Natural noncanonical protein splicing yields products with diverse β-amino acid residues

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Science  16 Feb 2018:
Vol. 359, Issue 6377, pp. 779-782
DOI: 10.1126/science.aao0157

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Protein backbone, broken and mended

Small, posttranslationally modified peptides are produced by microorganisms as antimicrobial agents or to communicate with neighboring cells. Alterations to the peptide backbone can change the structure of peptides or introduce reactive chemical moieties. Morinaka et al. characterized a bacterial enzyme that excises the side chain and α-carbon of a tyrosine residue from a short peptide, leaving behind an α-ketoamide. This backbone functional group is found in some protease inhibitors and is a valuable handle for bio-orthogonal chemistry. The enzyme accepts peptide substrates with a short recognition motif, suggesting that it could be used to generate libraries of modified peptides.

Science, this issue p. 779


Current textbook knowledge holds that the structural scope of ribosomal biosynthesis is based exclusively on α-amino acid backbone topology. Here we report the genome-guided discovery of bacterial pathways that posttranslationally create β-amino acid–containing products. The transformation is widespread in bacteria and is catalyzed by an enzyme belonging to a previously uncharacterized radical S-adenosylmethionine family. We show that the β-amino acids result from an unusual protein splicing process involving backbone carbon-carbon bond cleavage and net excision of tyramine. The reaction can be used to incorporate diverse and multiple β-amino acids into genetically encoded precursors in Escherichia coli. In addition to enlarging the set of basic amino acid components, the excision generates keto functions that are useful as orthogonal reaction sites for chemical diversification.

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