Human thioredoxin Reductases: Selenoproteins as Potential Drug Targets

人硫氧还蛋白还原酶：硒蛋白作为潜在的药物靶点

• 批准号: 5241800
• 负责人: Professorin Dr. Katja Becker
• 金额: --
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2000
• 资助国家: 德国
• 起止时间: 1999-12-31 至 2005-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5241800?language=en
• 关键词: Human; thioredoxin; Reductases; Selenoproteins; Potential

The selenoenzyme thioredoxin reductase (TrxR) and its product, reduced thioredoxin, represent cornerstones of the cellular thiol metabolism. They contribute to deoxyribonucleotide production, to the redox control of various metabolic pathways as well as to cell proliferation and differentiation. Human TrxR is so potently inhibited by different cytostatic and antirheumatic agents that the enzyme currently represents one of the most promising target molecules for the de novo development and improvement of drugs. In the proposed project we plan to crystallize cytosolic hTrxR and to elucidate its three-dimensional structure. Furthermore, the catalytic mechanism of the enzyme and the function of the redox-active selenocysteine shall be characterized. By systematic inhibitor screening (e.g. gold compounds, platinum complexes, and peroxynitrite) and the crystallization of hTrxR-inhibitor complexes new inhibition strategies will be developed. Mitochondrial and cytosolic hTrxR represent two of only four human selenoenzymes known so far. Studying structure and mechanism of hTrxRs but also genetic knockout experiments in animal models would essentially contribute to our understanding of the function of selenium in man.

硒酶硫氧还蛋白还原酶（TrxR）及其产物，还原硫氧还蛋白，代表细胞硫醇代谢的基石。它们有助于脱氧核糖核苷酸的产生，各种代谢途径的氧化还原控制以及细胞增殖和分化。人TrxR是如此有效地抑制不同的细胞生长抑制剂和抗风湿剂，该酶目前代表了一个最有前途的靶分子从头开发和改进的药物。在拟议的项目中，我们计划结晶胞质hTrxR，并阐明其三维结构。此外，酶的催化机制和氧化还原活性的硒代半胱氨酸的功能应进行表征。通过系统的抑制剂筛选（例如金化合物、铂络合物和过氧亚硝酸盐）和hTrxR-抑制剂络合物的结晶，将开发新的抑制策略。线粒体和胞质hTrxR代表迄今为止已知的仅有的四种人类硒酶中的两种。研究hTrxRs的结构和机制，以及在动物模型中的基因敲除实验，将从根本上有助于我们了解硒在人体中的功能。