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(vi) There is a three- to fourfold increase in the level of MetSO in human
skin collagen, over the range of 10-80 years (490).
(vii) The level of MetSO from young, mature, and senescent human eryth-
rocytes (separated by density gradient sedimentation) is about 50%
and 60% higher, respectively, than in the young erythrocytes (349,
507).
(viii) It is reported that there is a progressive age-related increase in the
oxidation of Met residues in Fisher 344 rat brain CaM, over the range
of 6-27 months, which is associated with a loss in the ability of the
protein to regulate plasma membrane ATP hydrolysis and ATP-
dependent Ca 2+ transport (508, 509). However, more recent studies
demonstrate that oxidation of CaM does not occur in currently avail-
able strains of rats, raised under present husbandry conditions.
(ix) MSR-A and MSR-B (hCBS-1) gene expression is downregulated
during replicative senescence of WI-38 human fibroblasts (510).
(x) Evidence that enhanced oxidation of protein by neutrophil-generated
ROS contributes to the development of chronic and acute bronchitis
is supported by the observation that these abnormalities are associ-
ated with substantial increases in the neutrophil content and in the
MetSO/Met ratio of bronchoalveolar lavage fluid of individuals suf-
fering from these disorders (502). Furthermore, during E. coli senes-
cence, induced by nitrogen starvation, there is a 1.5- to 2-fold increase
in the levels of MetSO and carbonyl content of proteins. There are
higher levels of MetSO in the brain regions compared to other organs,
with the exception of the cerebellum, which has relatively high activ-
ity of MSR-A (511).
Oxidatively sensitive calcium regulatory proteins that modulate the activity of
calcium channels and pumps include CaM and phospholamban, which contain
sensitive methionines whose oxidation to their corresponding methionine sulf-
oxides results in a disruption of secondary structure that modulates the activity
of the bound complex (512). In the course of aging or under conditions of
oxidative stress, methionine residues of CaM undergo oxidation, leading to
loss of biological activity of the protein. The calculated changes in affinity
for calcium and for the target peptide show opposing trends. Oxidation at
position 144 is predicted to enhance peptide binding and weaken calcium
binding, whereas oxidation at 145 weakens peptide binding and enhances
affinity for calcium (513). An increasing number of studies suggest that oxida-
tive damage to proteins can be correlated with the loss of calcium homeostasis
in a number of diseases and aging (362, 514, 515). In the case of CaM, oxida-
tive modifications of multiple methionines to sulfoxide have been identified
from in vivo studies of aged rat brains (508) and in vitro experiments involving
exposure to hydrogen peroxide or peroxynitrite (516). Oxidation significantly
decreased the CaM affinity for binding calcium (517). CaM contains nine
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