TY - JOUR
T1 - Desferrioxamine inhibits protein tyrosine nitration
T2 - Mechanisms and implications
AU - Adgent, Margaret A.
AU - Squadrito, Giuseppe L.
AU - Ballinger, Carol A.
AU - Krzywanski, David M.
AU - Lancaster, Jack R.
AU - Postlethwait, Edward M.
N1 - Funding Information:
This work was supported in part by NIH Grants R01 HL 54696 and P01 ES 11617 (E.M.P.) and R01 CA131653 (J.R.L.). Exposure capabilities were made available through the UAB Environmental Exposure Facility.
PY - 2012/8/15
Y1 - 2012/8/15
N2 - Tissues are exposed to exogenous and endogenous nitrogen dioxide (NO 2), which is the terminal agent in protein tyrosine nitration. Besides iron chelation, the hydroxamic acid (HA) desferrioxamine (DFO) shows multiple functionalities including nitration inhibition. To investigate mechanisms whereby DFO affects 3-nitrotyrosine (3-NT) formation, we utilized gas-phase NO2 exposures, to limit introduction of other reactive species, and a lung surface model wherein red cell membranes (RCM) were immobilized under a defined aqueous film. When RCM were exposed to NO 2 covered by /- DFO: (i) DFO inhibited 3-NT formation more effectively than other HA and non-HA chelators; (ii) 3-NT inhibition occurred at very low[DFO] for prolonged times; and (iii) 3-NT formation was iron independent but inhibition required DFO present. DFO poorly reacted with NO 2 compared to ascorbate, assessed via NO2 reactive absorption and aqueous-phase oxidation rates, yet limited 3-NT formation at far lower concentrations. DFO also inhibited nitration under aqueous bulk-phase conditions, and inhibited 3-NT generated by active myeloperoxidase bound to RCM. Per the above and kinetic analyses suggesting preferential DFO versus NO 2 reaction within membranes, we conclude that DFO inhibits 3-NT formation predominantly by facile repair of the tyrosyl radical intermediate, which prevents NO2 addition, and thus nitration, and potentially influences biochemical functionalities.
AB - Tissues are exposed to exogenous and endogenous nitrogen dioxide (NO 2), which is the terminal agent in protein tyrosine nitration. Besides iron chelation, the hydroxamic acid (HA) desferrioxamine (DFO) shows multiple functionalities including nitration inhibition. To investigate mechanisms whereby DFO affects 3-nitrotyrosine (3-NT) formation, we utilized gas-phase NO2 exposures, to limit introduction of other reactive species, and a lung surface model wherein red cell membranes (RCM) were immobilized under a defined aqueous film. When RCM were exposed to NO 2 covered by /- DFO: (i) DFO inhibited 3-NT formation more effectively than other HA and non-HA chelators; (ii) 3-NT inhibition occurred at very low[DFO] for prolonged times; and (iii) 3-NT formation was iron independent but inhibition required DFO present. DFO poorly reacted with NO 2 compared to ascorbate, assessed via NO2 reactive absorption and aqueous-phase oxidation rates, yet limited 3-NT formation at far lower concentrations. DFO also inhibited nitration under aqueous bulk-phase conditions, and inhibited 3-NT generated by active myeloperoxidase bound to RCM. Per the above and kinetic analyses suggesting preferential DFO versus NO 2 reaction within membranes, we conclude that DFO inhibits 3-NT formation predominantly by facile repair of the tyrosyl radical intermediate, which prevents NO2 addition, and thus nitration, and potentially influences biochemical functionalities.
KW - Desferrioxamine
KW - Epithelial lining fluid
KW - Hydroxamic acids
KW - Membrane proteins
KW - Nitration
KW - Nitrogen dioxide
KW - Reduction
KW - Repair
KW - Tyrosine
KW - Tyrosyl radicals
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U2 - 10.1016/j.freeradbiomed.2012.06.003
DO - 10.1016/j.freeradbiomed.2012.06.003
M3 - Article
C2 - 22705369
AN - SCOPUS:84864484055
SN - 0891-5849
VL - 53
SP - 951
EP - 961
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 4
ER -