Potential roles of aspartic acid D-isomerization in proteins implicated in the pathogenesis of Alzheimer’s disease

Potential roles of aspartic acid D-isomerization in proteins implicated in the pathogenesis of Alzheimer's diseaseNon-enzymatic isomerization of aspartic acid residues in proteins associated with Alzheimer's disease: Proteins are composed of L-amino acids following ribosomal translation.However, if they remain unmetabolized for an extended period, some residues (particularly aspartic acid [Asp]) undergo isomerization to the D-form.This process begins with nucleophilic attack (by the nitrogen atom of the amide group of an adjacent residue) on the side-chain carboxy group of an Asp residue.This forms a fivemembered L-succinimide intermediate (Figure 1A), which has two carbonyl carbons and can transform back to an L-Asp residue or isomerize into an L-isoAsp residue.The chiral center of the L-succinimide intermediate can easily invert to form a D-succinimide intermediate via keto-enol tautomerization.This D-succinimide intermediate then cleaves to yield a D-aspartic acid (D-Asp) or D-isoaspartate (D-isoAsp) residue (Figure 1A).Asp isomerization is usually undetectable because the turnover time of proteins is typically only a few days, much faster than the time required for Asp isomerization.However, certain proteins with half-lives ranging from days to months undergo Asp isomerization.Consequently, isomerized Asp residues are frequently observed in proteins in the eye lens, tooth dentin, and neuronal myelin; they also accumulate with aging (Man et al., 1983).Asp isomerization in proteins can alter their threedimensional structure, interactions with binding partners, and protein functions, potentially leading to age-related disorders.Isomerized Asp has been detected in crystallins, which accumulate in the lenses of patients with cataracts.It has also been found in amyloid-β (Aβ) peptides and tau proteins, which accumulate in the brains of patients with Alzheimer's disease (AD).These proteins undergo misfolding and fibrillization due to unknown mechanisms with aging, forming accumulations of insoluble aggregates in disease lesions.It has been hypothesized that the aggregation process of these proteins is partly triggered by a conformational change caused by Asp isomerization.