Enhancing Metal-binding with Noncanonical Coordinating Amino Acids

Abstract

More than 50% of proteinogenic amino acid sidechains can bind metal ions, enabling proteins and peptides to bear these ions as cofactors. Nevertheless, post-translational modifications and incorporation of noncanonical amino acids bestow peptides and proteins myriads of other coordination capabilities, thanks to an enhanced metal binding. Here we summarize selected examples of natural and artificial systems that contain one or more noncanonical amino acids coordinating a metal ion and subsequently achieve a new or enhanced function. We report on a wide array of systems: from disease-related proteins that undergo sulfurylation or phosphorylation through natural metallophores that selectively capture precious essential ions to synthetic selfassembly strategies, biocatalysts, and chelating agents against toxic metals. Regardless of their (bio)synthetic routes, all possess unique metal-binding properties that could not be effectively achieved by systems composed of canonical residues.

Thiolation and Carboxylation of Glutathione Synergistically Enhance Its Lead-Detoxification Capabilities

“…A fundamental question arose from these results: can this unique ncAA improve the Pb-binding capabilities of other peptidic scaffolds, thereby manifesting its general performance in Pb­(II) capture? We envisioned that the intrinsically low Pb­(II)-binding affinity of GSH ,− could be enhanced by replacing Cys with X. This not only would provide a deeper understanding of the contribution of X to Pb­(II) binding but also could improve the Pb-detoxification capability of GSH.…”

“…In conclusion, we succeeded in enhancing the Pb­(II)-detoxification properties of GSH by addressing its low affinity to the toxic metal. This was achieved by novel ncAAs that manifest the advantages in exploring unnatural side chains to enable selective and robust metal binding . The results also show the importance of metal affinity and selectivity in solving metal toxicity challenges and expanding the chemical toolbox against the toxic metal Pb.…”