D-QSAR),获得预测能力较好的定量构效关系(QSAR)模型,为进一步优化设计出新颖、高效的酪氨酸酶抑制剂提供了理论指导。
[Abstract]:Tyrosinase is a key rate-limiting enzyme for melanin production. The content and distribution of melanin determine the color of human skin and hair. In human body, tyrosinase activity is enhanced, melanin production is increased, excessive melanin production will cause melasma, macula, senile spot and other skin diseases. Therefore, inhibiting tyrosinase activity can effectively reduce the formation of melanin, thus play the role of desalination of such marks, and then achieve whitening effect. At present, some drugs have been found to inhibit tyrosinase activity, but in practical applications, there are often some toxic side effects, such as Guang Min effect, low stability, and even some carcinogenic risks. Therefore, the search for low-toxicity, high-efficiency tyrosinase inhibitors has become the top priority in the beauty industry. Rhubarb is a kind of traditional Chinese medicine in our country, which has the effect of "purging heat through intestine, removing blood stasis and clearing meridian, cooling blood and detoxifying". The results showed that the water extract of rhubarb had a good inhibitory effect on tyrosinase activity, but the material basis of its specific action was not clear. Anthraquinones were the main active components of rhubarb. Therefore, five anthraquinones in rhubarb (emodin, emodin methyl ether, aloe emodin, chrysophanol, Rhein) were used in this study. The inhibitory activity and mechanism of five anthraquinones on tyrosinase were studied by means of spectroscopy and molecular simulation. The results showed that all of the five anthraquinones had inhibitory effect on tyrosinase activity. The effects of emodin, aloe, emodin, chrysophanol and Rhein were all competitive inhibition. Spectroscopic and molecular simulation studies show that five anthraquinones directly enter the active sites of tyrosinase, and interact with the amino acid residues of tyrosinase by hydrophobic force and electrostatic force. Therefore, the secondary structure of tyrosinase was changed and the endogenous fluorescence of tyrosinase was quenched. The entry of anthraquinones into the active site of tyrosinase hinders the entry of substrates levodopa (L-DOPA) into the active site and forms a competitive inhibition which may be the main inhibitory mechanism. In addition, the two-dimensional quantitative structure-activity relationship (2D-QSAR) of tyrosinase inhibitors was established by consulting relevant literature and molecular simulation software. The quantitative structure-activity relationship (QSAR) model with good predictive ability was obtained, which was novel for further optimization. Efficient tyrosinase inhibitors provide theoretical guidance.
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R284;R285
[Abstract]:Tyrosinase is a key rate-limiting enzyme for melanin production. The content and distribution of melanin determine the color of human skin and hair. In human body, tyrosinase activity is enhanced, melanin production is increased, excessive melanin production will cause melasma, macula, senile spot and other skin diseases. Therefore, inhibiting tyrosinase activity can effectively reduce the formation of melanin, thus play the role of desalination of such marks, and then achieve whitening effect. At present, some drugs have been found to inhibit tyrosinase activity, but in practical applications, there are often some toxic side effects, such as Guang Min effect, low stability, and even some carcinogenic risks. Therefore, the search for low-toxicity, high-efficiency tyrosinase inhibitors has become the top priority in the beauty industry. Rhubarb is a kind of traditional Chinese medicine in our country, which has the effect of "purging heat through intestine, removing blood stasis and clearing meridian, cooling blood and detoxifying". The results showed that the water extract of rhubarb had a good inhibitory effect on tyrosinase activity, but the material basis of its specific action was not clear. Anthraquinones were the main active components of rhubarb. Therefore, five anthraquinones in rhubarb (emodin, emodin methyl ether, aloe emodin, chrysophanol, Rhein) were used in this study. The inhibitory activity and mechanism of five anthraquinones on tyrosinase were studied by means of spectroscopy and molecular simulation. The results showed that all of the five anthraquinones had inhibitory effect on tyrosinase activity. The effects of emodin, aloe, emodin, chrysophanol and Rhein were all competitive inhibition. Spectroscopic and molecular simulation studies show that five anthraquinones directly enter the active sites of tyrosinase, and interact with the amino acid residues of tyrosinase by hydrophobic force and electrostatic force. Therefore, the secondary structure of tyrosinase was changed and the endogenous fluorescence of tyrosinase was quenched. The entry of anthraquinones into the active site of tyrosinase hinders the entry of substrates levodopa (L-DOPA) into the active site and forms a competitive inhibition which may be the main inhibitory mechanism. In addition, the two-dimensional quantitative structure-activity relationship (2D-QSAR) of tyrosinase inhibitors was established by consulting relevant literature and molecular simulation software. The quantitative structure-activity relationship (QSAR) model with good predictive ability was obtained, which was novel for further optimization. Efficient tyrosinase inhibitors provide theoretical guidance.
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R284;R285
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