Bacterial enzyme turns α-amino acids into β-amino acids

After a ribosome in a cell synthesizes a peptide or protein, enzymes can modify that biomolecule and change its function through a variety of posttranslational modifications, such as adding phosphate groups or sugars.

Jörn Piel of ETH Zurich and coworkers have now found an enzyme that performs a surprising and unique posttranslational modification. It uses a previously unobserved protein-splicing reaction to introduce β-amino acids into proteins (Science 2018, DOI: 10.1126/science.aao0157). β-amino acids differ structurally from the α-amino acids that predominate in peptides and proteins in that they have two carbons instead of just one between the amino and carbonyl groups.

Scientists could use the new enzyme to incorporate a range of different β-amino acids into peptides and proteins for drug discovery. β-peptides resist enzymatic breakdown, giving them enhanced stability in the body.

The detailed mechanism of action of the enzyme, called PlpXY, requires further study. But overall, the enzyme removes tyramine—tyrosine without its carbonyl group—from a tyrosine-glycine pair in a protein. The enzyme then splices the resulting gap by linking the orphan carbonyl group with the adjacent amino acid’s carbonyl group, which turns the adjacent amino acid into an α-keto-β-amino acid. The β-amino acid’s extra keto group provides a chemical handle scientists can use to further modify the protein.

The study “describes unprecedented chemistry that expands the diversity of known ribosomally synthesized and posttranslationally modified peptides in an almost magical way,” says Alanna Schepartz of Yale University.