Journal Article

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

Morinaka, Brandon I., Verest, Marjan, Piel, Jörn, Sims, James, Lakis, Edgars, Helf, Maximilian J., Scalvenzi, Thibault, Sunagawa, Shinichi, Vagstad, Anna L., Gugger, Muriel

2018

Overview

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 A bacterial enzyme catalyzes rearrangement and removal of part of a tyrosine residue within short peptides. 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.

• Publisher: The American Association for the Advancement of Science
• Subject: Adenosylmethionine / Amides - chemistry / Amino Acid Sequence / Amino acids / Amino Acids - chemistry / Amino Acids - metabolism / Antimicrobial agents / Backbone / Bacteria / Bacterial Proteins - genetics / Bacterial Proteins - metabolism / Biosynthesis / Carbon / Cyanobacteria - genetics / Cyanobacteria - metabolism / E coli / Enzymes / Escherichia coli - genetics / Functional groups / Genetic code / Genetic Loci / Genetic transformation / Genomes / Microorganisms / Mutation / Organic Chemistry / Peptides / Protease inhibitors / Protein Processing, Post-Translational / Protein Splicing / Proteinase inhibitors / Proteins / S-Adenosylmethionine / Splicing / Substrates / Topology / Tyramine / Tyramine - chemistry / Tyrosine