Pyridoxal Photoenzymes for Organic Synthesis

用于有机合成的吡哆醛光酶

• 批准号: 10426622
• 负责人: Todd Kurt Hyster
• 金额: $ 23.71万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10426622
• 关键词: Aldehyde-Lyases; Amino Acids; Area; Biological; Catalysis; Drug Targeting; Enzymes; Essential Amino Acids; Esters; Foundations; Genetic Recombination; Glycine; Glycine Hydroxymethyltransferase; Goals; Grant; Health; Human; Hydroxymethyltransferases; Medicine; Methods; Organic Synthesis; Oxidation-Reduction; Pathway interactions; Pyridoxal; Reaction; Research; Science; Serine; Threonine; Triplet Multiple Birth; Work; absorption; aryl halide; catalyst; deprotonation; functional group; novel; tool

7. Project Summary The work described in this proposal aims to advance biocatalytic tools for use in the synthesis of medicinally valuable molecules. We will develop new reaction mechanisms for pyridoxal-dependent enzymes to enable the facile synthesis of non-canonical amino acids through photoexcitation of pyridoxal intermediates involved in the catalysis of threonine aldolase and serine hydroxymethyltransferase. The first goal is to photoexcite the PLP external aldimine enabling it to function as a photoacid. This mechanism will allow these enzymes to use a broader set of 𝛼-, 𝛽-, and 𝛾-amino acids as pronucleophiles. The second goal is to excite the PLP-quinonoid to access a more reducing excited state. This species can reduce alkyl halides, redox-active esters, and cyanoheterocyles to form radicals that can recombine with the PLP-quinonoid radical to produce various non-canonical amino acids. Collectively, these studies will provide a new tool for the synthesis of non- canonical amino acids and serve as the foundation for a new area in photoenzymatic catalysis. The methods and the goals proposed in the Specific Aims can streamline the synthesis of biological probes and drug targets, creating a significant benefit to human health and associated biomedical sciences.

7.项目总结 本提案中描述的工作旨在改进生物催化工具，用于合成 具有药用价值的分子。我们将为依赖吡哆醛的酶开发新的反应机理 通过光激发吡哆醛中间体使非正则氨基酸的合成变得容易 参与苏氨酸缩醛酶和丝氨酸羟甲基转移酶的催化作用。第一个目标是 光激发PLP的外源乙二胺，使其发挥光酸的作用。这个机制将允许这些 酶使用更广泛的𝛼-，𝛽-和𝛾-氨基酸作为亲核原。第二个目标是激发 PLP-喹酮类化合物，以获得更还原的激发态。该物种可还原烷基卤化物，具有氧化还原活性 酯和氰杂环形成的自由基可以与PLP-喹酮自由基重新结合生成 各种非标准氨基酸。总而言之，这些研究将为合成非化合物提供一个新的工具 并为光酶催化的一个新领域奠定了基础。这些方法 而在特定目标中提出的目标可以简化生物探针和药物靶标的合成， 为人类健康和相关的生物医学科学创造了巨大的好处。