Structure and Mechanism of Myo-Inositol Oxygenase
肌醇加氧酶的结构和机制
基本信息
- 批准号:7575616
- 负责人:
- 金额:$ 28.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-01-15 至 2010-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): Myo-inositol oxygenase (MIOX) catalyzes the first step in the only known pathway in humans for breakdown of myo-inositol (Ml), the sugar backbone of cell-signaling phosphoinositides. Evidence suggests that increased expression or activity of MIOX may contribute to pathologies commonly associated with diabetes mellitus, marking MIOX as a potential drug target. Our preliminary data show that the MIOX reaction proceeds via an unprecedented chemical mechanism. A non-heme diiron cluster in its mixed-valent, ll/lll, oxidation state, which probably coordinates one or more oxygen atoms of the substrate, reacts with molecular oxygen to generate a formally diiron(lll/lll)-superoxide complex, which abstracts hydrogen from the substrate. We seek to determine by biophysical and biochemical methods: (1) the structure of this unique enzyme and its diiron cofactor; (2) how the protein promotes initial formation and stability of the active, mixed-valent form (which is unstable in many other non-heme diiron proteins); (3) how the substrate interacts with the protein and cofactor; (4) whether and how this interaction activates the cofactor or substrate (or both) for subsequent reaction with O2; and (5) the nature and rate of each chemical step leading from addition of oxygen to the enzyme*substrate complex through release of the product along with the structures of two reactive intermediates that we have already discovered and additional intermediates that remain to be discovered in this sequence. By so doing, we hope to provide the necessary tools for rational design of MIOX inhibitors that could be useful in combating complications from diabetes mellitus.
描述(由申请人提供):肌醇氧合酶(MIOX)催化人类唯一已知的途径的第一步,即肌醇(ML)损坏,这是细胞信号磷酸固醇的糖骨架。有证据表明,MIOX的表达或活性增加可能有助于通常与糖尿病有关的病理,将Miox标记为潜在的药物靶标。我们的初步数据表明,Miox反应通过前所未有的化学机制进行。在其混合价值的LL/LLL,氧化状态中,非血红素二铁簇可能与底物的一个或多个氧原子配合,与分子氧反应形式上产生一种形式上的二铁(LLL/LLL)-Superoxide-superoxide络合物,从底物中抽象氢气。我们试图通过生物物理和生化方法来确定:(1)这种独特的酶及其二烯辅助因子的结构; (2)蛋白质如何促进活性,混合形式的初始形成和稳定性(在许多其他非血红素二铁蛋白中是不稳定的); (3)底物如何与蛋白质和辅因子相互作用; (4)这种相互作用是否以及如何激活辅因子或底物(或两者),以使其与O2进行后续反应; (5)从添加氧气到酶*底物复合物的每个化学步骤的性质和速率,以及我们已经发现的两个反应性中间体的结构以及在此序列中待发现的其他中间体的结构。通过这样做,我们希望为Miox抑制剂的合理设计提供必要的工具,这些工具可用于打击糖尿病并发症。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

暂无数据
数据更新时间:2024-06-01
JOSEPH M BOLLINGER的其他基金
Structures and Mechanisms of “Heme-oxygenase-like” Non-heme Di-iron Enzymes that Catalyze Complex N-oxygenation and Olefin-installing C–C-Fragmentation Reactions
催化复杂 N-氧化和烯烃安装 C-C 断裂反应的“类血红素加氧酶”非血红素双铁酶的结构和机制
- 批准号:1064784310647843
- 财政年份:2020
- 资助金额:$ 28.91万$ 28.91万
- 项目类别:
Structures and Mechanisms of “Heme-oxygenase-like” Non-heme Di-iron Enzymes that Catalyze Complex N-oxygenation and Olefin-installing C–C-Fragmentation Reactions
催化复杂 N-氧化和烯烃安装 C-C 断裂反应的“类血红素加氧酶”非血红素双铁酶的结构和机制
