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Enzymology of Dimethylargininase

二甲基精氨酸酶的酶学

基本信息

批准号：
8024500
负责人：
WALTER L FAST
金额：
$ 39.91万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8024500
关键词：
Address Area Biochemical Biological Assay Brain Injuries Cancer Biology Cancer Etiology Catalysis Chemicals Chemistry Chronic Citrulline Cysteine Data Data Collection Development Enzymatic Biochemistry Enzymes Eye Future Grant Health Human Human Resources Hydrogen Peroxide Inflammation Ischemic Stroke Kinetics Laboratories Learning Malignant Neoplasms Measures Methods Monitor Neurons Nitric Oxide Nitric Oxide Synthase Nitrogen Oxidants Oxidation-Reduction Oxidative Stress Oxygen Paper Pathway interactions Peer Review Physiological Play Positioning Attribute Preparation Principal Investigator Production Protein Isoforms Proteins Pseudomonas aeruginosa Public Health Publications Published Comment Publishing Recruitment Activity Regulation Research Risk Roentgen Rays Role Site Stress Stroke Structure Sulfhydryl Compounds Therapeutic Tissues Uncertainty Work base design dimethylargininase dimethylarginine enzyme activity experience inhibitor/antagonist interest malignant breast neoplasm mutant nitrosative stress novel therapeutics programs research study response small molecule tool tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Nitric oxide (NO) is a small reactive radical that plays a significant role in cancer biology. Aberrant production of NO and other oxidants is found in various types of tumors, including breast cancer, and also at sites of chronic inflammation, which have been associated with increased risk of human cancers. In addition, NO and other oxidants have been implicated in causing neuronal damage during ischemic stroke. Humans can regulate NO production by using endogenous inhibitors of NO synthase, monomethyl- and dimethylarginine. The concentrations of these inhibitors are controlled, in turn, by two tissue specific isoforms of dimethylargininase, DDAH-1 and DDAH-2, which hydrolyze these inhibitors to remove inhibition of NO production. These two DDAH isoforms represent attractive targets for pharmacological manipulation of NO, but not much is known about how these enzymes work, how they respond to oxidative and nitrosative stress, and whether they can be inhibited selectively by small molecules. This application has three specific aims 1) to determine the catalytic mechanism of DDAH, 2) to determine whether DDAH can be regulated by biologically relevant reactive oxygen or nitrogen species, and 3) to develop inhibitors of DDAH. These studies will be completed on purified proteins with an eye toward determining functional differences between isoforms that would impact their physiological roles and that can be exploited for design of selective inhibitors. By understanding the chemistry behind DDAH catalysis and regulation, we will develop new biochemical tools with therapeutic potential, and will learn more about the role that DDAH plays in cancer biology and in the general response to oxidative and nitrosative stress. Relevance to Public Health: This application studies a key control point for the production of nitric oxide, a reactive chemical that can cause significant health problems such as promoting tumor growth in certain cancers and causing brain damage during stroke if it is not properly regulated. An understanding of the chemistry behind how this control valve works will allow us to understand how humans react to stressful physiological conditions, and will give us new biochemical tools that can be later developed into novel therapeutics.

描述（由申请人提供）：一氧化氮（NO）是一种小的活性自由基，在癌症生物学中起着重要作用。NO和其他氧化剂的异常产生存在于各种类型的肿瘤中，包括乳腺癌，以及慢性炎症部位，这些部位与人类癌症风险增加有关。此外，NO和其他氧化剂与缺血性卒中期间引起神经元损伤有关。人类可以通过使用NO合成酶的内源性抑制剂单甲基精氨酸和二甲基精氨酸来调节NO的产生。这些抑制剂的浓度依次由二甲基精氨酸酶的两种组织特异性同种型DDAH-1和DDAH-2控制，所述DDAH-1和DDAH-2水解这些抑制剂以去除对NO产生的抑制。这两种DDAH亚型代表了NO药理学操作的有吸引力的靶点，但对这些酶如何工作，它们如何响应氧化和亚硝化应激以及它们是否可以被小分子选择性抑制知之甚少。本申请具有三个具体目的：1）确定DDAH的催化机制，2）确定DDAH是否可以由生物学相关的活性氧或氮物质调节，和3）开发DDAH的抑制剂。这些研究将在纯化的蛋白质上完成，着眼于确定异构体之间的功能差异，这些差异将影响其生理作用，并可用于设计选择性抑制剂。通过了解DDAH催化和调节背后的化学，我们将开发具有治疗潜力的新生化工具，并将更多地了解DDAH在癌症生物学中以及对氧化和亚硝化应激的一般反应中所起的作用。与公共卫生的相关性：该应用研究了一氧化氮产生的关键控制点，一氧化氮是一种反应性化学物质，如果没有得到适当的调节，可能会导致严重的健康问题，例如促进某些癌症的肿瘤生长，并在中风期间造成脑损伤。了解这种控制阀如何工作的化学原理将使我们了解人类如何对应激生理条件作出反应，并将为我们提供新的生化工具，这些工具可以在以后开发成新的治疗方法。