Discovery and development of penicillin-binding protein-type thioesterases as biocatalysts

Cyclic peptides are promising drug candidates, but their synthesis, especially the synthesis of small, strained rings, remains challenging. Penicillin-binding protein-type thioesterases (PBP-TEs) have emerged as versatile biocatalysts that catalyze head-to-tail macrocyclization of nonribosomal peptides. Unlike canonical thioesterase domains, which catalyze diverse offloading outcomes, PBP-TEs exclusively promote head-to-tail cyclization, offering predictable reactivity. Their ability to act on diverse substrates in vitro further underscores their potential as tools for peptide drug discovery. This review highlights PBP-TE discovery and substrate scope investigation, along with recent advances in structural characterization and engineering, establishing these enzymes as a promising platform for the biocatalytic synthesis of cyclic peptides.