NOVEL AMIDASES FOR SYNTHETIC ORGANIC CHEMISTRY

酰胺水解酶(酰胺酶)在体内催化酰胺键与相应的胺和羧酸的水解。酰胺酶的催化特性对开发具有细胞毒活性的新药和/或药物中间体具有重要意义。虽然这些氨基水解酶具有工业应用的潜力，但到目前为止还很少被描述，而且它们受到底物专一性和稳定性问题的限制。微生物酶在有机合成反应中的应用具有底物专一性高、反应条件温和、底物转化完全、产生化学废物少等优点。耐热酶通常提供所有这些特征以及增强的稳定性。Thermogen建议开发一种稳定的氨基水解酶工具箱和一种用于有机合成反应的高效、可扩展的技术。在第一阶段，我们将通过鉴定一组由新的酰胺酶或诱变的酰胺酶组成的10种酶来证明其可行性，这些酶具有更广泛的底物特异性和稳定性。在第二阶段，我们将开发优化合成条件、酶生产和扩大底物范围的方法，并进一步设计酶。在第三阶段，我们将把酶和技术商业化，供合成有机化学家和制药商使用。建议的商业应用：Thermogen建议开发新型的氨基水解酶，用作区域化学和立体选择性有机合成反应的合成工具。酰胺酶将有助于高效、经济地合成抗癌药物或中间体，并减少化学废物的产生。

Amidohydrolases (amidases) catalyze in vivo the hydrolysis of amide bonds to the corresponding amine and carboxylic acid. The catalytic properties of amidases are of great interest to develop new drugs and/or pharmaceutical intermediates with cytotoxic activity. While these amidohydrolases have potential for industrial applications, few have been described to date, and they are limited by substrate specificity and stability problems. The application of microbial enzymes for organic synthetic reactions can offer high substrate specificity, complete substrate conversion under mild reaction conditions, and less chemical waste generation. Thermostable enzymes in general offer all these features as well as enhanced stability. ThermoGen proposes to develop a toolbox of stable amidohydrolases and an efficient, scaleable technology for use in organic synthesis reactions. In Phase I we will show feasibility by identifying a set of ten enzymes made up of either new amidases or mutagenized amidases with broader substrate specificity and stability. In Phase II we will develop methods for optimal synthesis conditions, enzyme production, and expansion of the substrate range and further engineer the enzymes. In Phase III, we will commercialize the enzymes and technology for use by synthetic organic chemists and pharmaceutical manufacturers. PROPOSED COMMERCIAL APPLICATIONS: ThermoGen proposes to develop novel amidohydrolases for use as synthetic tools in regio- chemo- and stereoselective organic synthetic reactions. Amidases will help synthesize anticancer drugs or intermediates efficiently and economically and will reduce the chemical waste generation.