Amine N-Oxygenation by FMO3 and FMO4

FMO3 和 FMO4 的胺氮氧化

基本信息

批准号：
6874304
负责人：
John R Cashman
金额：
$ 37.44万
依托单位：
HUMAN BIOMOLECULAR RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-15 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6874304
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

项目摘要

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（由申请人提供）：神经递质的变化神经递质的转运蛋白，受体和异常水平潜在参与包括精神分裂症，双极的神经系统疾病情感障碍，自闭症，情感障碍，晚期阿尔茨海默氏病，帕金森氏病等。人类特征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并发展新的方法疗法。我们的中心假设是缺乏内源性解毒或异种生物胺是某些中枢神经系统疾病的病理状况。含有人类黄素单加氧酶（FMO）是主要人之一酶系统有助于内源性，环境的解毒和含氮物质。我们工作的总体目标是了解FMO介导的胺N氧化的细节和羟胺。中枢神经系统中羟胺的积累可能导致细胞毒性或凋亡。为了测试这一点，有关人类的基本信息需要脑FMO N-氧化。总体目标将通过针对五个具体目标，包括：目标1：cDNA-Express的主要形式人脑FMO；目标2：化学合成人脑的胺代谢物 fmo;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，包括细胞毒性和凋亡，目标5：研究胺代谢物在人神经递质上的机制功能。重要的是，基本的生化信息将关于内源性和异种生物和饮食的新见解胺在人脑中被代谢。这样的基本信息将是用于开发更安全的药物，预防不良药物反应和保护人免受疾病的保护。

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hepatic flavin-containing monooxygenase gene regulation in different mouse inflammation models.

不同小鼠炎症模型中肝脏含黄素单加氧酶基因的调控。

DOI：
10.1124/dmd.108.025338
发表时间：
2009
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
0
作者：
Zhang,Jun;Chaluvadi,MadhusudanaR;Reddy,Rob;Motika,MeikeS;Richardson,TerrilynA;Cashman,JohnR;Morgan,EdwardT
通讯作者：
Morgan,EdwardT

Effect of genetic variants of the human flavin-containing monooxygenase 3 on N- and S-oxygenation activities.

人含黄素单加氧酶 3 的遗传变异对 N-和 S-氧化活性的影响。

DOI：
发表时间：
2007
期刊：
Drug Metab Dispos. 35(3)
影响因子：
0
作者：
Shimizu;M. et al.;Shimizu M. et al.;Yamazaki H. et al.;Shimizu M. et al.
通讯作者：
Shimizu M. et al.

Novel variants of the human flavin-containing monooxygenase 3 (FMO3) gene associated with trimethylaminuria.

DOI：
10.1016/j.ymgme.2009.02.006
发表时间：
2009-06
期刊：
MOLECULAR GENETICS AND METABOLISM
影响因子：
3.8
作者：
Motika, Meike S.;Zhang, Jun;Zheng, Xueying;Riedler, Kiersten;Cashman, John R.
通讯作者：
Cashman, John R.

The role of flavin-containing monooxygenases in drug metabolism and development.

含黄素单加氧酶在药物代谢和开发中的作用。