title: Spontaneous cyclization of polypeptides with a penultimate Asp, Asn or isoAsp at the N-terminus and implications for cleavage by aminopeptidase.
abstract: A cyclic product that forms spontaneously from peptides that contain a penultimate Asp, Asn or isoAsp residue at the N-terminus has been characterized. This 2,5-diketopiperazine derivative forms under physiological conditions and is stable, showing little degradation even following heating at 60 °C. A mechanism for its formation from Asn and Asp peptides is proposed that involves a succinimide or isoaspartate intermediate. A diketopiperazine-modified peptide was also detected in human lens extracts. Since peptides that contain the diketopiperazine moiety are not readily hydrolysed by leucine aminopeptidase, it is hypothesized that proteins and peptides modified in this way in the body may not readily be digested by the normal proteolytic machinery of cells.
authors.affiliation: Save Sight Institute, University of Sydney, Sydney Eye Hospital, Australia.
authors.forename: Brian
authors.initials: B
authors.lastname: Lyons
authors.forename: Ann H
authors.initials: AH
authors.lastname: Kwan
authors.forename: Roger
authors.initials: R
authors.lastname: Truscott
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D001216:Asparagine / Q000737:chemistry*; D001224:Aspartic Acid / Q000737:chemistry; D003500:Cyclization; D054659:Diketopiperazines / Q000737:chemistry; D006801:Humans; D026581:Isoaspartic Acid / Q000737:chemistry*; D007908:Lens, Crystalline / Q000737:chemistry; D007931:Leucyl Aminopeptidase / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D010456:Peptides, Cyclic / Q000737:chemistry*; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D038203:alpha-Crystallin B Chain / Q000737:chemistry
chemical_list: D054659:Diketopiperazines; D026581:Isoaspartic Acid; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D038203:alpha-Crystallin B Chain; D001224:Aspartic Acid; D001216:Asparagine; D007931:Leucyl Aminopeptidase
keywords: connexin; diketopiperazine; lens; lipofuscin; proteasome