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J. Biol. Chem., Vol. 262, Issue 2, 785-794, Jan, 1987
T Geiger and S Clarke
Aspartyl and asparaginyl deamidation, isomerization, and racemization
reactions have been studied in synthetic peptides to model these
spontaneous processes that alter protein structure and function. We show
here that the peptide L-Val-L-Tyr-L-Pro-L-Asn-Gly-L-Ala undergoes a rapid
deamidation reaction with a half-life of only 1.4 days at 37 degrees C, pH
7.4, to give an aspartyl succinimide product. Under these conditions, the
succinimide product can further react by hydrolysis (half-time, 2.3h) and
by racemization (half-time, 19.5 h). The net product of the deamidation
reaction is a mixture of L- and D-normal aspartyl and beta-transpeptidation
(isoaspartyl) hexapeptides. Replacement of the asparagine residue by an
aspartic acid residue results in a 34-fold decrease in the rate of
succinimide formation. Significant racemization was found to accompany the
deamidation and isomerization reactions, and most of this could be
accounted for by the rapid racemization of the succinimide intermediate.
Replacement of the glycyl residue in the asparagine-containing peptide with
a bulky leucyl or prolyl residue results in a 33-50-fold decrease in the
rate of degradation. Peptide cleavage products are observed when these
Asn-Leu and Asn-Pro-containing peptides are incubated. Our studies indicate
that both aspartic acid and asparagine residues may be hot spots for the
nonenzymatic degradation of proteins, especially in cells such as
erythrocytes and eye lens, where these macromolecules must function for
periods of about 120 days and 80 years, respectively.
Deamidation, isomerization, and racemization at asparaginyl and aspartyl residues in peptides. Succinimide-linked reactions that contribute to protein degradation
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