Collaborative Research: Mechanistic Studies on Fe-type Nitrile Hydration Catalysts

合作研究：铁型腈水合催化剂的机理研究

• 批准号: 1058396
• 负责人: Brian Bennett
• 金额: $ 9万
• 依托单位: Medical College of Wisconsin
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1058396&HistoricalAwards=false
• 关键词: Collaborative; Research; Mechanistic; Studies; Fe

This collaborative research award in the Chemistry of Life Processes (CLP) program supports work by Prof. Brian Bennett of the Department of Biophysics at the Medical College of Wisconsin to carry out a time-resolved pulsed-electron paramagnetic resonance (EPR) spectroscopic study of the mechanism of iron- and cobalt-containing nitrile hydratases (NHases), in collaboration with Prof. Richard C. Holz (CHE-1058357) at Loyola University, Chicago. The mechanism of the stereospecific hydration of nitriles by NHases is of fundamental interest, and the reaction is of great practical and economic importance in the pharmaceutical industry. Isotopically labeled (H-2, C-13, N-15) substrates and NHase enzyme will be incubated and collected by rapid-freeze-quench to trap pre-steady-state and steady-state intermediates, and these will be interrogated by pulsed EPR methods. Simulations will be used to obtain spin-Hamiltonian parameters from which the structures of the intermediates can be elucidated, and a mechanism deduced.It is anticipated that this research will pave the way for the design of chemical catalysts and engineered enzymes whose properties can be tailored toward specific substrates and desired reaction properties. This will greatly increase the range of pharmaceuticals and intermediates that rely on stereoselective nitrile hydration that can be profitably brought to market, and stimulate further research into new compounds of this class.

该生命过程化学 (CLP) 项目的合作研究奖支持威斯康星医学院生物物理系的 Brian Bennett 教授开展时间分辨脉冲电子顺磁共振 (EPR) 波谱研究与 Loyola 的 Richard C. Holz 教授 (CHE-1058357) 合作研究含铁和钴的腈水合酶 (NHases) 的机制大学，芝加哥。 NHase对腈进行立体定向水合的机理具有重要意义，并且该反应在制药工业中具有重要的实际和经济意义。 同位素标记（H-2、C-13、N-15）底物和 NHase 酶将通过快速冷冻淬灭进行孵育和收集，以捕获稳态前和稳态中间体，并通过脉冲对这些底物进行询问EPR 方法。 模拟将用于获得自旋哈密尔顿参数，从中可以阐明中间体的结构，并推断出机制。预计这项研究将为化学催化剂和工程酶的设计铺平道路，其性能可以定制针对特定的底物和所需的反应特性。 这将大大增加依赖立体选择性腈水合的药物和中间体的范围，这些药物和中间体可以在市场上获利，并刺激对此类新化合物的进一步研究。