Addition by subtraction

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Posttranslational modifications (PTMs) are responsible for some of the most exotic ribosomally synthesized peptide backbones in biology. Examples include manipulations to generate D-amino acids, thioether linkages, and even formation amino acids with sp2 hybridized α-carbons [1]. In a recent publication by Jörn Piel’s research group in Science, bacteria are capable of making another unusual PTM - α-keto-β-amino amide formation [2].

The manuscript describes the identification of a radical S-adenosylmethionine (rSAM) enzyme (PlpXY) capable of excising a tyramine equivalent from a peptide, resulting in the formation of an -keto–amino amide motif. Multiple LC-MS and NMR experiments were performed to characterize the modification and multiple peptide substrates were analyzed to determine the minimal recognition sequence required for conversion. Piel and co-workers were also able to modify a peptide containing an α-keto-β-amino amide with a fluorophore using the motif as a synthetic handle. Finally, the investigators show that PlpXY can be used generate genetically encoded α-keto-β-amides that may be of great benefit to the pharmaceutical industry.

  1. McIntosh JA, Donia MS, & Schmidt EW (2009) Ribosomal peptide natural products: bridging the ribosomal and nonribosomal worlds. Nat Prod Rep 26(4):537-559. doi:10.1039/B714132G
  2. Morinaka BI, et al. (2018) Natural noncanonical protein splicing yields products with diverse beta-amino acid residues. Science 359(6377):779-782. doi:10.1126/science.aao0157

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