CONTROL OF EUCARYOTIC FUNCTION BY METHYLATION

通过甲基化控制真核功能

• 批准号: 6476335
• 负责人: STEVEN G CLARKE
• 金额: $ 43.86万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-12-01 至 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6476335
• 关键词: Krebs' cycle; RNA binding protein; Saccharomyces cerevisiae; aging; aspartate; biological signal transduction; brain metabolism; detoxification; enzyme activity; eukaryote; gene targeting; genetically modified animals; human genetic material tag; human tissue; laboratory mouse; methylation; methyltransferase; open reading frames; protein metabolism; protein structure function; tissue /cell culture; translation factor

The objective of this work is to understand the physiological role of several related members of a family of S-adenosylmethionine-dependent methyltransferases in aging, metabolic control, and signal transduction. We will continue our work to characterize the protein L-isoaspartate (D- aspartate) O-methyltransferase that recognizes age-damaged proteins and catalyzes the initial step of a protein repair reaction. Seizures occur as a result of the loss of function of this enzyme in transgenic knockout mice. We will investigate the factors leading to the onset of seizures to help understand the mechanisms involved in human epilepsy and its potential control. We will compare the role of this protein repair enzyme to an enzyme that we have recently discovered (trans-aconitate methyltransferase) that recognizes a spontaneously formed inhibitor of the citric acid cycle in a potential detoxification reaction. We also propose to characterize members of an expanding family of protein arginine methyltransferases. These enzymes interact with signaling molecules such as the interferon receptor, the TIS21 protein and SH3-domain-containing proteins. We will now characterize these gene products to better understand the role of these enzymes in metabolic control, including a novel enzyme we have recently discovered that methylates the delta, or internal guanidino nitrogen atom, or arginine residues. Finally, we will examine the enzymes that catalyze the carboxyl methylation of an elongation factor in protein synthesis that may be regulated by a methylation/demethylation cycle. These enzymes all appear to be members of one revolutionarily related family with a probably common three dimensional structure. While one group of enzymes appears to function in reducing the accumulation of the potentially toxic products generated spontaneously during the aging process, the other group appears to regulate the cell's metabolism and its signal transduction pathways.

这项工作的目的是了解 S-腺苷甲硫代依赖性家族的几个相关成员 甲基转移酶在衰老，代谢控制和信号转导中。 我们将继续我们的工作来表征蛋白质l-异冬天（D-） 天冬氨酸）O-甲基转移酶，识别年龄损坏的蛋白质和 催化蛋白质修复反应的初始步骤。癫痫发作作为一个 该酶在转基因基因敲除小鼠中功能丧失的结果。 我们将调查导致癫痫发作以帮助的因素 了解人类癫痫涉及的机制及其潜力 控制。我们将将这种蛋白质修复酶的作用与 我们最近发现的酶 甲基转移酶）识别自发形成的抑制剂 潜在解毒反应中的柠檬酸循环。我们也建议 为了表征不断扩展的蛋白质精氨酸家族的成员 甲基转移酶。这些酶与信号分子相互作用 作为干扰素受体，TIS21蛋白和含SH3域的蛋白 蛋白质。我们现在将这些基因产品的特征以更好 了解这些酶在代谢控制中的作用，包括 新型酶，我们最近发现甲基化三角洲或 内尼迪诺诺氮原子或精氨酸残基。最后，我们会的 检查催化羧基甲基化的酶 蛋白质合成中的伸长因子可能受A的调节 甲基化/脱甲基化周期。这些酶似乎都是 一个与一个革命性的家庭的成员，可能是一个常见的家庭 三维结构。一组酶似乎 在减少潜在有毒产品的积累中起作用 在衰老过程中自发产生，另一组 似乎调节细胞的代谢及其信号转导 途径。