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

这项生命过程化学（CLP）计划的合作研究奖支持威斯康星州医学院生物物理系的Brian班尼特教授与Richard C.霍尔茨（CHE-1058357）在洛约拉大学，芝加哥。 腈类化合物通过腈基水解酶的立体专一性水合反应的机理是人们感兴趣的基本问题，该反应在制药工业中具有重要的实用价值和经济价值。 将孵育同位素标记（H-2、C-13、N-15）底物和腈水合酶，并通过快速冷冻淬灭收集，以捕获预稳态和稳态中间体，并通过脉冲EPR方法对其进行询问。 模拟将被用来获得自旋哈密顿参数，从中可以阐明的中间体的结构，并推导出的mechanism.It预计，这项研究将铺平道路的化学催化剂和工程酶的设计，其性能可以针对特定的底物和所需的反应性能。 这将大大增加依赖于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被有利可图地推向市场，并刺激对这类新化合物的进一步研究。

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.