Investigation of a Pterin-Dithiolene Model Complex for the Molybdenum Cofactor

钼辅因子蝶呤-二硫醇模型复合物的研究

• 批准号: 8626671
• 负责人: SHARON Nieter BURGMAYER
• 金额: $ 28.47万
• 依托单位: BRYN MAWR COLLEGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-06 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8626671
• 关键词: Active Sites; Address; Affect; Behavior; Benchmarking; Biological Models; Biological Process; Carbon; Catalysis; Catalytic Domain; Chemicals; Chemistry; Complex; Copper; Cyclization; Disease; Electronics; Elements; Embryonic Development; Environment; Enzymes; Exhibits; Future; General Population; Goals; Grant; Health; Homo sapiens; Human; Infant; Inherited; Investigation; Iron; Knowledge; Life; Ligands; Link; Metals; Methods; Modeling; Molecular Conformation; Molybdenum; Neurologic; Nitrogen; Organism; Oxidation-Reduction; Play; Positioning Attribute; Property; Proteins; Pterins; Pyrans; Reaction; Research; Role; Site; Structure; Study models; Sulfur; System; Transition Elements; Tungsten; Zinc; base; design; electronic structure; enzyme activity; human disease; insight; interest; molybdenum cofactor; programs; public health relevance; pyranopterin

Summary/Abstract Molybdenum (Mo) is critical to the health of nearly every organism on earth. Humans have an absolute requirement for several molybdenum enzymes and one in particular is critical for proper embryo development to maturity. Inherited diseases in humans result in compromised molybdenum enzymes causing pervasive neurological problems at best and infant fatalities at worst. Despite fifty years' of research on molybdenum enzymes, the function and certain structural aspects of the unique ligand chelating Mo in these proteins remain a mystery. This ligand is a pterin-substituted dithiolene chelate and is found only in molybdenum and the related tungsten enzymes. Human diseases resulting from molybdoenzyme disfunction have been linked to errors in the pterin-dithiolene biosynthetic path which underscores the pivotal role of the ligand in enzyme function. This project will undertake a detailed study of the chemical behavior and reactivity of a Mo-pyranopterin- dithiolene model complex designed to be nearly identical to the Mo site in the enzymes. The goal is to understand how conformation and redox changes at the pterin influence the electronic structure of the entire pterin-dithiolene ligand coordinated to Mo in the enzymes. Of particular interest is establishing the pyran ring reactivity towards scission and how the gamut of known pterin redox chemistry is altered when pterin is fused to a pyran ring and a dithiolene ligand. Specific objectives are: (a) to determine those factors that influence pyran ring cyclization and cleavage on pterin-dithiolene ligands chelated to Mo; (b) to understand the redox chemistry and properties of pyranopterin dithiolene ligands using chemical and electrochemical methods; (c) to probe the electronic effects of pterins at different levels of reduction on the Mo-dithiolene unit; and (d) to accomplish full spectroscopic and structural characterization of all model compounds. The results are critical to a complete understanding of how the Mo site functions and how the pterin-dithiolene might be involved in dysfunctional enzymes. It is expected that these studies will: a) reveal what chemical reactivity exists for pterin-dithiolene ligands within the Mo enzymes, and this understanding will b) provide insights for how the protein environment could influence pterin behavior; (c) provide spectroscopic and structural benchmarks to aid interpretation of similar results from the enzymes and (d) describe fundamental chemistry of the active site chemistry of Mo and W enzymes to be exploited for possible future therapies.

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项目成果

Solvent-Dependent Pyranopterin Cyclization in Molybdenum Cofactor Model Complexes.

钼辅因子模型复合物中溶剂依赖性吡喃蝶呤环化。

• DOI: 10.1021/acs.inorgchem.5b00532
• 发表时间: 2015
• 期刊: Inorganic chemistry
• 影响因子: 4.6
• 作者: Williams,BenjaminR;Gisewhite,Douglas;Kalinsky,Anna;Esmail,Alisha;Burgmayer,SharonJNieter
• 通讯作者: Burgmayer,SharonJNieter

Making Moco: A Personal History.

• DOI: 10.3390/molecules28217296
• 发表时间: 2023-10-27
• 期刊: Molecules (Basel, Switzerland)
• 作者: Burgmayer SJN

Structure and reversible pyran formation in molybdenum pyranopterin dithiolene models of the molybdenum cofactor.

钼辅因子的吡喃蝶呤二硫烯模型的结构和可逆吡喃形成。

• DOI: 10.1021/ja310018e
• 发表时间: 2012
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Williams,BenjaminR;Fu,Yichun;Yap,GlennPA;Burgmayer,SharonJNieter
• 通讯作者: Burgmayer,SharonJNieter