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BSA, although the predicted product(s) from cleavage at this site could not
be detected. Glycine residues also appear to be important in the fragmentation
of calf skin collagen induced by a xanthine oxidase system (557). The cleavage
is probably induced by OH in this system, as the primary O 2 •− produced is
inactive in chain breakage. Of the N-terminal amino acids generated by frag-
mentation, 90% were glycine, even though the parent molecule contains only
approximately 30% glycine. Selective fragmentation has also been observed
with the apoB protein of LDL during either radiolysis or metal ion-catalyzed
damage (558); it is difficult to assess the relevance of cleavage at proline or
glycine in this case, due to difficulties in measuring fragment sizes. Using pro-
teins that lack one of Tyr, Trp or His, Guptasarma et al. (559) demonstrated
the importance of His in covalent protein cross-linking in the presence of O 2 .
Lys was also demonstrated to be involved; these cross-links may involve Schiff
base derivatives.
1.3.1
Protein Oxidation and Enzymatic Posttranslational Modifications
Posttranslational protein modifications play an important role in the regula-
tion of protein function through the modulation of protein structure, activity,
turnover, localization, and the nature of protein-protein complexes (560).
Today, more than 200 different posttranslational modifications are known
(561), which are the result of both enzymatic and nonenzymatic processes.
There is increasing evidence that posttranslational modifications of specific
proteins accompany pathologic processes and biological aging. An important
goal of global and targeted proteomic experiments must, therefore, be the
identification and functional characterization of posttranslationally modified
proteins in vivo , and to resolve the question whether such posttranslational
modifications are mechanistically related (in contrast to merely being associ-
ated with) to a disease process or a specific phenotype of aging.
The redox-sensitive Cys residue in the structure of protein tyrosine phos-
phatases may be converted by GSH disulfide into a mixed disulfide with
concomitant loss of catalytic activity (562). Cys sulfenic acids are highly reac-
tive and are expected to react with GSH at its relatively high intracellular
concentration. Therefore, it is reasonable to assume that ROS-induced oxida-
tion will also lead to the rapid glutathionylation of the redox-sensitive Cys
moiety. Glutamate is the major excitatory neurotransmitter of the central
nervous system. NMDA-type glutamate receptors have been implicated in
multiple physiological processes, including neuronal development (563).
However, overstimulation of NMDA receptors can cause excessive Ca 2+ influx,
free-radical generation, abnormal enzymatic activity, and thus contribute to a
number of neurodegenerative diseases (564). A variety of chemical modifica-
tions that modulate NMDA receptor activity have been reported, including
phosphorylation of tyrosine (565) and serine/threonine residues (566), redox
modulation of disulfide bonds, and S-nitrosylation of free thiol groups on
critical Cys residues (567, 568). It was shown that hypoxia enhances NO
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