Amine N-Oxygenation by FMO3 and FMO4

FMO3 和 FMO4 的胺 N 氧化

• 批准号: 6437030
• 负责人: John R Cashman
• 金额: $ 42.42万
• 依托单位: HUMAN BIOMOLECULAR RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-15 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6437030
• 关键词: amine oxidase (flavin); apoptosis; brain metabolism; cell line; clinical research; complementary DNA; cytotoxicity; flavins; hippocampus; human tissue; hydroxylamine; laboratory rat; neurons; neurotransmitters; nitrogen metabolism

DESCRIPTION (provided by applicant): Variation in neurotransmitter transporters, receptors and abnormal levels of neurotransmitters potentially are involved in neurological diseases including schizophrenia, bipolar affective disorder, autism, affective disorder, late onset Alzheimer's disease, Parkinson's disease and others. Fundamental information characterizing human neurotransmitter metabolism associated with neurodegenerative diseases could provide new approaches to understanding the pathology and developing new therapeutics. Our central hypothesis is that lack of detoxication of endogenous or xenobiotic amines underlies the pathological condition of some CNS diseases. The human flavin-containing monooxygenase (FMO) is one of the major human enzyme systems that contribute to the detoxication of endogenous, environmental and dietary nitrogen-containing substances. The overall goal of our work is to understand the details of FMO-mediated N-oxygenation of amines and hydroxylamines. Accumulation of hydroxylamines in the CNS may lead to cytotoxicity or apoptosis. To test this, fundamental information about human brain FMO N-oxygenation is required. The overall goal will be accomplished by addressing five Specific Aims including: Aim 1: cDNA-express the major forms of human brain FMO; Aim 2: Chemically synthesize amine metabolites of human brain FMO; Aim 3: Determine the kinetics and mechanism of human brain FMO amine N-oxygenation; Aim 4: Test the effects of human brain FMO amine metabolites on neuronal cell function including cytotoxicity and apoptosis, and Aim 5: Investigate the mechanism of amine metabolites on human neurotransmitter function. The significance is that fundamental biochemical information will result in new insight about the way endogenous and xenobiotic and dietary amines are metabolized in human brain. Such fundamental information will be useful in the development of safer drugs, the prevention of adverse drug reactions and the protection of humans from disease.

描述（申请人提供）：神经递质的变化 转运体、受体和神经递质水平异常可能 与神经系统疾病有关，包括精神分裂症， 情感障碍，自闭症，情感障碍，迟发性阿尔茨海默病， 帕金森氏症及其他人类基本特征信息 与神经退行性疾病相关的神经递质代谢可以 提供新的方法来理解病理学和开发新的 治疗学我们的中心假设是，缺乏内源性的解毒作用， 或异生物胺是某些中枢神经系统疾病病理状态的基础。 人含黄素单加氧酶（FMO）是人体内主要的 酶系统，有助于解毒的内源性，环境 和膳食含氮物质。我们工作的总体目标是 了解FMO介导的胺的N-氧化的细节， 羟胺中枢神经系统中羟胺的蓄积可能导致 细胞毒性或细胞凋亡。为了验证这一点，关于人类的基本信息 需要脑FMO N-氧合。总体目标将通过以下方式实现： 目标1：cDNA表达主要形式的 人脑FMO;目标2：化学合成人脑胺代谢物 目的3：确定人脑FMO胺的动力学和机制 目的4：测试人脑FMO胺代谢物对N-Oxygenation的影响。 神经元细胞功能，包括细胞毒性和细胞凋亡，以及目标5： 探讨胺类代谢产物对人体神经递质的作用机制 功能重要的是基本的生化信息 导致对内源性和外源性以及饮食方式的新见解 胺在人脑中代谢。这些基本信息将 有助于开发更安全的药物，预防药物不良反应， 反应和保护人类免受疾病。