Abstract
Spontaneous, nonenzymatic reactions in proteins are known to have relevance to aging and age-related diseases, such as cataract and Alzheimer’s disease. Among such reactions is the racemization of Ser residues, but its mechanism in vivo remains to be clarified. The most likely intermediate is an enol. Although being nonenzymatic, the enolization would need to be catalyzed to occur at a biologically relevant rate. In the present study, we computationally found plausible reaction pathways for the enolization of a Ser residue where a dihydrogen phosphate ion, H2PO4−, acts as a catalyst. The H2PO4− ion mediates the proton transfer required for the enolization by acting simultaneously as both a general base and a general acid. Using the B3LYP density functional theory method, reaction pathways were located in the gas phase and hydration effects were evaluated by single-point calculations using the SM8 continuum model. The activation barriers calculated for the reaction pathways found were around 100 kJ mol−1, which is consistent with spontaneous reactions occurring at physiological temperature. Our results are also consistent with experimental observations that Ser residue racemization occurs more readily in flexible regions in proteins.
Highlights
All common amino acids, except for glycine (Gly), have an asymmetric α-carbon atom, resulting in the occurrence of L- and D-forms
We have computationally found plausible reaction pathways for Ser residue enolization where an H2PO4 − ion acts as a catalyst
As in the previous study for the racemization of a succinimide residue [36], the H2PO4 − ion acts both as a general base and a general acid in a single step
Summary
Except for glycine (Gly), have an asymmetric α-carbon atom, resulting in the occurrence of L- and D-forms. Age‐dependent, progressive racemization of Ser was found for demonstrated lifelong proteins to be sites (crystallins) of normal human lenses by. We havecatalyzed computationally shown that the racemization the succinimide residue can be this ion mediates the proton transfer required for the enolization of the. Keto–enol tautomerism of simple aldehydes ion exists in a significant amount at a physiological pH of 7.4, and Ser residue racemization in vivo (propanal, 2‐methylpropanal, and butanal) has been shown to be catalyzed by a phosphate buffer of may bepH catalyzed by this ion. Enolization of the main chain of an amino acid residue catalyzed by a species which can Scheme 2
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