Upstream eventInteraction of α-diketones with arginine residues
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|α-diketone-induced bronchiolitis obliterans||adjacent||Not Specified||Not Specified|
Life Stage Applicability
Key Event Relationship Description
α-diketones are able to react with proteins, predominantly by covalent binding with arginine residues. This interaction with proteins can affect their structure and compromise their function. Arginine-rich proteins or enzymes with arginine residues at active sites are likely the critical molecular targets.
Evidence Supporting this KER
The toxic effects of the electrophilic α-diketones are likely associated with their direct covalent interactions with cellular nucleophiles. In this way, α-diketones react with proteins, displaying a great affinity for arginine residues. Since arginine residues are often located at the active sites of enzymes the interaction with α-diketones can cause loss of enzyme activity. Also the interaction with other proteins can result in altered structure and function.
The reaction of α-diketones with proteins has been known for decades (Harden en Norris, 1911). Also the selective interaction with arginine residues is well established (Mathews et al. 2010). Actually, the α-diketone diacetyl is used to identify functional arginine residues in enzymes (Chen and Chen, 2003). Besides the loss of enzyme activity the interaction with other proteins can also result in modification of protein structure and function (Ahmed and Thomalley, 2003). Furthermore, protein damage is implicated in the cytotoxicity observed after exposure to α-diketones (Hubbs et al. 2016). The reactivity of α-diketones depends on the carbon chain length. In general, the shorter the chain the higher the reactivity (Morgan et al. 2016, Xia et al. 1993).
Uncertainties and Inconsistencies
The target proteins are likely arginine-rich proteins or enzymes containing arginine residues at their active sites. However, at present it is unclear which proteins are the critical targets for the observed toxicity after the inhalation of α-diketones.
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Harden, A., Norris, D.,1911. The diacetyl reaction for proteins. J. Physiol. 42, 332–336.
Hubbs, A. F., Fluharty, K. L., Edwards, R. J., Barnabei, J. L., Grantham, J. T., Palmer, S. M., … Sriram, K. (2016). Accumulation of Ubiquitin and Sequestosome-1 Implicate Protein Damage in Diacetyl-Induced Cytotoxicity. In American Journal of Pathology (Vol. 186, pp. 2887–2908). https://doi.org/10.1016/j.ajpath.2016.07.018
Mathews, J. M., Watson, S. L., Snyder, R. W., Burgess, J. P., & Morgan, D. L. (2010). Reaction of the butter flavorant diacetyl (2,3-Butanedione) with N-??-acetylarginine: A model for epitope formation with pulmonary proteins in the etiology of obliterative bronchiolitis. Journal of Agricultural and Food Chemistry, 58(24), 12761–12768. https://doi.org/10.1021/jf103251w
Anders, M. W. (2017). Diacetyl and related flavorant α-Diketones: Biotransformation, cellular interactions, and respiratory-tract toxicity. Toxicology, 388, 21–29. https://doi.org/10.1016/j.tox.2017.02.002
Chen, G., Chen, X., 2003. Arginine residues in the active site of human phenol sulfotransferase (SULT1A1). J. Biol. Chem. 278, 36358–36364.
Ahmed, N., and Thomalley, P. J. (2003). Quantitative screening of protein biomarkers of early glycation, advanced glycation, oxidation and nitrosation of cellular and extracellular proteins by mass spectrometry multiple reaction monitoring. Biochem Soc Trans 31, 1417–22.
Xia, C., et al., 1993. Chemical modification of GSH transferase P 1-1 confirms the presence of Arg-13, Lys-44 and one carboxylate group in the GSH-binding domain of the active site. Biochem. J. 293, 357–362.
More, S.S., et al., 2012a. The butter flavorant, diacetyl, forms a covalent adduct with 2-deoxyguanosine, uncoils DNA, and leads to cell death. J. Agric. Food Chem. 60, 3311–3317.
Dorado, L., et al., 1992. A contribution to the study of the structure-mutagenicity relationship for a-dicarbonyl compounds using the Ames test. Mutat. Res. Fundam. Mol. Mech. Mutagen. 269, 301–306.