- 批准号:1042862410428624
- 财政年份:2020
- 资助金额:$ 28.91万$ 28.91万
- 项目类别:
Structures and Mechanisms of “Heme-oxygenase-like” Non-heme Di-iron Enzymes that Catalyze Complex N-oxygenation and Olefin-installing C–C-Fragmentation Reactions
催化复杂 N-氧化和烯烃安装 C-C 断裂反应的“类血红素加氧酶”非血红素双铁酶的结构和机制
- 批准号:1003521810035218
- 财政年份:2020
- 资助金额:$ 28.91万$ 28.91万
- 项目类别:
Structures and Mechanisms of “Heme-oxygenase-like” Non-heme Di-iron Enzymes that Catalyze Complex N-oxygenation and Olefin-installing C–C-Fragmentation Reactions
催化复杂 N-氧化和烯烃安装 C-C 断裂反应的“类血红素加氧酶”非血红素双铁酶的结构和机制
- 批准号:1020891010208910
- 财政年份:2020
- 资助金额:$ 28.91万$ 28.91万
- 项目类别:
Diverse Transition-Metal and Free-Radical Chemistry Enabling 2'-Deoxyribonucleotide Production by Bacteria in Restrictive Environments
多种过渡金属和自由基化学使细菌在限制性环境中生产 2-脱氧核糖核苷酸
- 批准号:1016575310165753
- 财政年份:2019
- 资助金额:$ 28.91万$ 28.91万
- 项目类别:
Diverse Transition-Metal and Free-Radical Chemistry Enabling 2'-Deoxyribonucleotide Production by Bacteria in Restrictive Environments
多种过渡金属和自由基化学使细菌在限制性环境中生产 2-脱氧核糖核苷酸
- 批准号:1041712510417125
- 财政年份:2019
- 资助金额:$ 28.91万$ 28.91万
- 项目类别:
Mechanisms and Reprogramming of Iron/2-Oxoglutarate Desaturases and Oxacyclases
铁/2-氧戊二酸去饱和酶和氧杂环酶的机制和重编程
- 批准号:92629899262989
- 财政年份:2016
- 资助金额:$ 28.91万$ 28.91万
- 项目类别:
Mechanisms and Reprogramming of Iron/2-Oxoglutarate Desaturases and Oxacyclases
铁/2-氧戊二酸去饱和酶和氧杂环酶的机制和重编程
- 批准号:90840039084003
- 财政年份:2016
- 资助金额:$ 28.91万$ 28.91万
- 项目类别:
Mechanisms of oxacycle- and olefin-installing iron/2-(oxo)glutarate oxygenases
安装氧杂环和烯烃的铁/2-(氧代)戊二酸加氧酶的机制
- 批准号:91399629139962
- 财政年份:2015
- 资助金额:$ 28.91万$ 28.91万
- 项目类别:
Mechanisms of oxacycle- and olefin-installing iron/2-(oxo)glutarate oxygenases
安装氧杂环和烯烃的铁/2-(氧代)戊二酸加氧酶的机制
- 批准号:89651038965103
- 财政年份:2015
- 资助金额:$ 28.91万$ 28.91万
- 项目类别:
相似国自然基金
拟南芥中EIN2蛋白调控mRNA翻译并激活乙烯信号的生化机制研究
- 批准号:31870254
- 批准年份:2018
- 资助金额:60.0 万元
- 项目类别:面上项目
大米蛋白/阿魏酸的结合机制对复合物的抗氧化及模拟胃肠消化性能的调控研究
- 批准号:31760433
- 批准年份:2017
- 资助金额:38.0 万元
- 项目类别:地区科学基金项目
拟南芥fimbrin5调控花粉管生长的细胞学基础和生化机制分析
- 批准号:31671390
- 批准年份:2016
- 资助金额:60.0 万元
- 项目类别:面上项目
拟南芥微丝解聚因子第三亚家族成员生理生化功能研究
- 批准号:31670180
- 批准年份:2016
- 资助金额:65.0 万元
- 项目类别:面上项目
结合神经分类的分子超光谱成像生化指标定量分析研究
- 批准号:61240006
- 批准年份:2012
- 资助金额:10.0 万元
- 项目类别:专项基金项目
相似海外基金
DNA repair pathway coordination during damage processing
损伤处理过程中 DNA 修复途径的协调
- 批准号:1074847910748479
- 财政年份:2024
- 资助金额:$ 28.91万$ 28.91万
- 项目类别:
Endothelial Cell Reprogramming in Familial Intracranial Aneurysm
家族性颅内动脉瘤的内皮细胞重编程
- 批准号:1059540410595404
- 财政年份:2023
- 资助金额:$ 28.91万$ 28.91万
- 项目类别:
Selective targeting of matrix metalloproteinases for developing preterm labor therapeutics
选择性靶向基质金属蛋白酶用于开发早产疗法
- 批准号:1050978610509786
- 财政年份:2023
- 资助金额:$ 28.91万$ 28.91万
- 项目类别:
Role of skeletal muscle IPMK in nutrient metabolism and exercise
骨骼肌IPMK在营养代谢和运动中的作用
- 批准号:1063907310639073
- 财政年份:2023
- 资助金额:$ 28.91万$ 28.91万
- 项目类别:
The role of ZCWPW1 in meiosis
ZCWPW1 在减数分裂中的作用
- 批准号:1068018910680189
- 财政年份:2023
- 资助金额:$ 28.91万$ 28.91万
- 项目类别: