Research reportLimited and selective adduction of carboxyl-terminal lysines in the high molecular weight neurofilament proteins by 2,5-hexanedione in vitro
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Cited by (25)
Diacetyl and related flavorant α-Diketones: Biotransformation, cellular interactions, and respiratory-tract toxicity
2017, ToxicologyCitation Excerpt :Comparison of the quantum-chemical parameters for 2,5-hexanedione (σ = 0.310 eV−1; ω = 2.09 eV) (LoPachin and Gavin, 2015) and α-diketones (Table 2) shows that 2,5-hexanedione is both softer and less electrophilic than α-diketones. Neurofiliament proteins are modified by 2,5-hexanedione but this modification is selective for neurofilament-H and −M proteins compared with neurofilament-L (DeCaprio and Fowke, 1992). The experimental and computational data indicate that chemical reactivity of compounds proposed as replacements parallels their pathology (Holden and Hines, 2016).
Toxic neuropathies: Mechanistic insights based on a chemical perspective
2015, Neuroscience LettersCitation Excerpt :The anterograde movement of these NFs is mediated by the fast transport motor protein, kinesin [23]. HD can form selective N-substituted 2,5-dimethylpyrrole adducts with lysine residues of KSP (lys-ser-pro) repeat motifs that are localized to the carboxy-terminal tail regions of medium (NFM) and heavy NF (NFH) protein subunits [24,25]. These tail regions are thought to mediate insertion of newly synthesized NF proteins into the stationary cytoskeleton [26] and, therefore, the physicochemical consequences of adduct formation at corresponding KSP motifs could jeopardize these turnover-related interactions.
Role of N-acetylcysteine in protecting against 2,5-hexanedione neurotoxicity in a rat model: Changes in urinary pyrroles levels and motor activity performance
2014, Environmental Toxicology and PharmacologyCitation Excerpt :One of the approaches to be applied in risk protection against n-hexane neurotoxicity is the development of antagonists that could interfere with its chemical mechanism of toxicity. It is well known that 2,5-hexanedione (2,5-HD) is the metabolite responsible by n-hexane neurotoxicity and mechanistic studies showed that this γ-diketone binds to amino groups of lysine in axonal cytoskeletal proteins forming 2,5-DMP (2,5-dimethylpyrrole) primary adducts, within specific regions of neurofilaments (NFs) (DeCaprio et al., 1982; Graham et al., 1982; DeCaprio and Fowke, 1992; DeCaprio et al., 1997; Zhang et al., 2010). Secondary autoxidative reactions of 2,5-DMP leads to electrophilic pyrrolylmethyl intermediates followed by their capture by unoxidized pyrroles, forming pyrrole dimers which produce intra- and intermolecular cross-linkings in neurofilament proteins (Graham et al., 1982; Genter et al., 1988; LoPachin and Lehning, 1997).