Work

Tyrosyl radical generated by myeloperoxidase is a physiological catalyst for the initiation of lipid peroxidation in low density lipoprotein.

Year: 1994

Type: article

Abstract: Myeloperoxidase, a heme protein secreted by activated phagocytes, is expressed in human atherosclerotic lesions.The enzyme uses H20, generated by the cells to oxidize L-tyrosine to tyrosyl radical, a catalyst for protein dityrosine synthesis.We have explored the possibility that tyrosyl radical initiates lipid peroxidation, which may be of pivotal importance in transforming low density lipoprotein (LDL) into atherogenic particles.Exposure of LDL to L-tyrosine and activated human neutrophils caused peroxidation of LDL lipids.LDL oxidation required L-tyrosine but was independent of free metal ions; catalase and heme poisons were inhibitory.Incubation of LDL with L-tyrosine, myeloperoxidase, and H,O, likewise caused lipid peroxidation, and this reaction was inhibited by heme poisons and catalase.Replacement of L-tyrosine with O-methyltyrosine, which cannot form tyrosyl radical, inhibited LDL oxidation by both activated neutrophils and myeloperoxidase.The antioxidants ascorbate and probucol, but not vitamin E, inhibited LDL oxidation by myeloperoxidase, HzOz, and L-tyrosine.Ascorbate blocked dityrosine synthesis, while probucol scavenged chain-propagating peroxyl radicals in the lipid phase of LDL.These results indicate that tyrosyl radical stimulates LDL lipid peroxidation.In striking contrast to other cell-mediated mechanisms for LDL oxidation, the myeloperoxidase-catalyzed reaction is independent of free metal ions.This raises the possibility that tyrosyl radical generated by myeloperoxidase is of physiological importance in making LDL atherogenic.An elevated levei of low density lipoprotein (LDL)' is a major risk factor for premature coronary artery disease (I).The onset of this disorder is marked by the appearance of lipid-laden macrophages in the intima of the arterial wall (2, 3).In vitro studies have shown that oxidized LDL, but not native LDL, can Heart Association and by National Institutes of Health Grant R01 * This work

Source: Journal of Biological Chemistry

DOI: 10.1016/s0021-9258(17)32005-7

Authors: M.L. Savenkova, D.M. Mueller, J.W. Heinecke

Institutions: National Academy of Sciences of Belarus, Washington University in St. Louis, Institute of Bioorganic Chemistry

Language: English

Topic: Neutrophil, Myeloperoxidase and Oxidative Mechanisms

Subfield: Immunology

Field: Immunology and Microbiology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,430