4-Oxo-2-nonenal is both more neurotoxic and more protein reactive than 4-hydroxy-2-nonenal.
Electrophilic aldehydes, generated from oxidation of polyunsaturated fatty acyl chains under conditions of oxidative stress, bind to proteins and polynucleotides and can lead to cell death. 4-Hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE) have been shown here to be toxic to human neuroblastoma cells in culture at low micromolar concentrations. ONE is 4-5 times more neurotoxic at concentrations near the threshold of lethality. The reactions of these two aldehydes with two model proteins, ribonuclease A and beta-lactoglobulin, and their Lys epsilon-dimethylamino derivatives, have been followed spectrophotometrically. On the basis of t(1/2) measurements for the disappearance of the alpha,beta-unsaturated chromophore, ONE is 6-31 times more reactive with these proteins. The fastest reaction of ONE with proteins involves Schiff base formation at Lys epsilon-amino groups, whereas Schiff base formation is not spectroscopically apparent for HNE. Detailed kinetic studies of the initial reactions of HNE and ONE have been carried out with amino acids and amino acid surrogates. Whereas the reactions with imidazole and thiol nucleophiles involve straightforward Michael adduct formation, kinetics analyses reveal the reversibility of both the HNE Michael adduction of amines and the ONE Schiff base adduction of amines. Although ONE is more reactive than HNE toward conjugate addition of imidazole and thiol nucleophiles, it is less reactive than HNE toward Lys/amine Michael adduction. The greater neurotoxicity of ONE could reflect in part the different reactivity characteristics of ONE as compared to HNE.
Lin
De
D
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Lee
Hyoung-gon
HG
Liu
Quan
Q
Perry
George
G
Smith
Mark A
MA
Sayre
Lawrence M
LM
D000447:Aldehydes / Q000737:chemistry* / Q000633:toxicity*; D002082:Butylamines / Q000737:chemistry; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003545:Cysteine / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000633:toxicity*; D006639:Histidine / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D007202:Indicators and Reagents; D007700:Kinetics; D008239:Lysine / Q000737:chemistry; D009474:Neurons / Q000187:drug effects*; D020258:Neurotoxicity Syndromes / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D011506:Proteins / Q000737:chemistry*; D012545:Schiff Bases; D013056:Spectrophotometry, Ultraviolet
C403894:4-oxo-2-nonenal; D000447:Aldehydes; D002082:Butylamines; D015853:Cysteine Proteinase Inhibitors; D007202:Indicators and Reagents; D011506:Proteins; D012545:Schiff Bases; D006639:Histidine; C027576:4-hydroxy-2-nonenal; D008239:Lysine; D003545:Cysteine