Theoretical Study On The Reaction Mechanism Of Metal Proteases And Metal Ions With Flavonoid Inhibitors

As a kind of biological macromolecule, the enzymes play important roles in the life activities of organisms. Metalloproteases (MMPs) are special proteases which contain one or more metal active centers, and they are important in the catalysis and transport of living organisms. In this paper, two kinds of widely used with unique structures of metal proteases were studied, namely copper amine oxidases and tyrosinases. Copper amine oxidases (CuAOs) are responsible for the oxidative deamination of primary amines to their corresponding aldehydes. It is an essential MMP in the metabolism of primary amines. In this thesis, the reaction process of CuAOs and ethylenediamine was studied to reveal the reaction mechanism of the half reaction. What's more, the synthesis process of TPQ was also calculated.Tyrosinases are involved in the formation of melanin, which are the vital enzymes in melanin production. For the research, this article focuses on three kinds of oxidized forms of tyrosinases. The links and differences among them have been found. Besides,the monophenolase activity reaction mechanism of oxy-tyrosinase was studied in order to find more effective related inhibitors, which can be better applied in the cosmetics industry, medicine and other fields. Flavone-metal ion complexes with a different metal-ligand relationship have been displayed in many assays measuring anti-tumor,antioxidant, anti-inflammatory, and anti-coagulant activities. In recent years, the potential applications of novel flavonoid-metal complexes in various fields have promoted concerted efforts towards the synthesis and characterization of these compounds. Types of complexes depend on the different types of flavonoids and metals and the interaction between them. Therefore, the coordination properties of three kinds of flavone-metal ion complexes were studied to reveal their different chemical properties. The full paper is divided into five chapters, as followed:In the first chapter, the main theoretical basis and calculation method used in this paper have been summarized. Additionally, it summarizes the research on the field of metalloproteinases, especially focus on the related structures and applications of copper amine oxidases and tyrosinases.In the second chapter, it was mainly studied about the reaction mechanism of CuAOs with ethylenediamine and the synthesis process of TPQ by using Density Functional Theory (DFT). The structures of transition states and multiple intermediates in the reaction process were obtained by calculating. The varieties in the reaction of each point's main geometric parameters such as bond lengths, bond angles and charge have been analyzed and summarized. Then the energy barrier value of each step reaction and imaginary frequency of each transition state were obtained. And finally,the most reasonable reaction path of the whole process was determined.In the third chapter, the three kinds of oxidized forms of tyrosinases have been optimized by using the Density Functional Theory (DFT). The variety in the reaction of their main geometric parameters such as bond lengths, bond angles and charge have been analyzed, which can indicate the differences and links in sturctures between them.What's more, the reaction mechanism of the oxidation activity of tyrosinase was calculated. Besides, the theoretical value of the transition state and the activation energy was obtained.In the fourth chapter, three different kinds of flavanone-metal ion complexes have been studied by using DFT at GGA/PBE level. After calculating and analyzing the configurations, charges and frontier molecular orbital of complexes, the results indicated that the structure of the complex is the most stable when (Nar)2 is coordinated with metal Zn2+, and the chemical properties of the complex are the most active when (Nar)2 is coordinated with Cu2+. At the same time, the structure of the complex is the most stable when (Nar)(Phe) is coordinated with metal Cu2+, and the chemical properties of the complex are the most active when (Nar)(Phe) is coordinated with Al3+. At last, the structure of the complex is the most stable when (Imna) is coordinated with metal Mg2+, and the chemical properties of the complex are the most active when (Imna) is coordinated with Al3+.In the fifth chapter, the conclusions of all the researches have been summarized.Besides, the outlooks and plans about the further research are expounded and prospected.