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Dihydropteridine Reductase: Mechanism of Enzyme Action

二氢蝶啶还原酶：酶作用机制

基本信息

批准号：
8401521
负责人：
RUEL Z B DESAMERO
金额：
$ 11.36万
依托单位：
YORK COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8401521
关键词：
7,8-dihydrobiopterin Address American Applications Grants Basic Science Binding Biochemical Reaction Biochemistry Brain Caenorhabditis elegans Catalysis Catecholamines Chemicals Chemistry Collaborations Complex Cysteine Defect Department of Defense Development Diffusion Dihydropteridine Reductase Deficiency Disease Dinucleoside Phosphates Disease Disulfides Docking Drug Design Engineering Ensure Enzymatic Biochemistry Enzymes Event Face Fluorescence Funding Future Goals Grant Growth Factor Health Hormone Receptor Human Hydrogen Peroxide Indoles Investigation Kinetics Letters Ligands Measurement Measures Mediating Medicine Metals Molecular Monitor NADH Neurotransmitters Niacinamide Nutrient Oxidants Oxidoreductase Paper Petroleum Play Positioning Attribute Preparation Process Productivity Protein Biochemistry Protein Conformation Proteins Publications Published Comment Quinones Rattus Reaction Recycling Reducing Agents Regulation Reporting Research Research Personnel Research Support Roentgen Rays Role Secure Serotonin Societies Source Spectrum Analysis Structure Substrate Interaction Sulfhydryl Compounds System Techniques Tryptophan Work Writing base career cofactor college dihydropteridine reductase dimer enzyme mechanism enzyme substrate improved inhibitor/antagonist insight instrument interest monomer nervous system disorder programs protein structure simulation small molecule temperature jump tetrahydrobiopterin willingness

项目摘要

DESCRIPTION (provided by applicant): Enzyme-substrate interactions have long been recognized as representing an extreme expression of structural complementarities in biological chemistry. An enzymatic reaction can be broken down into two main aspects. The first involves the diffusion-controlled formation of the encounter complex, and the second involves the appropriate structural and dynamical arrangements of the enzyme domains as dictated by the reaction chemistry. It is the long-term goal of the PIs research program to investigate enzyme-small molecule (inhibitor, substrate, or cofactor) interactions in order to unravel the structural and dynamical aspects of its reaction. This proposal aims to study the hydride transfer mechanism involved in DHPR. Dehydropteridine reductase (DHPR) catalyses the NADH-mediated reduction of quinonoid dihydrobiopterin (qBH2) to yield tetrahydrobiopterin (BH4). BH4 functions as an essential cofactor, and its absence leads to depletion in the brain of precursors of catecholamine and serotonin neurotransmitters. Regulation of DHPR became of interest when a new form of hyperphenylalanineanemia (atypical phenylketonuria) associated with a defect in BH4 recycling was discovered. In the light of other new emerging functions, there is a growing need to completely understand how DHPR works. The overall objective of the investigation is to understand the structural changes that occur when DHPR binds cofactor, substrate or inhibitor. Using advanced fluorescence and vibrational techniques, we will identify catalytically important bonds as well as detect major protein conformational changes that may accompany binding and catalysis. We will also look at the dynamical aspects of the binding and catalytic events using fluorescence-based temperature-jump studies. The results will be married to the solved X-ray crystal structures of DHPR to gain insights into the mechanism of enzyme action. In particular, we would like to address the mechanistic role of the cofactor and the conserved Cys residue. Since DHPR belongs to a superfamily of biologically important short-chain dehydrogenases/reductases (SDRs), it is hoped that the gathered results could provide some mechanistic details useful for studying SDRs. SDRs have diverse functions. Some are good pharmacological targets while others are important in controlling the cellular availability of a hormone receptor ligand. There are also those that have essential role in growth factors or nutrient synthesis. Understanding the enzymology of DHPR at the molecular level will play a part in realizing the untold potential for drug design, enzyme regulation, and enzyme engineering.

描述（由申请人提供）：酶-底物相互作用长期以来被认为是生物化学中结构互补性的极端表达。酶促反应可以分为两个主要方面。第一个涉及的扩散控制的形成的遭遇复杂的，第二个涉及适当的结构和动力学安排的酶结构域所规定的反应化学。研究酶-小分子（抑制剂、底物或辅因子）相互作用以揭示其反应的结构和动力学方面是PI研究计划的长期目标。本研究旨在探讨DHPR的氢化物转移机制。脱氢蝶啶还原酶（DHPR）催化NADH介导的喹喔啉二氢生物蝶呤（qBH 2）的还原以产生四氢生物蝶呤（BH 4）。BH 4作为一种重要的辅因子发挥作用，它的缺乏导致脑中儿茶酚胺和5-羟色胺神经递质前体的耗尽。当发现一种与BH 4再循环缺陷相关的新形式的高苯丙氨酸贫血（非典型苯丙酮尿症）时，DHPR的调节变得有趣。鉴于其他新出现的功能，越来越需要完全了解DHPR是如何工作的。研究的总体目标是了解DHPR结合辅因子、底物或抑制剂时发生的结构变化。使用先进的荧光和振动技术，我们将确定催化重要的债券，以及检测主要蛋白质构象的变化，可能伴随着结合和催化。我们还将着眼于使用基于荧光的温度跳跃研究的结合和催化事件的动力学方面。这些结果将与DHPR的X射线晶体结构相结合，以深入了解酶的作用机制。特别是，我们想解决的辅助因子和保守的半胱氨酸残基的机械作用。由于DHPR属于生物学上重要的短链还原酶（SDRs）超家族，因此希望收集的结果可以为研究SDRs提供一些有用的机制细节。特别提款权具有多种功能。一些是良好的药理学靶点，而另一些在控制激素受体配体的细胞可用性方面是重要的。还有那些在生长因子或营养合成中起重要作用的。在分子水平上理解DHPR的酶学将在实现药物设计，酶调节和酶工程的无限潜力中发挥作用。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Conformational Differentiation of α-Cyanohydroxycinnamic Acid Isomers: A Raman Spectroscopic Study.

DOI：
10.1002/jrs.5209
发表时间：
2017-10
期刊：
Journal of Raman spectroscopy : JRS
影响因子：
0
作者：
Vedad J;Domaradzki ME;Mojica EE;Chang EJ;Profit AA;Desamero RZB
通讯作者：
Desamero RZB

Evidence of π-stacking interactions in the self-assembly of hIAPP(22-29).

DOI：
10.1002/prot.24229
发表时间：
2013-04
期刊：
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
影响因子：
2.9
作者：
Profit, Adam A.;Felsen, Valentina;Chinwong, Justina;Mojica, Elmer-Rico E.;Desamero, Ruel Z. B.
通讯作者：
Desamero, Ruel Z. B.

Raman Spectroscopic Discrimination of Estrogens.