Nutrient Regulation of BHMT Expression

BHMT 表达的营养调节

• 批准号: 6698031
• 负责人: TIMOTHY A GARROW
• 金额: $ 29.8万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6698031
• 关键词: active sites; aminoacid metabolism; betaine compound; enzyme activity; gene expression; genetically modified animals; high performance liquid chromatography; homocysteine; homocystinuria; hydrogen peroxide; intracellular; laboratory mouse; methyltransferase; nitric oxide; nutrient bioavailability; nutrition related tag; oxidation reduction reaction; protein structure function; thiols; tissue /cell culture; western blottings; zinc

DESCRIPTION (provided by applicant): Hyperhomocysteinemia is reportedly a prevalent, independent and graded risk factor for all major forms of vascular disease and thrombosis, and more recently it has been associated with neural tube defects and Alzheimer's disease. Betaine-homocysteine methyltransferase (BHMT) is proposed to have a major role in the regulation of blood homocysteine (Hcy) levels. The physical and mechanistic properties of BHMT and the extent to which variation at the BHMT locus contributes to the incidence of hyperhomocysteinemia represent major gaps in our understanding of Hcy metabolism in both normal and pathological states. Our long-term goal is to elucidate the role BHMT has in regulating Hcy levels in humans. The objective of this application is to characterize further the physical and mechanistic properties of human BHMT, and to elucidate how changes in redox status, including changes in intracellular thiols, hydrogen peroxide (H2O2) and nitric oxide NO) have on its activity. Our central hypothesis is that BHMT is required for normal Hcy netabolism and that drugs or pathological states that increase oxidative stress will inhibit or nactivate BHMT and cause hyperhomocysteinemia. The specific aims of this proposal are (1) to .elucidate structure-function relationships of human BHMT, and (2) to determine the mechanism(s) by which BHMT activity is modulated by nutrient- and pharmacologically induced changes in redox status, including changes in intracellular thiols, H2O2 and NO. Our collaborators and we are well prepared to perform the research outlined in this proposal. We have recently shown that human BHMT activity is regulated by thiols, H2O2 and NO in vitro, and we have obtained the crystal structure of the enzyme. The outcomes of the proposed studies will include novel information on IBHMT's structure and function and its regulation by nutritional and physiological factors influencing Iredox status.

描述（由申请人提供）：据报道，高脑类结晶血症是所有主要形式的血管疾病和血栓形式的普遍，独立和分级的危险因素，最近它与神经管缺陷和阿尔茨海默氏病有关。提议丁丁氏蛋白酶甲基转移酶（BHMT）在血液同型半胱氨酸水平（HCY）水平的调节中起主要作用。 BHMT的物理和机械特性以及BHMT基因座的变异在多大程度上有助于超同性恋半胱氨酸血症的发生率，这在我们对正常状态和病理状态的HCY代谢的理解中占主要差距。我们的长期目标是阐明BHMT在调节人类HCY水平方面的作用。该应用的目的是进一步表征人BHMT的物理和机械特性，并阐明氧化还原状态的变化，包括细胞内硫醇，过氧化氢（H2O2）和一氧化氮NO的变化）在其活性上具有。我们的中心假设是，正常的Hcy Netabolism需要BHMT，而增加氧化应激的药物或病理状态将抑制或脱位BHMT并引起高脑结构血症。该提案的具体目的是（1）降低人BHMT的结构 - 功能关系，（2）确定BHMT活性通过营养和药理诱导的氧化还原状态变化调节的机制，包括细胞内硫醇内硫醇，H2O2和NO的变化。我们的合作者和我们已经准备好执行此提案中概述的研究。我们最近表明，人BHMT活性受硫醇，H2O2和无体外调节，并且我们获得了酶的晶体结构。拟议的研究的结果将包括有关IBHMT的结构和功能的新信息，以及其对影响IREDOX状态的营养和生理因素的调节。