Aspartate and asparagine, two of the 20 different amino acids that make up proteins, can spontaneously isomerize to form isoaspartate. This chemical reaction does not affect free amino acids, but can happen when aspartate (Asp) or asparagine (Asn) is part of a peptide (protein) chain--i.e., an aspartyl or asparaginyl residue. As shown below, the nitrogen in the peptide backbone (shown in blue) next to an Asp or Asn can attack the side-chain carbonyl carbon, forming a 5-member succinimide ring¹. Asn is deamidated (loses an NH₃) in the process.

Hydrolysis of this unstable succinimide intermediate occurs rapidly. As shown below, hydrolysis can occur on either side of the nitrogen in the succinimide ring. Hydrolysis on one side produces a normal Asp (though Asn cannot be regenerated, due to the deamidation). Hydrolysis on the other side (which is favored by about 3:1) produces isoaspartate.

Protein activity could be impaired by this abnormal isoAsp residue in at least three ways². (i) The original Asp or Asn may have been located at the active site or otherwise crucial to the function of the protein; the difference in structure (and charge, for Asn) at this site could disrupt function. (ii) The original Asp or Asn may have been critical for the protein's 3D structure, so that conformational damage results. (iii) Notice that the peptide backbone (blue) now goes through what was previously the side-chain carbon; this "kink" could also disrupt protein structure.

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¹Geiger, T., and S. Clarke. 1987. Deamidation, isomerization, and racemization at asparaginyl and aspartyl residues in peptides: succinimide-linked reactions that contribute to protein degradation. J. Biol. Chem. 262:785-794.

²Reviewed in: Clarke, S. 2003. Aging as war between chemical and biochemical processes: protein methylation and the recognition of age-damaged proteins for repair. Ageing Res. Rev. 2:263-285.