Journal article
Covalent modification of amino acid nucleophiles by the lipid peroxidation products 4-hydroxy-2-nonenal and 4-oxo-2-nonenal
Chemical research in toxicology, Vol.15(11), pp.1445-1450
11/2002
DOI: 10.1021/tx025590o
PMID: 12437335
Abstract
Lipid peroxidation yields the aldehydes 4-hydroxynonenal (4HNE) and 4-oxononenal (4ONE). Protein adduction by 4HNE is thought to be involved in the pathogenesis of several diseases. Currently, the reactivity of 4ONE toward proteins is unknown. The purpose of this study was to identify amino acids that react with 4HNE and 4ONE, characterize the chemical structure of the adduct, and determine the preference for amino acid modification. Model peptides containing one or more nucleophilic residues (i.e., Arg, Cys, His, Met, and Lys) were reacted with 4HNE and 4ONE and analyzed using matrix-assisted laser desorption/ionization mass spectrometry. Post-source decay analysis was used to confirm peptide modification. The bimolecular rate constant for adduction of amino acids and peptides by 4HNE and 4ONE was measured. Results of this work indicate that Cys, His, and Lys are modified by 4HNE and 4ONE. In addition, Arg was adducted by 4ONE. The predominant adduct resulting from modification of peptides by 4HNE or 4ONE had a mass of 156 or 154 Da (respectively), indicating that adduction occurs via Michael addition. Reactivity of amino acids toward 4HNE and 4ONE was found to have the following order: Cys >> His > Lys (> Arg for 4ONE). The presence of an Arg on a Cys-containing peptide increased the reaction rate with 4HNE and 4ONE by a factor of approximately 5-6 compared to the Cys nucleophile alone. Rate constants determined for the modification of Cys by the lipid aldehydes demonstrated a >100-fold difference in reactivity between 4HNE and 4ONE toward Cys. Results of the present study indicate that both 4HNE and 4ONE modify amino acid nucleophiles; however, the reactivity between these two lipid aldehydes differs both qualitatively and quantitatively.
Details
- Title: Subtitle
- Covalent modification of amino acid nucleophiles by the lipid peroxidation products 4-hydroxy-2-nonenal and 4-oxo-2-nonenal
- Creators
- Jonathan A Doorn - Department of Pharmaceutical Sciences, School of Pharmacy, The University of Colorado Health Sciences Center, Denver 80262, USADennis R Petersen
- Resource Type
- Journal article
- Publication Details
- Chemical research in toxicology, Vol.15(11), pp.1445-1450
- Publisher
- United States
- DOI
- 10.1021/tx025590o
- PMID
- 12437335
- ISSN
- 0893-228X
- eISSN
- 1520-5010
- Grant note
- F32ES11937 / NIEHS NIH HHS T32AA07464 / NIAAA NIH HHS R01ES09410 / NIEHS NIH HHS R01AA09300 / NIAAA NIH HHS
- Language
- English
- Date published
- 11/2002
- Academic Unit
- Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984070275002771
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