pyroglutamylation

Pyroglutamylation is a post-translational modification in which the N-terminal amino acid, typically glutamine or glutamic acid, cyclizes to form pyroglutamate (5-oxoproline) at the N-terminus of a protein or peptide. The modification often develops during or after translation and can affect stability and function.

The reaction is catalyzed by glutaminyl cyclase (QC) and chemical cyclization can occur spontaneously under certain conditions. The resulting N-terminal pyroglutamate is a cyclic lactam, which can resist exopeptidase cleavage. Some organisms also have pyroglutamyl aminopeptidases that can remove the pyroglutamyl block to regenerate the free N-terminus.

Pyroglutamylation is common in secreted and extracellular peptides and hormones, as well as neuropeptides, and in some antimicrobial or signaling peptides. The modification can increase peptide stability by protecting against aminopeptidases, alter receptor binding, and influence biological half-life or immunogenicity.

In humans, pyroglutamylated forms of amyloid beta peptides (notably pGlu3-Aβ) have been found in Alzheimer's disease and are associated with increased aggregation, resistance to degradation, and neurotoxicity, making them a focus of research and therapeutic strategies.

Detection and research methods include mass spectrometry and pyroglutamyl-specific antibodies; inhibitors of glutaminyl cyclase are studied as potential therapeutics to reduce formation of pyroglutamylated peptides. The modification occurs across various taxa and biological contexts.