Engineered aldehyde dehydrogenases for amide bond formation

• 成果类型: Article
• 署名作者: Gao, Lei; Qiu, Xiang; Yang, Jun; Hu, Kangdelong; Li, Peilin; Li, Wei; Gao, Feng; Gallou, Fabrice; Kleinbeck, Florian; Lei, Xiaoguang
• 署名单位: Peking University; Wuhan University; Peking University; Novartis
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adw3365
• 发表日期: 2026-01-29
• 页码: eadw3365
• 关键词: BENZALDEHYDE DEHYDROGENASE; alcohol-dehydrogenase; amidation; specificity; oxidation; ligases; enzyme; tool

摘要

Amide bond formation is widely used in pharmaceutical synthesis, typically involving stoichiometric coupling reagents to activate carboxylic acid substrates for a condensation reaction. As an alternative approach, we repurposed aldehyde dehydrogenases into oxidative amidases by creating a more hydrophobic and spacious catalytic pocket for amines to capture the thioester intermediate. This biocatalyst efficiently facilitates the formation of amide bonds between diverse aldehydes and amines. We also developed a two-step enzymatic cascade to synthesize amides from broadly available aliphatic alcohols. This biocatalytic strategy enabled the redesign of synthetic routes for five drug molecules. Our findings highlight the potential of oxidative amidases in advancing the synthesis of structurally diverse drug molecules through efficient amide bond formation.