Amine N-Oxygenation by FMO3 and FMO4

描述(申请人提供)：神经递质变异 转运体、受体和神经递质的异常水平 与神经疾病有关，包括精神分裂症、躁郁症 情感障碍，自闭症，情感障碍，迟发性阿尔茨海默病， 帕金森氏症和其他疾病。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 或异物胺是某些中枢神经系统疾病的病理基础。 人含黄素单加氧酶(FMO)是人类主要的 有助于内源、环境中的毒素解毒的酶系统 和饮食中的含氮物质。我们工作的总目标是 了解FMO介导的胺的N-氧化的细节和 羟胺。中枢神经系统中羟胺的积累可能会导致 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 脑部FMO-N-氧合是必需的。总体目标将通过以下方式实现 解决五个具体目标，包括：目标1：表达主要形式的 人脑FMO；目标2：化学合成人脑的胺代谢物 目的3：确定人脑FMO胺的动力学和机制 N-氧合作用；目标4：测试人脑FMO胺代谢产物对 神经细胞功能，包括细胞毒性和细胞凋亡，以及目标5： 胺类代谢产物对人体神经递质作用机制的研究 功能。重要的是，基本的生化信息将 对内源性和外源性以及饮食的方式有了新的见解 胺在人脑中代谢。这样的基本信息将是 有益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袭。

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.