Beta-linked isoaspartyl (isoAsp) peptide bonds can arise spontaneously via succinimide-linked deamidation of asparagine (Asn) or dehydration of aspartate (Asp). The peptide bond becomes linked through the beta-carboxyl group of the Asp or Asn side-chain, leaving the alpha-carboxyl group of the original peptide bond free. The symmetry of the resulting succinimide intermediate leads to two possible products, either aspartate or isoaspartate, which is an atypical beta-amino acid. The mechanism favours approximately 7:3 the 'iso' form (Bornstein & Balian 1977, Aswad 1984, Murray & Clarke 1984, Di Donato et al. 1986). Formation of the succinimidyl intermediate and its cleavage occur spontaneously. The propensity to form isoaspartyl linkages depends on the residues flanking the asparaginyl site, with small resdiues such as Gly favouring linkage formation, as well as on the local conformation and flexibility of the polypeptide chain (Clarke 1987, Galletti et al. 1989).

These reactions are a significant source of protein damage under physiological conditions and represent both a mechanism that can usefully determine the lifetime of a protein (Robinson et al. 1970) and a component of the pathological process of ageing (Clarke 2003).