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tertiary structures. However, the origin of the protein, whether extracellular,
cytosolic, nuclear, native or recombinant, seems not to have any importance.
Oxidized hemoglobin, superoxide dismutase, catalase, histones, glycolytic
enzymes, ferritin, serum albumin, myoglobin, aconitase, and many more pro-
teins of different sources have, until now, been used as substrates by various
laboratories as well as isolated protein substrates, and were showing essentially
the same properties during testing. Although the concentration or dosage of
the used oxidants differs widely, due to the different reactivity and stability of
each oxidizing agent, an increase in proteolytic susceptibility could always be
achieved at an optimal oxidant exposure. Therefore, the increase in proteolytic
susceptibility depends on the oxidizing agent, the protein substrate, and the
exact experimental conditions. Several studies also revealed that heavily oxi-
dized proteins are poor substrates for proteolytic degradation due to extensive
cross-linking and aggregation (253-256).
Interestingly, there are some exceptions. As was stated above, such a bipha-
sic behavior is typical for all globular, soluble proteins with defined structures,
however several proteins do not have a native folded structure. These essen-
tially structureless proteins include casein but also the tau (257, 258) and the
α
-synuclein proteins (259). These proteins are inherently good substrates for
proteolysis and their susceptibility is not increased by mild oxidation. These
proteins are already excellent proteasomal substrates without oxidation. How-
ever, if heavily oxidized, these proteins can also become cross-linked and poor
substrates for degradation (260, 261).
In a large number of these experiments, the origin of the substrate protein
in question and the source of the proteasome do not match, but still, the oxi-
dized substrate is selectively recognized by the proteasome. Therefore, one can
assume a general, cell-type, and species overlapping mechanism for the recog-
nition of oxidized proteins. So the question “What forms the recognition motif
of oxidized proteins for the proteasome?” was one of the key research ques-
tions about the fate of oxidized proteins. The selective oxidation of marker
amino acids and the resulting products were proposed as possible recognition
markers. Therefore, Levine et al. (34) could clearly demonstrate an increase
in the proteolysis of glutamine synthetase after oxidizing a threshold level of
methionine residues. Moreover, Lasch et al. (262) found a clear correlation
between tyrosine oxidation and proteasomal degradation of RNase A. Other
examples of single amino acid oxidations that correlate with altered proteo-
lytic susceptibility can be found in the literature. However, the amino acid
composition of all folded, soluble proteins seems to be so different that a
rather more overlapping principle can be proposed. This principle seems to be
the unfolding process resulting from oxidation. Due to the laws of thermody-
namics, normally (in a naturally folded state) the hydrophobic amino acids are
located in the core of the folded protein, not exposed to the surface, in order
to prevent the contact to water. Oxidation disrupts this folding, perhaps due
to the introduction of additional functional groups in the oxidized protein.
Therefore, an increase in the number of hydrophobic amino acids exposed to
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