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surface-exposed residues, Met 1 and Met 159 , were readily oxidized, but with
negligible effects on biological activity. Met 27 was oxidized at about one-third
the rate of the rapidly oxidized residues, again with little effect on activity. The
remaining two residues, Met 36 and Met 48 , were much less susceptible to oxida-
tion and modification of either residue was accompanied by a substantial loss
of biological activity. Similarly, Gitlin and colleagues established that oxidation
of Met 111 in interferon
-2b did not alter its biological activity (535). Nabuchi
and coauthors reported studies on hydrogen peroxide-mediated oxidation of
the two methionine residues present in human parathyroid hormone (536).
Oxidation of Met 8 slightly reduced biological activity while oxidation of Met 18
substantially reduced activity. Keck showed that two surface-exposed methio-
nine residues of interferon or three methionine residues of tissue plasminogen
activation could be oxidized without loss of biological activity (481). A similar
result with keratinocyte growth factor has been summarized recently (537).
While solvent-exposed methionine residues are likely to protect from envi-
ronmentally proximate oxidizing agents, residues in or near active sites may
protect enzymes from “autoxidation” by substrates or cofactors. For example,
oxidation of a single methionine in rabbit 15-lipoxygenase was known to be
mediated by substrates or products, and the appearance of the methionine
sulfoxide had been correlated with loss of catalytic activity. However, the
studies of Gan and colleagues established that replacement of the methionine
residue by leucine did not prevent inactivation by substrates, demonstrating
that formation of methionine sulfoxide was not the cause of inactivation (538).
It was suggested that oxidation of the active site methionine may actually
retard the inactivation of the lipoxygenase. It is notable that a significant
number of methionine residues in GS may be oxidized without an increase in
surface hydrophobicity or proteolytic susceptibility. The methionine sulfoxide
content of human skin collagen increases from about 4% in the young to about
12% of methionine at age 80 (490).
Ciorba et al. (539) showed that oxidation of a methionine residue in a
voltage-dependent potassium channel modulates its inactivation. When this
methionine residue is oxidized to methionine sulfoxide, the inactivation is
disrupted, and it is reversed by coexpression with peptide MSR. The results
suggest that oxidation and reduction of methionine could play a dynamic role
in the cellular signal transduction process in a variety of systems (62).
Cysteine Modifications and Disulfide Bond Formation
Oxidation of two Cys residues of the same protein or of two different proteins
can lead to the formation of intra- or interdisulfide cross-linked derivatives
(Fig. 1.19) (29). The formation of disulfide bonds can be reversed by glutare-
doxin 1 and by Trx (540).
Cys, homocysteine (Hcys), GSH, and cysteinylglycine (CysGly) are the most
abundant low-molecular-mass sulfhydryls (LMM-SHs) occurring in the extra-
cellular milieu and, together with albumin, represent almost all the thiols in
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