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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(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。

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）

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。

DOI：
发表时间：
2003
期刊：
Current opinion in drug discovery & development.
影响因子：
0
作者：
Cashman,JohnR
通讯作者：
Cashman,JohnR

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

Stop codon mutations in the flavin-containing monooxygenase 3 (FMO3) gene responsible for trimethylaminuria in a Japanese population