Co(II) Radical Pair Dynamics in B12 Enzyme Catalysis

B12 酶催化中的 Co(II) 自由基对动力学

基本信息

  • 批准号:
    10701941
  • 负责人:
  • 金额:
    $ 32.38万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1998
  • 资助国家:
    美国
  • 起止时间:
    1998-03-15 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

Project Summary The goal of the proposed research is to elucidate fundamental physical-chemical principles that govern catalysis in enzymes, with a focus on radical catalysis in coenzyme B12 (adenosylcobalamin) –dependent enzymes. This goal will be enacted through a program of biochemical and physical studies of representatives of all three classes of B12 enzymes: methylmalonyl-CoA mutase (MCM, Class I; human and Methylobacter extorquens), ethanolamine ammonia- lyase (EAL, Class II; Salmonella typhimurium), and lysine-5,6-aminomutase (Class III; LAM, Clostridium stricklandii). The approaches will be extended to address molecular mechanism in the intracellular cobalamin (B12) trafficking pathway in humans by the CblC and CblD proteins, and to the assembly and function of the bacterial microcompartment (BMC), an in vivo context of the EAL enzyme. Innovative methods, sofware and hardware for high-resolution pulsed- electron paramagnetic resonance (EPR) spectroscopy, in parallel with time- resolved, single-step reaction kinetics and steady-state solvent dynamics from continuous-wave EPR methods, applied in unique, low-temperature systems, will enable comprehensive characterization of the structural and dynamical contributions of solvent-protein-reaction coupling to radical rearrangement catalysis in the B12 enzymes. Significant biomedical and human health outcomes include: (i) fundamental knowledge about the role of protein and coupled solvent configurational states in enzyme function, latent at physiological temperatures, that contribute new tools, models and targets to the developing roadmap for leveraging these states in drug development and enzyme engineering, (ii) characterization of EAL, a contributor to the role of the gut microbiome in human health and disease progression, including links with inflammatory bowel disease, obesity, and diabetes, (iii) characterization of the assembly and function of the ethanolamine utilization (eut) BMC, one of a recently-recognized, widespread class of primitive, protein-encased bacterial organelles, (iv) insights into the molecular mechanistic basis of human metabolic disorders identified with the cbl gene cluster, and in particular, the role of the human CblC (MMACHC, methylmalonic aciduria type C and homocystinuria) and CblD proteins.
项目摘要 拟议研究的目标是阐明基本的物理化学 酶催化的原理,重点是自由基催化, 辅酶B12(腺苷钴胺素)依赖性酶。这一目标将 通过生物化学和物理研究计划制定, 所有三类B12酶的代表:甲基丙二酰辅酶A (MCM,I类;人和扭脱甲基杆菌),乙醇胺氨- 裂合酶(EAL,II类;鼠伤寒沙门氏菌)和赖氨酸-5,6-氨基变位酶 (III类; LAM,斯氏梭菌)。这些方法将扩展到 解决细胞内钴胺素(B12)运输的分子机制 通过CblC和CblD蛋白在人类中的途径,以及组装和 细菌微区室(BMC)的功能,EAL的体内背景 酵素创新的方法,软件和硬件,用于高分辨率脉冲- 电子顺磁共振(EPR)光谱,与时间平行, 解析的单步反应动力学和稳态溶剂动力学, 连续波EPR方法,应用于独特的,低温系统,将 能够全面表征结构和动力 溶剂-蛋白质-反应耦合对自由基重排的贡献 B12酶的催化作用重大的生物医学和人类健康成果 包括:(i)关于蛋白质和偶联溶剂作用的基本知识 酶功能中的构型状态,在生理温度下潜伏, 为开发路线图提供新的工具、模型和目标, 在药物开发和酶工程中利用这些状态,(ii) EAL的表征,这是人类肠道微生物组作用的贡献者 健康和疾病进展,包括与炎症性肠病的联系, 肥胖症和糖尿病,(iii)表征的组装和功能, 乙醇胺利用(eut)BMC,最近公认的,广泛的 一类原始的,蛋白质包裹的细菌细胞器,(四)洞察到 CBL鉴定的人类代谢紊乱的分子机制基础 基因簇,特别是人CblC(MMACHC, 甲基丙二酸尿症C型和高胱氨酸尿症)和CblD蛋白。

