Inhibition of cathepsins and related proteases by amino acid, peptide, and protein hydroperoxides
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Inhibition of cathepsins and related proteases by amino acid, peptide, and protein hydroperoxides. / Headlam, Henrietta A; Gracanin, Michelle; Rodgers, Kenneth J; Davies, Michael Jonathan.
In: Free Radical Biology & Medicine, Vol. 40, No. 9, 01.05.2006, p. 1539-48.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Inhibition of cathepsins and related proteases by amino acid, peptide, and protein hydroperoxides
AU - Headlam, Henrietta A
AU - Gracanin, Michelle
AU - Rodgers, Kenneth J
AU - Davies, Michael Jonathan
PY - 2006/5/1
Y1 - 2006/5/1
N2 - Reaction of radicals in the presence of O2, and singlet oxygen, with some amino acids, peptides, and proteins yields hydroperoxides. These species are key intermediates in chain reactions and protein damage. Previously we have shown that peptide and protein hydroperoxides react rapidly with thiols, and that this can result in inactivation of thiol-dependent enzymes. The major route for the cellular removal of damaged proteins is via catabolism mediated by proteosomal and lysosomal pathways; cysteine proteases (cathepsins) play a key role in the latter system. We hypothesized that inactivation of cysteine proteases by hydroperoxide-containing oxidised proteins may contribute to the accumulation of modified proteins within cells. We show here that thiol-dependent cathepsins, either isolated or in cell lysates, are rapidly and efficiently inactivated by amino acid, peptide, and protein hydroperoxides in a time- and concentration-dependent manner; this occurs with similar efficacy to equimolar H2O2. Inactivation involves reaction of the hydroperoxide with Cys residues as evidenced by thiol loss and formation of sulfenic acid intermediates. Structurally related, non-thiol-dependent cathepsins are less readily inactivated by these hydroperoxides. This inhibition, by oxidized proteins, of the system designed to remove modified proteins, may contribute to the accumulation of damaged proteins in cells subject to oxidative stress.
AB - Reaction of radicals in the presence of O2, and singlet oxygen, with some amino acids, peptides, and proteins yields hydroperoxides. These species are key intermediates in chain reactions and protein damage. Previously we have shown that peptide and protein hydroperoxides react rapidly with thiols, and that this can result in inactivation of thiol-dependent enzymes. The major route for the cellular removal of damaged proteins is via catabolism mediated by proteosomal and lysosomal pathways; cysteine proteases (cathepsins) play a key role in the latter system. We hypothesized that inactivation of cysteine proteases by hydroperoxide-containing oxidised proteins may contribute to the accumulation of modified proteins within cells. We show here that thiol-dependent cathepsins, either isolated or in cell lysates, are rapidly and efficiently inactivated by amino acid, peptide, and protein hydroperoxides in a time- and concentration-dependent manner; this occurs with similar efficacy to equimolar H2O2. Inactivation involves reaction of the hydroperoxide with Cys residues as evidenced by thiol loss and formation of sulfenic acid intermediates. Structurally related, non-thiol-dependent cathepsins are less readily inactivated by these hydroperoxides. This inhibition, by oxidized proteins, of the system designed to remove modified proteins, may contribute to the accumulation of damaged proteins in cells subject to oxidative stress.
KW - Amino Acids
KW - Animals
KW - Cathepsins
KW - Cell Line
KW - Free Radicals
KW - Hydrogen Peroxide
KW - Macrophages
KW - Mice
KW - Oxidation-Reduction
KW - Peptide Hydrolases
KW - Peptides
U2 - 10.1016/j.freeradbiomed.2005.12.036
DO - 10.1016/j.freeradbiomed.2005.12.036
M3 - Journal article
C2 - 16632114
VL - 40
SP - 1539
EP - 1548
JO - Free Radical Biology & Medicine
JF - Free Radical Biology & Medicine
SN - 0891-5849
IS - 9
ER -
ID: 129671596