Science359, 779–782 (2018)

Natural ribosomes incorporate only α-amino acids into peptides and proteins; though β-amino acids have been found in some natural products, they are the result of nonribosomal peptide and polyketide biosynthesis. Morinaka et al. now report the discovery of a new group of ribosomally synthesized and post-translationally modified natural products that contain β-amino acids as the result of a post-translational splicing reaction. A radical-SAM enzyme termed a splicase (PlpX), in conjunction with a putative leader peptide recognition protein (PlpY), excises a tyrosine-derived tyramine equivalent from the precursor peptide and then rejoins the backbone to form an α-keto-β-amino amide. Although the reaction requires the presence of a Tyr–Gly motif at the splice site, PlpX is otherwise somewhat tolerant to mutations to the native precursor peptide sequence, including at the residue immediately N-terminal to the splice site. Modification at this position thus enables the generation of peptides containing various β-amino acids. The ketoamine moiety is also useful for bioorthogonal labeling, as it can be converted to an oxime by methoxyamine or directly conjugated to a thiosemicarbazide-labeled fluorophore. The PlpXY system could be used to generate libraries of compounds for drug screening, which the authors demonstrated by biosynthesizing an analog of the hepatitis C protease inhibitor boceprevir.

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