REGULATION OF FLAVIN-MONOOXYGENASE GENE EXPRESSION

黄素单加氧酶基因表达的调控

• 批准号: 2733016
• 负责人: RONALD N HINES
• 金额: $ 14.14万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-07-05 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2733016
• 关键词: amine oxidase (flavin); animal genetic material tag; chemical carcinogenesis; detoxification; enzyme mechanism; gene expression; genetic polymorphism; genetic regulatory element; human genetic material tag; isozymes; species difference; transcription factor

DESCRIPTION (Adapted from the Investigator's Abstract): The flavin-containing monoxygenases (FMO) exhibit a broad substrate specificity for soft nucleophiles, including nitrogen-, sulfur-, and phosphorous-containing xenobiotics. The enzyme appears most active in the detoxication of several such compounds, although the FMO also participate in the metabolic activation of several procarcinogens and protoxins. As such, this enzyme plays an important role in the early events of chemical carcinogenesis and toxicity. Molecular cloning studies have now identified 5 distinct members of the FMO gene family sharing 52 to 57 percent sequence identity. The different FMO isozymes exhibit dramatic differences in their tissue-specific expression. These differences will contribute to the target organ specificity of many toxic xenobiotics due to differential detoxication or bioactivation. However, no studies have appeared regarding the molecular mechanism(s) controlling the expression of these enzymes. The hypothesis of this proposal is that the tissue-specific expression of the FMO is regulated by the differential binding of specific transcription factors to regulatory sequences. It is further hypothesized that the overall molecular mechanism regulating these genes will be conserved between species, although its application to different genes will exhibit species-specificity. Finally, it is hypothesized that interindividual differences in xenobiotic metabolism is due in part to polymorphisms in one or more the human FMO enzymes. These hypotheses will be tested by completion of the following specific aims: (1) Extend initial studies on the isolation and characterization of the major rabbit and human FMO genes; (2) Determine and characterize tissue- and cell-specific regulatory mechanisms by identifying and characterizing FMO cis- and trans-regulatory elements; and (3) Identify, characterize, and determine the significance of FMO polymorphisms in the human population. Completion of these studies will add greatly to the understanding of the mechanisms controlling the expression of this important enzyme system and its impact on several human pathologies.

描述（改编自研究者摘要）： 含黄素单加氧酶（FMO）具有广泛的底物特异性 对于软亲核试剂，包括氮-，硫-， 含磷的异生物质 这种酶似乎在 解毒的几个这样的化合物，虽然FMO也参与 几种原致癌物和原毒素的代谢活化。 因此，在本发明的一个方面， 这种酶在化学反应的早期事件中起着重要作用。 致癌性和毒性。 分子克隆研究已经发现 FMO基因家族的5个不同成员共享52%至57%的序列 身份 不同的FMO同工酶在它们的功能上表现出显著的差异。 组织特异性表达。 这些差异将有助于实现目标 由于不同的解毒作用，许多有毒异生物质的器官特异性 或生物活化。 然而，还没有研究表明， 控制这些酶的表达的机制。 的假设 这一建议是FMO的组织特异性表达受到调节， 通过特异性转录因子与调节因子的差异结合， 序列的 进一步假设， 调节这些基因的基因在物种之间是保守的，尽管它 对不同基因的应用将表现出物种特异性。 最后， 据推测，异生物质代谢的个体间差异 部分是由于一种或多种人FMO酶的多态性。 这些 将通过完成以下具体目标来检验假设：（1） 扩大关于主要的 兔和人FMO基因;（2）确定和表征组织-和 通过识别和表征FMO的细胞特异性调节机制 顺式和反式调节元件;和（3）鉴定、表征和 确定FMO多态性在人群中的意义。 完成这些研究将大大增加对 控制这一重要酶系统表达的机制， 它对几种人类疾病的影响。