New Enzyme Class Discovered Assembling Complex Peptide Rings in Nature

Macrocyclic peptides are among nature's most potent bioactive molecules, and understanding how enzymes construct their ring structures is critical for drug discovery and synthetic biology. Until now, α-ketoglutarate-dependent dioxygenases (αKGDs) were not known to participate in the macrocyclization of ribosomally synthesized and post-translationally modified peptides (RiPPs), a rapidly growing class of natural products.

In this study, researchers performed large-scale bioinformatic analysis and identified that JmjC domain-containing αKGDs (JMJDs) frequently co-occur with diverse RiPP biosynthetic gene clusters across bacterial genomes. This suggested an underappreciated enzymatic role waiting to be characterized.

Focusing on the cor gene cluster from Streptomyces corchorusii, the team used heterologous reconstitution — expressing the genes in a different host organism — to produce a novel lanthipeptide natural product they named corsin. Corsin features both a methyllanthionine ring installed by the lanthipeptide synthetase CorM and a rare Cys(S)-Tyr(Cβ) cross-link generated by the αKGD enzyme pair CorB and CorD.

Mechanistically, CorD acts as a radical catalyst, abstracting a hydrogen atom from the Cβ position of tyrosine and generating a para-quinone methide intermediate. This reactive species then undergoes a Michael addition reaction with a nearby cysteine residue, forging the macrocyclic cross-link. Notably, CorB is an inactive homologue of CorD yet is essential for the catalytic reaction, revealing an unusual two-component enzyme architecture.

These findings introduce αKGDs as a new class of macrocyclization catalysts in RiPP biosynthesis. While the direct clinical relevance is not yet established, the expansion of enzymatic strategies for ring formation could guide the design of novel peptide-based antibiotics or therapeutics. The work is limited by its biochemical scope and awaits in vivo biological activity studies on corsin itself.