Amine N-Oxygenation by FMO3 and FMO4

FMO3 和 FMO4 的胺氮氧化

• 批准号: 6722773
• 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
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-15 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6722773
• 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（由申请人提供）：神经递质变异