Document Detail

Covalent modification of amino acid nucleophiles by the lipid peroxidation products 4-hydroxy-2-nonenal and 4-oxo-2-nonenal.
MedLine Citation:
PMID:  12437335     Owner:  NLM     Status:  MEDLINE    
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.
Jonathan A Doorn; Dennis R Petersen
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Chemical research in toxicology     Volume:  15     ISSN:  0893-228X     ISO Abbreviation:  Chem. Res. Toxicol.     Publication Date:  2002 Nov 
Date Detail:
Created Date:  2002-11-19     Completed Date:  2003-06-20     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  8807448     Medline TA:  Chem Res Toxicol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1445-50     Citation Subset:  IM    
Department of Pharmaceutical Sciences, School of Pharmacy, The University of Colorado Health Sciences Center, Denver 80262, USA.
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MeSH Terms
Aldehydes / chemistry*
Amino Acids / chemistry*
Arginine / chemistry
Cysteine / chemistry
Histidine / chemistry
Lipid Peroxidation
Lysine / chemistry
Protein Processing, Post-Translational*
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Substrate Specificity
Grant Support
Reg. No./Substance:
0/4-oxo-2-nonenal; 0/Aldehydes; 0/Amino Acids; 29343-52-0/4-hydroxy-2-nonenal; 52-90-4/Cysteine; 56-87-1/Lysine; 71-00-1/Histidine; 74-79-3/Arginine

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