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: 1412443
• 负责人: Richard Holz
• 金额: $ 20.4万
• 依托单位: Marquette University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1412443&HistoricalAwards=false
• 关键词: Collaborative; Research; Mechanistic; Studies; Fe

Nitriles are used extensively in the production of specialty chemicals like the polyamide nylon. Nitrile hydratases (NHases) catalyze the hydration of nitriles to amides at ambient temperatures in neutral water. The currently employed industrial conditions for the hydration of nitriles to amides use either strong acids or bases, and are often incompatible with the sensitive structures of the compounds to be produced. NHases have therefore attracted substantial interest as biocatalysts in preparative organic chemistry. Despite the industrial importance of NHase enzymes, the details of how they work remain poorly understood. The objective of this research proposal is to fill this knowledge gap. The interdisciplinary nature of the effort will serve as a platform to increase the participation of women and classically underrepresented graduate and undergraduate students in scientific careers in biophysics, chemistry, and biochemistry. As part of the proposed project, both PI's will participate in the SMART program that mentors Milwaukee area public high school students in research projects.With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Drs. Richard C. Holz and Brian Bennett from Marquette University to elucidate the catalytic mechanism of NHase enzymes. An interdisciplinary approach will be used that will incorporate kinetics, spectroscopy, biochemistry, computational chemistry, and both X-ray and neutron crystallography. The proposed experimental approach is designed to address three key questions: i) What is the transition-state structure of nitrile hydration? ii) What are the protonation states of catalytically important species throughout the reaction? and iii) What controls metallocenter assembly in a purported eukaryotic NHase? The successful completion of this research will greatly benefit society by facilitating the intelligent design and manufacture of nitrile-based chiral pharmaceuticals and industrially important specialty chemicals, with enhanced synthetic flexibility and lower environmental impact, than at present.

腈广泛用于生产聚酰胺尼龙等特种化学品。 腈水合酶 (NHase) 在环境温度下在中性水中催化腈水合为酰胺。 目前用于将腈水合成酰胺的工业条件使用强酸或强碱，并且通常与待生产的化合物的敏感结构不相容。因此，NHase 作为制备有机化学中的生物催化剂引起了人们的极大兴趣。 尽管 NHase 酶在工业上具有重要意义，但人们对其工作原理的细节仍知之甚少。 本研究提案的目的是填补这一知识空白。 这项工作的跨学科性质将成为一个平台，以增加女性和传统上代表性不足的研究生和本科生在生物物理学、化学和生物化学科学职业中的参与。 作为拟议项目的一部分，两位 PI 将参加 SMART 计划，该计划指导密尔沃基地区公立高中学生的研究项目。通过该奖项，化学部门的生命过程化学计划将资助 Drs.马凯特大学的 Richard C. Holz 和 Brian Bennett 阐明了 NHase 酶的催化机制。 将采用跨学科方法，将动力学、光谱学、生物化学、计算化学以及 X 射线和中子晶体学结合起来。 所提出的实验方法旨在解决三个关键问题：i）腈水合的过渡态结构是什么？ ii) 在整个反应过程中，催化重要物质的质子化状态是什么？ iii) 真核 NHase 中的金属中心组装由什么控制？ 这项研究的成功完成将促进基于腈的手性药物和工业上重要的特种化学品的智能设计和制造，与目前相比，具有更高的合成灵活性和更低的环境影响，从而极大造福社会。