Retrosynthetic Design of Dinuclear Copper Enzymes for Azide-Alkyne Cycloaddition via Clickable Noncanonical Amino Acids.

ABSTRACT: Copper-catalyzed azide-alkyne cycloaddition (CuAAC) has enabled numerous synthetic and biological applications, driven by advances in the synthesis and optimization of copper-binding ligands. However, to the best of our knowledge, no bottom-up protein-based ligands have been specifically developed to catalyze this reaction. Here, we present a retrosynthetic protein design that leverages the introduction, duplication, and diversification of metal-chelating amino acid residues via a clickable noncanonical amino acid and CuAAC-mediated post-translational modification. A naturally occurring homodimer, dTDP-4-keto-6-deoxy-D-hexulose 3,5-epimerase, was engineered to structurally mimic the molecular framework of well-known CuAAC ligands, featuring multidentate triazole-containing motifs with four

SUBMITTER: Lee Y 

PROVIDER: S-EPMC12576778 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature