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.