cyclodehydratases

Cyclodehydratases are enzymes that catalyze the cyclodehydration of peptide backbones to form azoline rings, most commonly thiazoline and oxazoline, within certain natural product biosynthetic pathways. They are especially associated with ribosomally synthesized and post-translationally modified peptides (RiPPs), including cyanobactins, thiopeptides, and related families.

In their action, cyclodehydratases typically modify serine, threonine, or cysteine residues in a precursor peptide, promoting the formation of a covalent ring and the loss of a water molecule. In many RiPP pathways, this reaction is coupled to ATP-dependent activation by a partner enzyme, which facilitates substrate processing and ring formation. The resulting azoline rings can undergo further oxidation by dedicated dehydrogenases to yield the more aromatic oxazole or thiazole rings, contributing to the rigid and complex structures characteristic of these natural products.

Biochemically, cyclodehydratases are often found as components of multi-protein complexes within biosynthetic gene clusters. Activity is influenced by factors such as the leader peptide that guides recognition, substrate sequence context, and the presence of accessory proteins. Structural studies have revealed diverse folds among cyclodehydratases, with some members belonging to YcaO-domain families, which coordinate ATP-dependent chemistry to drive cyclization.

Significance and applications include the expansion of chemical diversity in natural products and potential engineering of RiPPs to create novel azoline-containing compounds. Understanding cyclodehydratases supports efforts in antibiotic discovery, synthetic biology, and the development of new biocatalysts for selective heterocyclization.