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Structural and Mechanistic Study of Mammalian Thiol Dioxygenases

哺乳动物硫醇双加氧酶的结构和机制研究

基本信息

批准号：
1808637
负责人：
Aimin Liu
金额：
$ 45万
依托单位：
University of Texas at San Antonio
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2022-09-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1808637&HistoricalAwards=false
关键词：
Structural Mechanistic Study Mammalian Thiol

项目摘要

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Aimin Liu from The University of Texas at San Antonio to investigate the structure and mechanism of two human enzymes involved in the oxidative sulfur metabolism. The two enzymes of interest, cysteine dioxygenase and cysteamine dioxygenase, are responsible for activating oxygen to process organic thiol moieties. The activity of these two enzymes is essential to manage metabolic cysteine and taurine concentrations and it is associated with autoimmune and neurological conditions, cellular signaling, energy balance, and fat metabolism. Integrated training is incorporated in the research project, which provides to students comprehensive and hands-on learning opportunities in biochemical and structural biology techniques. A multimedia presentation on electron paramagnetic resonance spectroscopy will be created and used to provide to students a tangible demonstration of how this advanced spectroscopy can clarify chemical properties of critical biomolecular systems. This research project seeks to reveal the mechanistic implications of adding oxygen atoms to electron-rich sulfur as well as the nature of the catalytic contribution of a protein-derived cofactor. The thiol dioxygenases utilize a mononuclear ferrous center to facilitate the incorporation of molecular oxygen into the thiol moiety of their respective substrates. These enzymes stand out as unique among dioxygenases because they add two of the oxygen atoms of molecular oxygen to a single substrate atom. Though other dioxygenases have been well studied, thiol dioxygenation is expected to proceed via a distinct mechanism that has not been well established yet. Dr. Liu is investigating the formation of the catalytic ensemble of these enzymes, namely an iron- and oxygen-dependent process for generating a catalytic amplifier known as the protein-derived cofactor. A wide array of techniques, including protein engineering, EPR spectroscopy, stopped-flow rapid kinetics, and protein X-ray crystallography, are employed in the determination of the chemical steps of cofactor biogenesis and sulfur oxygenation. The completion of this project is expected to reveal new mechanistic implications of adding two oxygen atoms to one electron-rich sulfur as well as the nature of the catalytic contribution of the protein-derived cofactor to sulfur metabolism.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

有了这个奖项，化学部的生命过程化学项目正在资助德克萨斯大学圣安东尼奥分校的刘爱民博士研究参与氧化硫代谢的两种人类酶的结构和机制。感兴趣的两种酶，半胱氨酸双加氧酶和半胱胺双加氧酶，负责活化氧以加工有机硫醇部分。这两种酶的活性对于管理代谢半胱氨酸和牛磺酸浓度是必不可少的，并且它与自身免疫和神经病症、细胞信号传导、能量平衡和脂肪代谢相关。研究计划包括综合训练，为学生提供全面和实践的学习机会，学习生物化学和结构生物学技术。电子顺磁共振光谱学的多媒体演示将被创建并用于为学生提供这种先进的光谱学如何澄清关键生物分子系统的化学性质的有形演示。该研究项目旨在揭示将氧原子添加到富含电子的硫中的机械含义以及蛋白质衍生辅因子的催化贡献的性质。硫醇双加氧酶利用单核亚铁中心来促进分子氧掺入其各自底物的硫醇部分中。这些酶在双加氧酶中脱颖而出，因为它们将分子氧的两个氧原子添加到单个底物原子上。虽然其他双加氧酶已经得到很好的研究，硫醇双加氧预计将通过一个独特的机制，尚未得到很好的建立。刘博士正在研究这些酶的催化体系的形成，即一个铁和氧依赖的过程，用于产生一种被称为蛋白质衍生辅因子的催化放大器。一系列广泛的技术，包括蛋白质工程，EPR光谱，停流快速动力学，和蛋白质X射线晶体学，在确定的化学步骤的辅因子生物合成和硫氧化。该项目的完成有望揭示将两个氧原子添加到一个富含电子的硫的新的机理含义，以及蛋白质衍生的辅因子对硫代谢的催化作用的性质。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cofactor Biogenesis in Cysteamine Dioxygenase: C−F Bond Cleavage with Genetically Incorporated Unnatural Tyrosine

半胱胺双加氧酶中的辅因子生物发生：基因掺入的非天然酪氨酸导致 C–F 键断裂

DOI：
10.1002/ange.201803907
发表时间：
2018
期刊：
Angewandte Chemie
影响因子：
0
作者：
Wang, Yifan;Griffith, Wendell P.;Li, Jiasong;Koto, Teruaki;Wherritt, Daniel J.;Fritz, Elizabeth;Liu, Aimin
通讯作者：
Liu, Aimin

Probing Extradiol Dioxygenase Mechanism in NAD+ Biosynthesis by Viewing Reaction Cycle Intermediates

通过观察反应循环中间体探讨 NAD 生物合成中的外二醇双加氧酶机制

DOI：
10.1002/9781119951438.eibc2813
发表时间：
2022
期刊：
Encyclopedia of Inorganic and Bioinorganic Chemistry
影响因子：
0
作者：
Davis, Ian;Liu, Aimin
通讯作者：
Liu, Aimin

Observing 3-hydroxyanthranilate-3,4-dioxygenase in action through a crystalline lens

通过晶状体观察 3-羟基邻氨基苯甲酸-3,4-双加氧酶的作用

DOI：
10.1073/pnas.2005327117
发表时间：
2020
期刊：
Proceedings of the National Academy of Sciences
影响因子：
0
作者：
Wang, Yifan;Liu, Kathy Fange;Yang, Yu;Davis, Ian;Liu, Aimin
通讯作者：
Liu, Aimin

Probing the Cys-Tyr Cofactor Biogenesis in Cysteine Dioxygenase by the Genetic Incorporation of Fluorotyrosine

DOI：
10.1021/acs.biochem.9b00006
发表时间：
2019-04-30
期刊：
BIOCHEMISTRY
影响因子：
2.9
作者：
Li, Jiasong;Koto, Teruaki;Liu, Aimin
通讯作者：
Liu, Aimin

Characterization of the non-heme iron center of cysteamine dioxygenase and its interaction with substrates

半胱胺双加氧酶非血红素铁中心的表征及其与底物的相互作用

DOI：
10.1074/jbc.ra120.013915
发表时间：
2020
期刊：
Journal of Biological Chemistry
影响因子：
4.8
作者：
Wang, Yifan;Davis, Ian;Chen, Yan;Naik, Sunil G.;Griffith, Wendell P.;Liu, Aimin
通讯作者：
Liu, Aimin