Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:1.6.3.1 (
NADPH oxidase
)
11,281
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Reactive intermediates generated by phagocytic white blood cells are of central importance in destroying microorganisms, but they may also damage normal tissue at sites of inflammation. To investigate the potential role of such oxidants in tissue injury, we used gas chromatography/mass spectrometry to quantify levels of
o,o'-dityrosine
in mouse peritoneal neutrophils and urine. In wild-type animals, neutrophils markedly increased their content of protein-bound dityrosine when they were activated in vivo. This increase failed to occur in mice that were deficient in the phagocyte
NADPH oxidase
. Levels of
o,o'-dityrosine
in urine mirrored those in neutrophil proteins. When o,o'-[(14)C]dityrosine was injected intravenously into mice, the radiolabel was not metabolized or incorporated into tissue proteins: instead, it was recovered in urine with near-quantitative yield. Patients with sepsis markedly increased their output of
o,o'-dityrosine
into urine, suggesting that systemic inflammation also may be a potent source of oxidative stress in humans. These observations demonstrate that activated neutrophils produce
o,o'-dityrosine
cross-links in tissue proteins, which may subsequently be degraded into free amino acids and excreted into urine. Our results indicate that mouse phagocytes use oxidants produced by the
NADPH oxidase
to create
o,o'-dityrosine
cross-links in vivo and raise the possibility that reactive intermediates produced by this pathway promote inflammatory tissue damage in humans.
...
PMID:NADPH oxidase of neutrophils elevates o,o'-dityrosine cross-links in proteins and urine during inflammation. 1167 67
To kill invading bacteria, viruses, and fungi, phagocytes secrete hydrogen peroxide (H(2)O(2)) and the heme enzyme myeloperoxidase. We have explored the possibility that myeloperoxidase might use H(2)O(2) to convert L-tyrosine to tyrosyl radical. Activated human neutrophils and monocytes used the system to oxidize free L-tyrosine to
o,o'-dityrosine
, a stable product of tyrosyl radical. Protein-bound tyrosyl residues exposed to myeloperoxidase, H(2)O(2), and L-tyrosine were also oxidized to
o,o'-dityrosine
. The cross-linking reaction required free L-tyrosine, suggesting that myeloperoxidase converts the amino acid to a diffusible radical catalyst that promotes protein oxidation. We used electron paramagnetic resonance to provide direct evidence that the oxidizing intermediate is free tyrosyl radical. Myeloperoxidase-generated tyrosyl radical also initiates lipid peroxidation, suggesting that activated phagocytes might also be able to oxidize lipids in host tissues. Moreover, myeloperoxidase is present and active in human atherosclerotic tissue, and levels of protein-bound dityrosine are elevated in such lesions. Our recent studies indicate that activated neutrophils use oxidants generated by the phagocyte
NADPH oxidase
to produce protein-bound dityrosine during acute inflammation. Collectively, these findings suggest that generation of tyrosyl radical by myeloperoxidase allows activated phagocytes to damage both proteins and lipids. Elevated levels of
o,o'-dityrosine
have been detected in inflammatory lung disease, neurodegenerative disorders, and aging. Thus, oxidation of tyrosine to tyrosyl radical might play a role in the pathogenesis of many diseases.
...
PMID:Tyrosyl radical production by myeloperoxidase: a phagocyte pathway for lipid peroxidation and dityrosine cross-linking of proteins. 1212 92
