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Stable molecules exist because covalent bonds hold the atoms together. The strength of a covalent bond is measured by the energy required to break it, that is, the energy necessary to separate the bonded atoms. Separating any pair of bonded atoms requires energy — the stronger a bond, the greater the energy required to break it.
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Aldol condensation is an important route in synthetic organic chemistry used to generate a new carbon–carbon bond under basic or acidic conditions. The aldol condensation reaction presented in Figure 1 constitutes an aldol addition reaction followed by the dehydration process.
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Enamine formation involves the addition of carbonyl compounds to a secondary amine through a series of reactions. The mechanism begins with the generation of carbinolamine, a nucleophilic attack followed by several proton transfer reactions. The hydroxyl group of the carbinolamine is converted into water to make a better leaving group that can push the reaction forward by eliminating a water molecule. In enamine formation, the last step involves the abstraction of a proton from the α carbon to...
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Engineered aldehyde dehydrogenases for amide bond formation.

Lei Gao1,2, Xiang Qiu1, Jun Yang1,3

  • 1Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of the Ministry of Education, College of Chemistry and Molecular Engineering, New Cornerstone Science Laboratory, Peking University, Beijing, China.

Science (New York, N.Y.)
|January 29, 2026
PubMed
Summary
This summary is machine-generated.

Researchers repurposed aldehyde dehydrogenases into oxidative amidases for efficient amide bond formation. This biocatalytic approach enables amide synthesis from alcohols and streamlines drug molecule synthesis.

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Area of Science:

  • Biocatalysis
  • Organic Synthesis
  • Enzymology

Background:

  • Amide bond formation is crucial in pharmaceutical synthesis, often relying on stoichiometric reagents.
  • Current methods for amide synthesis can be inefficient and generate significant waste.

Purpose of the Study:

  • To develop a novel biocatalytic method for amide bond formation.
  • To engineer oxidative amidases from aldehyde dehydrogenases for enhanced substrate scope.
  • To establish an enzymatic cascade for synthesizing amides from readily available alcohols.

Main Methods:

  • Repurposing aldehyde dehydrogenases by modifying the catalytic pocket to create oxidative amidases.
  • Utilizing engineered oxidative amidases for amide synthesis from diverse aldehydes and amines.
  • Developing a two-step enzymatic cascade for amide synthesis from aliphatic alcohols.

Main Results:

  • Engineered oxidative amidases efficiently formed amide bonds between various aldehydes and amines.
  • A two-step enzymatic cascade successfully synthesized amides from aliphatic alcohols.
  • The biocatalytic strategy was applied to redesign synthetic routes for five drug molecules, demonstrating its practical utility.

Conclusions:

  • Oxidative amidases offer a sustainable and efficient alternative to traditional coupling reagents for amide bond formation.
  • This biocatalytic approach has significant potential for advancing the synthesis of structurally diverse pharmaceutical compounds.
  • Enzymatic cascades provide a powerful platform for streamlined and green synthesis in drug discovery and development.