Amine N-Oxygenation by FMO3 and FMO4

描述（由申请人提供）：神经递质的变化 转运蛋白、受体和神经递质的异常水平可能 涉及神经系统疾病，包括精神分裂症、双向情感障碍 情感障碍、自闭症、情感障碍、迟发性阿尔茨海默病、 帕金森病等。表征人类的基本信息 与神经退行性疾病相关的神经递质代谢可能 提供了解病理学和开发新方法的新方法 疗法。我们的中心假设是缺乏内源性解毒 或异生胺是某些中枢神经系统疾病病理状况的基础。 人类含黄素单加氧酶（FMO）是人类主要的酶之一 有助于内源性、环境性物质解毒的酶系统 和饮食中的含氮物质。我们工作的总体目标是 了解 FMO 介导的胺 N-氧化的细节，以及 羟胺。羟胺在中枢神经系统中的积累可能会导致 细胞毒性或细胞凋亡。为了测试这一点，关于人类的基本信息 大脑需要 FMO N 氧合。总体目标将通过 解决五个具体目标，包括： 目标 1：cDNA 表达主要形式 人脑FMO；目标2：化学合成人脑胺代谢物 FMMO；目标 3：确定人脑 FMO 胺的动力学和机制 N-氧化；目标 4：测试人脑 FMO 胺代谢物对 神经元细胞功能，包括细胞毒性和细胞凋亡，目标 5： 研究胺代谢物对人类神经递质的作用机制 功能。其意义在于基本的生化信息将 得出关于内源性和外源性与饮食方式的新见解 胺在人脑中代谢。这些基本信息将是 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侵害。

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.