Analogues of Zinc Enzymes with Sulfur-Rich Active Sites

具有富硫活性位点的锌酶类似物

• 批准号: 7253415
• 负责人: GERARD PARKIN
• 金额: $ 25.46万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7253415
• 关键词: Active Sites; Adult; Alcohol dehydrogenase; Alkylation; Aminolevulinate; Area; Be++ element; Beryllium; Biochemistry; Bioinorganic Chemistry; Biological; Biological Availability; Biological Process; Carbohydrates; Chemistry; Class; Common Cold; Communicable Diseases; Complex; Cysteine; DNA repair protein; Elements; Environment; Enzymes; Genetic Transcription; Growth and Development function; Heme; Human; Hydrolase; Immune; Investigation; Ions; Iron; Isomerase; Lead; Lead Poisoning; Length; Life; Ligands; Ligase; Lipids; Liver; Lyase; Malaria; Mononuclear; Nitrogen; Nucleic Acids; Organ; Oxidoreductase; Oxygen; Play; Pneumonia; Porphobilinogen Synthase; Proteins; Public Health; Regulation; Reporting; Research; Role; Site; Spectrum Analysis; Structure; Sulfur; System; Therapeutic; Therapeutic Intervention; Trace metal; Transferase; Viral; Zinc; analog; chemical property; design; gluconate; hepatitis C virus NS3 protein; malformation; small molecule; solid state

DESCRIPTION (provided by applicant): Zinc is widely recognized as an element that is essential to all forms of life, and especially that of humans. Thus, zinc plays important functions in numerous biological processes (e.g. carbohydrate, lipid, protein and nucleic acid synthesis, regulation and degradation; gene transcription; viral and immune phenomena) and is an indispensable element for effective growth and development, with deficiency resulting in organ malformations. The public health implications of zinc have, therefore, recently been strongly emphasized, thereby making the bioinorganic chemistry of zinc an essential and critical area of investigation. The principal aims of the proposed research are concerned with an effort to elucidate the biological chemistry of zinc that is performed by more than 300 enzymes, with representatives for each of the fundamental enzyme classes (oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases). Paramount to understanding the many roles of zinc in biological systems is a determination of how the chemistry of zinc is modulated by its coordination environment. A specific objective of the research proposed is to provide an understanding of the chemistry of zinc in a sulfur rich environment which is of relevance to enzymes such as liver alcohol dehydrogenase, the Ada DNA repair protein, and 5-aminolevulinate dehydratase. For example, the zinc enzyme 5-aminolevulinate dehydratase is necessary for the early steps of heme formation, and its inactivation by lead is one of the principal reasons why lead is poisonous to humans. The objectives of this proposal will be achieved by investigating synthetic analogues (i.e. small molecules that mimic both the structures and functions of the active sites of zinc enzymes) that are constructed using sulfur donor tripodal ligands to emulate the protein residues that coordinate to zinc in the enzymes. Elucidation of the roles that zinc plays in biological systems will provide the information that is necessary to allow for the possibility of rational therapeutic intervention.

描述（由申请人提供）：锌被广泛认为是对各种生活形式，尤其是人类必不可少的元素。因此，锌在众多生物学过程（例如碳水化合物，脂质，蛋白质和核酸合成，调节和降解；基因转录；病毒和免疫现象）中起重要功能，并且是有效生长和发育的必不可少元素，导致器官畸形导致不足。因此，最近强烈强调了锌的公共卫生影响，从而使锌的生物无机化学成为研究的重要和关键领域。拟议研究的主要目的是涉及努力阐明由300多个酶执行的锌的生物化学，并为每个基本酶类别（氧化酶，转移酶，水解酶，裂解酶，裂解酶，异构酶，异构酶和韧带）提供代表。了解锌在生物系统中的许多作用的重要性是确定锌的化学如何通过其协调环境调节。提出的研究的一个具体目标是在富含硫的环境中对锌的化学理解，这与诸如肝醇脱氢酶，ADA DNA修复蛋白和5-氨基苯甲酸脱氢酶等酶相关。例如，对于血红素形成的早期步骤，锌酶5-氨基甲基脱水酶是必不可少的，而铅的灭活是铅对人类有毒的主要原因之一。该提案的目标将通过研究合成类似物（即模仿锌酶的活性位点的结构和功能的小分子），这些分子是使用硫供体三座配体构建的，以模仿蛋白质残基，以仿真蛋白质残基在enzymes中均匀地与锌配合锌。阐明锌在生物系统中所起的作用将提供必要的信息，以允许进行理性的治疗干预。