isoaspartyl

Isoaspartyl, or isoaspartate, refers to a noncanonical form of an aspartic acid residue in proteins in which the peptide chain is linked through the beta-carboxyl group of the residue rather than the usual alpha-carboxyl group. This creates a beta-linkage and effectively adds an extra methylene group into the protein backbone, which can perturb local structure and function.

Formation of isoaspartyl residues primarily occurs through the spontaneous degradation of proteins: deamidation of asparagine and, to a lesser extent, dehydration of aspartic acid. Both pathways can produce a succinimide intermediate that hydrolyzes to either aspartate or isoaspartate. The resulting isoaspartyl linkages can disrupt folding, stability, and enzymatic activity, and they tend to accumulate in long-lived proteins under physiological or oxidative stress.

Biological significance is linked to aging and protein damage. Isoaspartyl residues are found in many proteins and are often enriched in tissues with slow turnover, such as lenses, brain, and connective tissue. Their presence can alter protein conformation, aggregation propensity, and interactions, contributing to functional decline and, in some contexts, disease-related processes.

Repair of isoaspartyl damage is catalyzed by protein L-isoaspartyl methyltransferase (PIMT, PCMT1). This enzyme methylates the alpha-carboxyl group of the isoaspartyl residue, using S-adenosyl-L-methionine as a methyl donor. The methyl ester can promote hydrolysis of the succinimide and restoration of normal aspartate, thereby partially reversing the damage. Defects in this repair pathway can lead to increased isoaspartyl accumulation and associated functional impairments.