Remodeling of ribosomally synthesized peptide backbones based on posttranslational modifications

Abstract

Covering: 2013–2024

Benefiting significantly from recent advances in genome mining, ribosomally synthesized and posttranslationally modified peptide (RiPP) natural products have emerged as a source of chemical inspiration to drive the discovery of therapeutic agents and the development of new biological tools for addressing challenges to synthetic approaches. Despite being confined to twenty proteinogenic amino acid building blocks, the structural complexity and diversity of RiPPs that arise from enzymatic posttranslational modifications (PTMs) surpass expectations and are now believed to be comparable to those produced by non-ribosomal peptide synthetases. Here, we highlight the PTM enzymes characterized over the past decade that engage the –(NH–C_α–CO)_n– repeating units in transformations, particularly those leading to structural rearrangements by peptide backbone remodeling. Unveiling the catalytic mechanisms of these unusual PTM enzymes deepens the understanding in RiPP biosynthesis and, eventually, will enhance our capability of rational design, development and production of functional peptide agents using synthetic biology strategies.