Description

For years, artificial metalloenzymes have chased a simple idea: take the best tricks from organometallic catalysis and put them inside a protein. You get selectivity, water compatibility, and evolvability. But noble metals like Au(I) have a problem in proteins: they like soft ligands (think thiolates), and the standard 20 amino acids don't give you the right kind of, well-behaved, genetically placeable soft handle.

These authors use a non-canonical amino acid 4-mercaptophenylalanine (pSHF) — a thiophenol side chain — and install it at a defined site in the LmrR scaffold via Amber-codon suppression. Now the protein contains a purpose-built noble-metal-binding residue that can stabilise low-oxidation-state metals like Au(I), the same oxidation state that does classic π-activation chemistry. This behaves like a fine-tunable gold catalyst from within the protein itself.

Citation: Veen et al., 2024

Artificial metalloenzymes combine the selectivity of proteins with the reactivity of metal catalysts. The limitation has been coordinating metals like gold, which require soft ligand environments that the 20 standard amino acids do not readily provide in a genetically controlled way.

4-mercaptophenylalanine (pSHF), an ncAA with a thiophenol side chain, addresses this by providing a genetically encoded soft metal-binding residue. Installed at a defined site in the LmrR protein scaffold, pSHF stabilises Au(I) in its catalytically active low-oxidation state. The resulting metalloenzyme performs pi-activation chemistry, the type of gold-catalysed reaction widely used in synthetic organic chemistry, within a protein framework (Veen et al., 2024).

This demonstrates that ncAAs can introduce entirely new chemical functionalities into proteins, not just modify existing ones. The combination of genetic encoding (for precise placement) and non-natural coordination chemistry (for novel reactivity) opens a design space that neither protein engineering nor synthetic chemistry can access alone.

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