Functions of thioredoxin reductases and their targets

硫氧还蛋白还原酶的功能及其靶标

• 批准号: 9187945
• 负责人: Vadim N. Gladyshev
• 金额: $ 41.04万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9187945
• 关键词: Active Sites; Address; Affect; Animal Model; Apoptosis; Area; Binding; Biochemical; Bioinformatics; Biology; Cell physiology; Controlled Study; Cysteine; Data; Development; Dietary Selenium; Disulfides; Enzymes; Funding Mechanisms; Heterodimerization; Homeostasis; Hydrogen Peroxide; In Vitro; Instruction; Link; Malignant Neoplasms; Mammals; Metabolism; Metals; Methods; Molecular Target; Organism; Oxidation-Reduction; Oxidoreductase; Pathway interactions; Phase; Physiological Processes; Positioning Attribute; Preparation; Property; Protein Isoforms; Proteins; Proteome; Proteomics; Publications; Publishing; Regulation; Research; Selenocysteine; Set protein; Signal Transduction; Site; Specificity; Sulfhydryl Compounds; Surface; System; TXN gene; Yeasts; base; glutaredoxin; thioredoxin reductase; thioredoxin-like protein

Redox biology is a rapidly expanding area of research. Recent studies have shown that the major cellular processes are regulated by redox, yet specific mechanisnns are poorly understood. With the exception of several exannples, the molecular targets of redox control, specificity of redox regulation, and the sets of proteins that maintain cellular redox homeostasis are not known. Thiol-based redox regulation has emerged as a prevalent mechanism to regulate cellular processes. Its major components, thioredoxin (Trx) and thioredoxin reductase (TR), are present in nearly all organisms. TRs control the redox state of Trxs, which in turn regulate cellular processes by controlling the redox state of cysteine (Cys) residues in proteins. Mammals have three TRs, and all three contain catalytic selenocysteine (Sec) residues; therefore, the mammalian Trx system is dependent on dietary selenium. Besides TRs and Trxs, numerous Trx-like proteins and other thiol oxidoreductases (i.e., proteins that use catalytic redox Cys) exist, but their functions are mostly unknown. It is also unknown which proteins are targeted by these enzymes. We would like to characterize TRs, Trxs, thiol oxidoreductases and protein targets regulated by these proteins to define the major pathways of thiol-based redox regulation in mammals. Specifically, we will carry out the following studies: (1) Characterize organismal sets of thiol oxidoreductases and their protein targets using bioinformatics, proteomics, and biochemical methods; (2) Analyze general features of thiol-based redox regulation; (3) Characterize interplay between cysteine and selenocysteine in the active sites of oxidoreductases; and (4) Examine interrelationship between hydrogen peroxide metabolism and thiol-based redox control. RELEVANCE (See instructions): Thioredoxin reductase and thioredoxin are the main redox regulators of cysteines in proteins, whereby controlling cellular processes. This system has been implicated in cell signaling, apoptosis, cancer development, and many other physiological processes. We propose to characterize functions of thioredoxin reductases, thiol oxidoreductases and their targets to define mechanisms of thiol-based redox regulation.

氧化还原生物学是一个迅速扩展的研究领域。最近的研究表明， 过程受氧化还原调节，但具体机制知之甚少。但不包括 几个例子，氧化还原控制的分子靶点，氧化还原调节的特异性，以及氧化还原调节的集合。 维持细胞氧化还原稳态的蛋白质是未知的。基于巯基的氧化还原调节已经出现 作为调节细胞过程的普遍机制。其主要成分硫氧还蛋白（Trx）和 硫氧还蛋白还原酶（TR）存在于几乎所有生物体中。TRs控制Trx的氧化还原状态， 反过来通过控制蛋白质中半胱氨酸（Cys）残基的氧化还原状态来调节细胞过程。 哺乳动物具有三个TR，并且所有三个TR都含有催化性硒代半胱氨酸（Sec）残基;因此， 哺乳动物的Trx系统依赖于膳食硒。除了TRs和Trx，许多Trx样 蛋白质和其它硫醇氧化还原酶（即，使用催化氧化还原半胱氨酸的蛋白质）存在，但它们的功能 大部分是未知的。也不知道这些酶靶向哪些蛋白质。我们想 表征TRs、Trx、硫醇氧化还原酶和由这些蛋白质调节的蛋白质靶点，以定义 哺乳动物中基于巯基的氧化还原调节的主要途径。具体来说，我们会进行以下工作 研究：（1）使用生物化学方法表征硫醇氧化还原酶及其蛋白质靶点的生物体组 生物信息学、蛋白质组学和生物化学方法;（2）分析巯基氧化还原的一般特征 （3）表征半胱氨酸和硒代半胱氨酸在蛋白酶的活性位点中的相互作用。 氧化还原酶;和（4）检查过氧化氢代谢和硫醇基 氧化还原控制 相关性（参见说明）： 硫氧还蛋白还原酶和硫氧还蛋白是蛋白质中半胱氨酸的主要氧化还原调节剂， 控制细胞过程。该系统与细胞信号传导、细胞凋亡、癌症 发育和许多其他生理过程。我们提出硫氧还蛋白的功能特点 还原酶、硫醇氧化还原酶和它们的靶标来定义基于硫醇的氧化还原调节的机制。