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Journal of Lipid Research, Vol. 46, 1440-1449, July 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Chemical modification of proteins during peroxidation of phospholipids

Andrzej S. Januszewski^*, Nathan L. Alderson^*, Alicia J. Jenkins, Suzanne R. Thorpe^* and John W. Baynes^1,*,

^* Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208
Department of Medicine, St. Vincent's Hospital, University of Melbourne, Melbourne, Australia
School of Medicine, University of South Carolina, Columbia, SC 29208

Published, JLR Papers in Press, April 1, 2005. DOI 10.1194/jlr.M400442-JLR200

¹ To whom correspondence should be addressed. e-mail: john.baynes{at}sc.edu

Chemical modification of proteins by advanced glycation and lipoxidation end products is implicated in the pathogenesis of macrovascular disease in aging and diabetes. To identify biomarkers of the lipoxidative modification of protein, we studied the oxidation of phospholipids in the presence of the model protein RNase A and compared protein-bound products formed in these reactions with those formed during oxidation of plasma proteins. Metal-catalyzed oxidation of 1-palmitoyl-2-arachidonoyl-phosphatidylcholine or 1-palmitoyl-2-linoleoyl-phosphatidylcholine in the presence of RNase led to the loss of amino groups in RNase and the incorporation of phosphate, hexanoate, pentanedioate, nonanedioate, and palmitate into protein. Protein-bound palmitate and phosphate correlated strongly with one another, and protein-bound pentanedioate and nonanedioate, derived from arachidonate and linoleate, respectively, accounted for 20% of the cross-linking of lipid phosphorus to protein. Similar results were obtained on oxidation of total plasma or isolated LDL.

We conclude that alkanedioic acids are quantitatively important linkers of oxidized phospholipids to proteins and that measurement of protein-bound phosphate and long-chain fatty acids may be useful for assessing long-term lipid peroxidative damage to proteins in vivo. Analyses of plasma proteins from control and diabetic patients indicated significant increases in lipoxidative modification of protein in diabetic compared with control subjects.

Abbreviations: CBL, N-(carboxybutyl)lysine; CML, N-(carboxymethyl)lysine; DTPA, diethylenetriaminepentaacetic acid; HNE, 4-hydroxynonenal; MDA, malondialdehyde; NDA, nonanedioic (azelaic) acid; OxLDL, oxidized low density lipoprotein; PAPC, 1-palmitoyl-2-arachidonoyl-phosphatidylcholine; PDA, pentanedioic (glutaric) acid; PLPC, 1-palmitoyl-2-linoleoyl-phosphatidylcholine; SIM-GC-MS, selected ion monitoring-gas chromatography-mass spectrometry

Supplementary key words advanced lipoxidation end products • atherosclerosis • lipid peroxidation • lipoprotein oxidation • lipoxidation

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