Enzymatic crosslinking of histidine side chains in peptide natural products

Covering: 2019 to 2024Peptide macrocyclization stands as the pivotal step in the biosynthesis journey of bioactive cyclic peptide natural products, spanning both ribosomal and non-ribosomal origins. Beyond the enzymatic N- to C-terminus macrocyclization, natural cyclic peptides frequently display side chain-to-side chain crosslinks, which markedly bolster their stability and biological potency. Traditionally, histidine, with its imidazole side chain, has been regarded as chemically unreactive, leading to relatively sparse reports of histidine-containing crosslinks in cyclic peptide natural products. However, recent advancements in research have illuminated a novel perspective on the role of histidine (His) residues in peptide macrocyclization, revealing that His participation in this process is far more ubiquitous than previously envisioned. This highlight underscores the significance of His-containing crosslinks in natural cyclic peptides and delves into the enzymatic mechanisms underlying their formation.