Dityrosine, a specific marker of oxidation, is synthesized by the myeloperoxidase-hydrogen peroxide system of human neutrophils and macrophages.
Myeloperoxidase, secreted by activated phagocytes, produces the powerful cytotoxin hypochlorous acid from H2O2 and Cl-. We show that the enzyme can also employ H2O2 to oxidize L-tyrosine to tyrosyl radical, yielding the stable cross-linked product dityrosine. Dityrosine synthesis by the myeloperoxidase-H2O2 system did not require halide and was partially inhibited by Cl-. At physiological concentrations of Cl-, L-tyrosine, and other plasma amino acids, purified myeloperoxidase utilized 26% of the H2O2 in the reaction mixture to form dityrosine. Aminotriazole, cyanide, and azide inhibited the reaction. Phorbol ester-stimulated human neutrophils and monocyte-derived macrophages similarly generated dityrosine from L-tyrosine by a pathway inhibited by catalase, aminotriazole, and azide. The requirement for H2O2 and the inhibition by heme poisons suggest that activated phagocytes synthesize dityrosine by a peroxidative mechanism. These results indicate that L-tyrosine can compete effectively with Cl- as a substrate for myeloperoxidase and raise the possibility that formation of tyrosyl radical may play a role in the phagocyte inflammatory response. Because dityrosine is protease-resistant, stable to acid hydrolysis, and intensely fluorescent, its identification in tissues may pinpoint targets where phagocytes inflict oxidative damage in vivo.
Heinecke
J W
JW
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
Li
W
W
Daehnke
H L
HL
Goldstein
J A
JA
D002478:Cells, Cultured; D002853:Chromatography, Liquid; D005609:Free Radicals; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism*; D013058:Mass Spectrometry; D009504:Neutrophils / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000378:metabolism*; D013057:Spectrum Analysis; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism
D005609:Free Radicals; D014443:Tyrosine; D006861:Hydrogen Peroxide; C007543:dityrosine; D009195:Peroxidase