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.