Neurotoxic mechanisms of electrophilic type-2 Alkenes

Soft-soft interactions described by quantum mechanical parameters

Richard M. LoPachin, Terrence Gavin, Brian C. Geohagen, Soma Das

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Conjugated Type-2 alkenes, such as acrylamide (ACR), are soft electrophiles that produce neurotoxicity by forming adducts with soft nucleophilic sulfhydryl groups on proteins. Soft-soft interactions are governed by frontier molecular orbital characteristics and can be defined by quantum mechanical parameters such as softness (σ) and chemical potential (μ). The neurotoxic potency of ACR is likely related to the rate of adduct formation, which is reflected in values of σ. Correspondingly, differences in μ, the ability of a nucleophile to transfer electrons to an electrophile, could determine protein targets of these chemicals. Here, σ and μ were calculated for a series of structurally similar Type-2 alkenes and their potential sulfhydryl targets. Results show that N-ethylmaleimide, acrolein and methylvinyl ketone were softer electrophiles than methyl acrylate or ACR. Softness (σ) was closely correlated to corresponding second-order rate constants (k2) for electrophile reactions with sulfhydryl groups on N-acetyl-L-cysteine (NAC). The rank order of softness was also directly related to neurotoxic potency as determined by impairment of synaptosomal function and sulfhydryl loss. Calculations of μ showed that the thiolate state of several cysteine analogs was the preferred nucleophilic target of alkene electrophiles. In addition, μ was directly related to the thiolate rate constant (k) for the reaction of the Type-2 alkenes with the cysteine compounds. Finally, in accordance with respective μ values, we found that NAC, but not N-acetyl-L-lysine, protected synaptosomes from toxicity. These findings suggest that the neurotoxicity of ACR and its conjugated alkene analogs is related to electrophilic softness and that the thiolate state of cysteine residues is the corresponding adduct target.

Original languageEnglish (US)
Pages (from-to)561-570
Number of pages10
JournalToxicological Sciences
Volume98
Issue number2
DOIs
StatePublished - Aug 2007

Fingerprint

Alkenes
Acrylamide
Cysteine
Acetylcysteine
Rate constants
Acrolein
Nucleophiles
Ethylmaleimide
Synaptosomes
Chemical potential
Molecular orbitals
Lysine
Toxicity
Proteins
Electrons

Keywords

  • Acrolein
  • Acrylamide
  • Adduct formation
  • Distal axonopathy
  • Nerve terminal
  • Neurotoxicity
  • Type-2 alkenes

ASJC Scopus subject areas

  • Toxicology

Cite this

Neurotoxic mechanisms of electrophilic type-2 Alkenes : Soft-soft interactions described by quantum mechanical parameters. / LoPachin, Richard M.; Gavin, Terrence; Geohagen, Brian C.; Das, Soma.

In: Toxicological Sciences, Vol. 98, No. 2, 08.2007, p. 561-570.

Research output: Contribution to journalArticle

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abstract = "Conjugated Type-2 alkenes, such as acrylamide (ACR), are soft electrophiles that produce neurotoxicity by forming adducts with soft nucleophilic sulfhydryl groups on proteins. Soft-soft interactions are governed by frontier molecular orbital characteristics and can be defined by quantum mechanical parameters such as softness (σ) and chemical potential (μ). The neurotoxic potency of ACR is likely related to the rate of adduct formation, which is reflected in values of σ. Correspondingly, differences in μ, the ability of a nucleophile to transfer electrons to an electrophile, could determine protein targets of these chemicals. Here, σ and μ were calculated for a series of structurally similar Type-2 alkenes and their potential sulfhydryl targets. Results show that N-ethylmaleimide, acrolein and methylvinyl ketone were softer electrophiles than methyl acrylate or ACR. Softness (σ) was closely correlated to corresponding second-order rate constants (k2) for electrophile reactions with sulfhydryl groups on N-acetyl-L-cysteine (NAC). The rank order of softness was also directly related to neurotoxic potency as determined by impairment of synaptosomal function and sulfhydryl loss. Calculations of μ showed that the thiolate state of several cysteine analogs was the preferred nucleophilic target of alkene electrophiles. In addition, μ was directly related to the thiolate rate constant (k) for the reaction of the Type-2 alkenes with the cysteine compounds. Finally, in accordance with respective μ values, we found that NAC, but not N-acetyl-L-lysine, protected synaptosomes from toxicity. These findings suggest that the neurotoxicity of ACR and its conjugated alkene analogs is related to electrophilic softness and that the thiolate state of cysteine residues is the corresponding adduct target.",
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