NOVEL DHAP-DEPENDENT ALDOLASES FOR ORGANIC SYNTHESIS

用于有机合成的新型 DHAP 依赖性醛缩酶

• 批准号: 6072124
• 负责人: FRANCISCO MORIS-VARAS
• 金额: $ 11.31万
• 依托单位: THERMOGEN,INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-15 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6072124
• 关键词: aldehyde lyase; biological products; biotransformation; chemical stability; chemical synthesis; dihydroxyacetone; enzyme activity; enzyme substrate; high throughput technology; phosphates; technology /technique development; thermostability

DHAP-dependent aldolases catalyze the C-C bond condensation of DHAP and an aldehyde. The products of this reaction show high therapeutic value as drugs or pharmaceutical intermediates. While these aldolases have potential for industrial applications, the enzymes described to date have stability problems and are limited by their substrate specificities. 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 set of stable DHAP-dependent aldolases and an efficient, scaleable technology for use in organic synthesis reactions. In Phase I we will show feasibility by identifying a set of four enzymes with different stereoselectivities made up of either new aldolases or mutagenized aldolases with broader substrate specificities and stability. We will also identify key reaction parameters to test synthetic utility and demonstrate their ability to catalyze model synthetic reactions. In Phase II we will develop methods for optimal synthesis conditions, enzyme production, and expand the substrate range. 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 DHAP-dependent aldolases for use as synthetic tools in stereoselective organic synthetic reactions. Aldolases will help syntheses or pharmaceutical drugs or intermediates efficiently and economically and reduce the chemical waste generation.

DHAP 依赖性醛缩酶催化 DHAP 和醛的 C-C 键缩合。该反应产物作为药物或医药中间体显示出很高的治疗价值。虽然这些醛缩酶具有工业应用的潜力，但迄今为止描述的酶存在稳定性问题并且受到其底物特异性的限制。将微生物酶应用于有机合成反应可以提供较高的底物特异性，在温和的反应条件下底物转化完全，并且减少化学废物的产生。热稳定性酶通常提供所有这些特征以及增强的稳定性。 ThermoGen 建议开发一套稳定的 DHAP 依赖性醛缩酶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具有不同立体选择性的四种酶来展示可行性，这些酶由新的醛缩酶或具有更广泛底物特异性和稳定性的诱变醛缩酶组成。我们还将确定关键反应参数来测试合成效用并证明它们催化模型合成反应的能力。在第二阶段，我们将开发最佳合成条件、酶生产的方法，并扩大底物范围。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药品制造商使用。拟议的商业应用：ThermoGen 提议开发新型 DHAP 依赖性醛缩酶，用作立体选择性有机合成反应的合成工具。醛缩酶将有助于高效、经济地合成药物或中间体，并减少化学废物的产生。