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oxidative (or nitrative) stress. In vivo , the skeletal muscle creatine kinase
suffers nitration of both Tyr 14 and Tyr 20 , but not measurably of any of the other
seven Tyr residues at positions 39, 82, 125, 140, 173, 174, and 279. Tryptic pep-
tides containing all these remaining Tyr residues were covered by MS/MS
analysis of the protein, indicating the validity of the analytical method. In
contrast, the in vitro exposure of creatine kinase to peroxynitrite in the pres-
ence of CO 2 resulted in the exclusive nitration of Tyr 82 (668). Again, tryptic
peptides containing all of the other eight Tyr residues were covered by MS/
MS analysis. Nitration of tyrosine residues within the GSH disulfide binding
site of GR resulted in a nearly 1000-fold decrease in catalytic efficiency of the
enzyme (669).
It is well established that structural analogues of L-tyrosine, such as
3-iodotyrosine, 3-fluorotyrosine, and 3,4-dihydroxy-L-phenylalanine, are
incorporated by posttranscriptional mechanisms into
-tubulin (670). The
mechanism appears to involve tubulin L-tyrosine ligase, an enzyme that seems
to have promiscuous substrate specificity (671, 672). 3-NY generated by RNS
can subsequently be incorporated into tubulin by this mechanism (671).
Modification of tyrosine residues in receptor molecules has been shown to
impair signaling pathways (673); for example, nitration is able to block the
cycle of phosphorylation/dephosphorylation of tyrosine (674). In fact, nitration
of tyrosine blocks its phosphorylation (675, 676). This was demonstrated
for the insulin receptor containing key tyrosine residue sensitive to nitration
(677).
Therefore, oxidative damage to key signaling proteins might directly con-
tribute to age- or disease-related changes of cellular metabolism (665, 678, 679)
Ischiropoulos et al. established that a nitrated tyrosine hydroxylase is selec-
tively degraded by chymotrypsin and the proteasome (680). Interestingly, the
existence of a repair enzyme for nitrated tyrosines, the “nitrotyrosine nitrase,”
was also proposed, but not finally shown (681).
Leeuwenburgh et al. (682) demonstrated an increase of 3-NY levels with
age in rat and mice liver. However, the results suggest that proteins oxidized
by RNS do not accumulate dramatically. Therefore, an investigation by Viner
et al. on the SERCA2a nitration from rat skeletal muscle demonstrated an
increase with age, but only one out of four Tyr were modified (683). However,
further studies suggest that this might already reduce SERCA2a function
(684). 3-NY has also been reported to be increased in neurodegenerative
diseases such as AD, PD, and HD (685, 686).
α
1.3.6.1 Dityrosines Dityrosine cross-links, which apparently arises follow-
ing the reaction between two tyrosyl radicals, are generated by peroxidases
and other heme proteins. Dityrosine cross-linking of proteins has been found
to increase with age in mouse skeletal muscle and heart, but not in the brain
or liver (27).
Heinecke et al. reported that o,o
-dityrosine generated by activated phago-
cyte causes cross-links in proteins and lipoproteins in vitro . o,o
-Dityrosine
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