Engineered aldehyde dehydrogenases for amide bond formation

Lei Gao, Xiang Qiu, Jun Yang, Kangdelong Hu, Peilin Li, Wei Li, Feng Gao, Fabrice Gallou, Florian Kleinbeck, Xiaoguang Lei* SCIENCE，29 JAN 2026 ，VOL 391, ISSUE 6784，DOI: 10.1126/SCIENCE.ADW336 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

Lei Gao, Xiang Qiu, Jun Yang, Kangdelong Hu, Peilin Li, Wei Li, Feng Gao, Fabrice Gallou, Florian Kleinbeck, Xiaoguang Lei*

SCIENCE，29 Jan 2026 ，Vol 391, Issue 6784，DOI: 10.1126/science.adw336

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