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。项目摘要 该提案中描述的工作旨在推进生物催化工具，以合成 有价值的分子。我们将开发新的吡啶还原依赖性酶的反应机制 为了通过吡啶毒素中间体的光激发促进非官方氨基酸的便利合成 参与苏氨酸醛酸酶和丝氨酸羟基转移酶的催化。第一个目标是 PhothExcite PLP外部醛氨酸使其能够充当光酸。这种机制将允许这些 酶将更宽的𝛼-，𝛽-和𝛾氨基酸作为原核寄移剂。第二个目标是激发 PLP喹啉以访问更降低的激发态。该物种可以减少酒精卤化物，氧化还原活性 酯和蓝骨网络形成可以与PLP喹啉自由基重组以产生的自由基 各种非典型氨基酸。总的来说，这些研究将为合成非 - 规范氨基酸，并作为光酶催化新区域的基础。方法 并且特定目的中提出的目标可以简化生物问题和药物靶标的合成， 为人类健康和相关的生物医学带来重大好处。