The objective of this research proposal is to determine the reactivity of 4-oxononenal (4ONE), a major product of lipid peroxidation, toward peptides/protein. 4ONE is structurally analogous to the known cytotoxic lipid aldehyde 4-hydroxynonenal (4HNE) but is likely more reactive because of its chemical structure. Protein modification by 4HNE has been characterized and is thought to be an initiating factor in the pathogenesis of human diseases (e.g. atherosclerosis); however, the adduction of peptides/proteins by 4ONE has not been studied or even demonstrated. In order to fulfill the objective of this research proposal, the following working hypotheses will be tested: 4ONE covalently modifies peptides and proteins with residue specificity and can inhibit enzymes that metabolize 4HNE; furthermore, 4ONE generated in the mitochondria from lipid peroxidation can modify mitochonidrial proteins/enzymes important in respiration and metabolism. To test the hypothesis, experiments will be performed to identify peptide residues adducted by 4ONE, characterize the preference of the compound toward specific amino acids, and determine the chemical structure of 4ONE adducts. Work will be done to ascertain whether 4ONE inhibits enzymes important for metabolism of 4HNE. Furthermore, experiments will be conducted to determine whether 4ONE generated via mitochondrial lipid peroxidation adducts mitochondrial enzymes/proteins important in respiration and metabolism. Completion of these aims will provide scientific data to achieve the objective of the research proposal and assess the toxicological/physiological significance of protein adduction by 4ONE.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F10 (20))
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Shreffler, Carol K
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University of Colorado Denver
Schools of Pharmacy
United States
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Roede, James R; Carbone, David L; Doorn, Jonathan A et al. (2008) In vitro and in silico characterization of peroxiredoxin 6 modified by 4-hydroxynonenal and 4-oxononenal. Chem Res Toxicol 21:2289-99
Doorn, Jonathan A; Hurley, Thomas D; Petersen, Dennis R (2006) Inhibition of human mitochondrial aldehyde dehydrogenase by 4-hydroxynon-2-enal and 4-oxonon-2-enal. Chem Res Toxicol 19:102-10
Carbone, David L; Doorn, Jonathan A; Kiebler, Zachary et al. (2005) Cysteine modification by lipid peroxidation products inhibits protein disulfide isomerase. Chem Res Toxicol 18:1324-31
Carbone, David L; Doorn, Jonathan A; Kiebler, Zachary et al. (2005) Modification of heat shock protein 90 by 4-hydroxynonenal in a rat model of chronic alcoholic liver disease. J Pharmacol Exp Ther 315:8-15
Carbone, David L; Doorn, Jonathan A; Kiebler, Zachary et al. (2004) Inhibition of Hsp72-mediated protein refolding by 4-hydroxy-2-nonenal. Chem Res Toxicol 17:1459-67
Petersen, Dennis R; Doorn, Jonathan A (2004) Reactions of 4-hydroxynonenal with proteins and cellular targets. Free Radic Biol Med 37:937-45
Carbone, David L; Doorn, Jonathan A; Petersen, Dennis R (2004) 4-Hydroxynonenal regulates 26S proteasomal degradation of alcohol dehydrogenase. Free Radic Biol Med 37:1430-9
Doorn, Jonathan A; Maser, Edmund; Blum, Andreas et al. (2004) Human carbonyl reductase catalyzes reduction of 4-oxonon-2-enal. Biochemistry 43:13106-14
Reichard, John F; Doorn, Jonathan A; Simon, Franz et al. (2003) Characterization of multidrug resistance-associated protein 2 in the hepatocellular disposition of 4-hydroxynonenal. Arch Biochem Biophys 411:243-50
Doorn, Jonathan A; Srivastava, Satish K; Petersen, Dennis R (2003) Aldose reductase catalyzes reduction of the lipid peroxidation product 4-oxonon-2-enal. Chem Res Toxicol 16:1418-23

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