STRUCTURE AND FUNCTION OF UNIQUE NON-HEME IRON DIOXYGENASES

独特的非血红素铁双加氧酶的结构和功能

• 批准号: 8170330
• 负责人: MICHAEL J MARONEY
• 金额: $ 0.03万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8170330
• 关键词: Active Sites; Address; Binding; Cancer Etiology; Chemistry; Collaborations; Complex; Computer Retrieval of Information on Scientific Projects Database; Cysteamine; Cysteine; Cysteine dioxygenase; DNA; Data; Dioxygenases; Enzymes; Family; Funding; Grant; Heme; Heme Iron; Homologous Gene; Institution; Ions; Iron; Lead; Ligands; Mutation; Nature; Oxidation-Reduction; Oxygen; Play; Reaction; Reducing Agents; Research; Research Personnel; Resources; Role; Source; Structure; United States National Institutes of Health; enzyme mechanism; medical schools; member; research study

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The proposed XAS experiments are part of a project aimed at characterizing the reaction mechanisms of two members of the nonheme Fe(II) dioxygenase family of enzymes, AlkB homologue 2 (ABH2, in collaboration with Prof. Max Costa, NYU School of Medicine) and cysteine dioxygenase (CDO). Specifically, we seek to use XAS to elucidate the mechanism by which Ni(II) ions inhibit AlkB and thus produce hypermethylated DNA, which in turn can cause cancer and lead to genetic defects. Second, we seek to understand the role played by cysteine and cysteamine in the redox chemistry of CDO. In the case of ABH2, XAS will provide some of the information regarding the sequential reaction mechanism (binding of a-ketoglutarate, not binding but change the iron geometry upon substrate binding, and oxygen activation) which in comparison with similar data from the Ni(II) complex will lead to a detailed understanding of the reaction mechanism and the mechanism by which Ni(II) inhibits the enzyme. In the case of CDO, the roles of cysteine and cysteamine as reductants and/or ligands will be addressed. By comparing and contrasting the mechanisms of these enzymes, we hope to further the understanding of how nature tunes the active sites of non-heme Fe(II) enzymes in order to catalyze the wide variety of different reactions that is a feature of this enzyme family.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 提出的XAS实验是一个项目的一部分，旨在表征酶的非血红素Fe（ii）二氧酶家族的两个成员，ALKB同源物2（ABH2）（ABH2，与Max Costa，NYU医学院）和Casteine dioxygengenase（CDO）合作。具体而言，我们试图使用XAS阐明Ni（II）离子抑制ALKB并因此产生高甲基化DNA的机制，从而导致癌症并导致遗传缺陷。其次，我们试图了解半胱氨酸和cysteamine在CDO的氧化还原化学中所扮演的角色。在ABH2的情况下，XAS将提供有关顺序反应机制的一些信息（A-酮戊二酸，不是结合，而不是结合，而是在底物结合时改变铁的几何形状和氧激活），与Ni（ii）的相似数据相比，这些信息与Ni（II）的详细理解Ni（II II INI）相比，这些数据将导致对ENI（II）的详细理解。在CDO的情况下，将解决半胱氨酸和半胱胺作为还原剂和/或配体的作用。通过比较和对比这些酶的机制，我们希望能够进一步理解自然如何调整非血红素Fe（II）酶的活性位点，以催化这种酶家族特征的各种不同反应。