isoaspartate

Isoaspartate, or isoaspartic acid, is an abnormal amino acid residue that can appear in proteins when asparagine deamidates or aspartate isomerizes. In isoaspartyl residues the backbone is extended by one methylene group and the peptide bond is formed through the beta-carboxyl of the aspartate side chain, creating a beta-linkage that can distort local structure.

Formation occurs through spontaneous post-translational modifications. Deamidation of asparagine can produce a succinimide intermediate that hydrolyzes to aspartate or isoaspartate, and aspartate residues can isomerize to the beta form. These changes accumulate in long-lived proteins and are favored by aging, heat, and pH changes. Isoaspartate residues can disrupt folding, proteolysis, and overall protein function.

Repair mechanisms involve the enzyme protein L-isoaspartyl methyltransferase (PIMT, PCMT1). This enzyme recognizes isoaspartyl residues and methylates the alpha-carboxyl group using S-adenosyl-L-methionine. The resulting methyl ester can spontaneously revert to normal L-aspartate, providing a repair cycle; in some cases the residue may reform isoaspartate, allowing multiple cycles of turnover.

Biological and practical relevance includes the idea that isoaspartate accumulation is a marker of protein aging and has been investigated in relation to aging and some neurodegenerative contexts. In biotechnology, formation of isoaspartate can affect the stability and immunogenicity of therapeutic proteins, prompting strategies to minimize its occurrence during production and storage. Detection methods include mass spectrometry, specialized chromatography, and isoaspartate-specific antibodies.