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  • Title: Identification of advanced reaction products originating from the initial 4-oxo-2-nonenal-cysteine Michael adducts.
    Author: Shimozu Y, Shibata T, Ojika M, Uchida K.
    Journal: Chem Res Toxicol; 2009 May; 22(5):957-64. PubMed ID: 19368367.
    Abstract:
    4-Oxo-2-nonenal (ONE), an aldehyde originating from the peroxidation of omega6 polyunsaturated fatty acids, preferentially reacts with the cysteine residues of protein. Despite the fact that there has been significant recent interest in the protein reactivity and biological activity of ONE, the structural basis of the ONE-cysteine adducts remain to be established. In the present study, to gain a structural insight into the sulfhydryl modification by ONE, we characterized reaction products that originated from the initial ONE-cysteine Michael adducts. N-Acetyl-L-cysteine (10 mM) was incubated with an equimolar concentration of ONE in 0.1 M phosphate buffer (pH 7.4) at 37 degrees C. Within 1 h of incubation, the reaction of N-acetyl-L-cysteine with ONE resulted in the formation of two (C-2 and C-3) Michael addition products possessing a carbonyl functionality. Subsequent incubation of the reaction mixture resulted in their disappearance and concomitant formation of advanced reaction products, including a minor product III and major products IVa, IVb, and V. Product III was identified to be a thiomorpholine derivative, 4-acetyl-5-hydroxyl-6-(2-oxoheptyl)thiomorpholine-3-carboxylic acid, which might have originated from the C-2 Michael addition product. The major products were identified to be the novel 2-cyclopentenone derivatives, that is, 2-(acetylamino)-3-[(3-butyl-4-oxocyclopent-2-en-1-yl)sulfanyl]propionic acid (IVa and its isomer IVb) and 2-(acetylamino)-3-[(4-butyl-5-oxocyclopent-3-en-1-yl)sulfanyl]propionic acid (V), which might be generated through the base-catalyzed cyclization of the C-2 and C-3 Michael addition products, respectively. The furan derivative, which has been reported as the end product of the Michael adducts, was found to be formed only under acidic conditions. Thus, this study identified the novel ONE-cysteine adducts, including the most prominent 2-cyclopentenone derivatives, that originated from the initial Michael adducts.
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