项目成果

期刊论文数量(40)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Photolysis of adenosylcobalamin and radical pair recombination in ethanolamine ammonia-lyase probed on the micro- to millisecond time scale by using time-resolved optical absorption spectroscopy.
使用时间分辨光学吸收光谱在微秒到毫秒的时间尺度上探测腺苷钴胺素的光解和乙醇胺解氨酶中的自由基对重组。
  • DOI:
    10.1021/bi801659e
  • 发表时间:
    2009
  • 期刊:
  • 影响因子:
    2.9
  • 作者:
    Robertson,WesleyD;Warncke,Kurt
  • 通讯作者:
    Warncke,Kurt
Dynamic Elevation of Aromatic Amino Acids in Hepatitis C Virus-Induced Cirrhosis After a Standard Meal.
标准膳食后丙型肝炎病毒引起的肝硬化中芳香氨基酸的动态升高。
  • DOI:
    10.14309/ctg.0000000000000666
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    3.6
  • 作者:
    Hill,KareenL;Haddad,JamesA;Ali,RababO;Zhang,GraceY;Quinn,GabriellaM;Townsend,Elizabeth;Everson,GregoryT;Helmke,SteveM;Bagheri,Mohammadhadi;Schoenfeld,Megan;Yang,Shanna;Koh,Christopher;Levy,ElliotB;Kleiner,DavidE;Sacks,
  • 通讯作者:
    Sacks,
Internal degrees of freedom, structural motifs, and conformational energetics of the 5'-deoxyadenosyl radical: implications for function in adenosylcobalamin-dependent enzymes. A computational study.
5-脱氧腺苷自由基的内部自由度、结构基序和构象能量学:对腺苷钴胺依赖性酶功能的影响。
  • DOI:
    10.1021/ja028393k
  • 发表时间:
    2003
  • 期刊:
  • 影响因子:
    15
  • 作者:
    Khoroshun,DmitryV;Warncke,Kurt;Ke,Shyue-Chu;Musaev,DjamaladdinG;Morokuma,Keiji
  • 通讯作者:
    Morokuma,Keiji
Control of Solvent Dynamics around the B12-Dependent Ethanolamine Ammonia-Lyase Enzyme in Frozen Aqueous Solution by Using Dimethyl Sulfoxide Modulation of Mesodomain Volume.
  • DOI:
    10.1021/acs.jpcb.9b02239
  • 发表时间:
    2019-06
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Benjamen Nforneh;K. Warncke
  • 通讯作者:
    Benjamen Nforneh;K. Warncke
Local structure and global patterning of Cu2+ binding in fibrillar amyloid-β [Aβ(1-40)] protein.
  • DOI:
    10.1021/ja306946q
  • 发表时间:
    2012-11-07
  • 期刊:
  • 影响因子:
    15
  • 作者:
    Gunderson WA;Hernández-Guzmán J;Karr JW;Sun L;Szalai VA;Warncke K
  • 通讯作者:
    Warncke K
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KURT WARNCKE其他文献

KURT WARNCKE的其他文献

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{{ truncateString('KURT WARNCKE', 18)}}的其他基金

Electron Paramagnetic Resonance Spectrometer
电子顺磁共振波谱仪
  • 批准号:
    6582101
  • 财政年份:
    2003
  • 资助金额:
    $ 32.38万
  • 项目类别:
COBALT(II)-RADICAL PAIR DYNAMICS IN B12 ENZYME CATALYSIS
B12 酶催化中的钴 (II)-自由基对动力学
  • 批准号:
    2703673
  • 财政年份:
    1998
  • 资助金额:
    $ 32.38万
  • 项目类别:
Co(II)-Radical Pair Dynamics in B12 Enzyme Catalysis
B12 酶催化中的 Co(II)-自由基对动力学
  • 批准号:
    7653881
  • 财政年份:
    1998
  • 资助金额:
    $ 32.38万
  • 项目类别:
COBALT(II)-RADICAL PAIR DYNAMICS IN B12 ENZYME CATALYSIS
B12 酶催化中的钴 (II)-自由基对动力学
  • 批准号:
    6489712
  • 财政年份:
    1998
  • 资助金额:
    $ 32.38万
  • 项目类别:
Co(II) Radical Pair Dynamics in B12 Enzyme Catalysis
B12 酶催化中的 Co(II) 自由基对动力学
  • 批准号:
    8918207
  • 财政年份:
    1998
  • 资助金额:
    $ 32.38万
  • 项目类别:
Co(II)-Radical Pair Dynamics in B12 Enzyme Catalysis
B12 酶催化中的 Co(II)-自由基对动力学
  • 批准号:
    7163573
  • 财政年份:
    1998
  • 资助金额:
    $ 32.38万
  • 项目类别:
Co(II)-Radical Pair Dynamics in B12 Enzyme Catalysis
B12 酶催化中的 Co(II)-自由基对动力学
  • 批准号:
    8266392
  • 财政年份:
    1998
  • 资助金额:
    $ 32.38万
  • 项目类别:
Co(II)-Radical Pair Dynamics in B12 Enzyme Catalysis
B12 酶催化中的 Co(II)-自由基对动力学
  • 批准号:
    6581018
  • 财政年份:
    1998
  • 资助金额:
    $ 32.38万
  • 项目类别:
COBALT(II)-RADICAL PAIR DYNAMICS IN B12 ENZYME CATALYSIS
B12 酶催化中的钴 (II)-自由基对动力学
  • 批准号:
    2856844
  • 财政年份:
    1998
  • 资助金额:
    $ 32.38万
  • 项目类别:
Co(II)-Radical Pair Dynamics in B12 Enzyme Catalysis
B12 酶催化中的 Co(II)-自由基对动力学
  • 批准号:
    7803563
  • 财政年份:
    1998
  • 资助金额:
    $ 32.38万
  • 项目类别:

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