权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
KURT WARNCKE
金额：
$ 32.38万
依托单位：
EMORY UNIVERSITY
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

来源：
https://reporter.nih.gov/project-details/10701941
关键词：
Active Sites Address Articulation Biochemical CBL Protein CBL gene Catalysis Chemicals Chemistry Clostridium Cobalamin Computer software Coupled Coupling Dependence Diabetes Mellitus Disease Disease Progression Drug Modelings Electron Spin Resonance Spectroscopy Encapsulated Engineering Enzymes Ethanolamine Ammonia-Lyase Ethanolamines Foundations Funding Gene Cluster Goals Health Homocystinuria Human In Vitro Inflammatory Bowel Diseases Kinetics Knowledge Link Lysine Mediating Membrane Proteins Metabolic Diseases Methods Methylmalonyl-CoA Mutase Modeling Molecular Molecular Conformation Molecular Structure Obesity Organelles Outcome Pathway interactions Physiologic pulse Physiological Proteins Reaction Research Resolution Role Salmonella typhimurium Site Solvents Spin Labels Structure System Temperature Time analytical method cobamamide cold temperature drug development fluidity gut microbiome in vivo innovation insight methylmalonic aciduria programs repaired tool trafficking

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.

项目总结

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：
Biochemistry
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：
Clinical and translational gastroenterology
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：
Journal of the American Chemical Society
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.