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.

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）在芝加哥洛约拉大学。 NHASE立体特异性水合的机制具有基本利益，并且在制药行业中，这种反应具有极大的实践和经济意义。 同位素标记（H-2，C-13，N-15）底物和NHASE酶将通过快速冻结液体孵育并收集，以捕获前稳态和稳态中间体，并且这些中间体将受到脉冲EPR方法的质疑。 模拟将用于获取自旋 - 汉密尔顿参数，可以从中阐明中间体的结构，并推导出一种机制。预计这项研究将为设计化学催化剂和工程酶的设计铺平道路，这些酶可以针对特定的底物和所需的反应定制。 这将大大增加依赖于可以获利推向市场的立体选择性水合的药品和中间体的范围，并刺激对该类别的新化合物的进一步研究。