Key active site residues in the inhibition of acetylcholinesterases by soman

Qian, Naifeng; Kovach, Ildiko M.

doi:10.1016/0014-5793(93)80816-d

Cited by 46 publications

(64 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The interaction energies arising from the hydrogen bonding of C = O or P = O have been the most significant stabilizing forces in the active site region of serine hydrolase enzymes (Qian & Kovach, 1993). The optimal orientation for each of the 2 stereoisomers of Huperzine A in the active-site pockets of FBS AChE, Torpedo AChE, and human BChE was then determined.…”

Section: Discussionmentioning

confidence: 99%

Identification of amino acid residues involved in the binding of Huperzine A to cholinesterases

et al. 1994

Self Cite

View full text Add to dashboard Cite

Huperzine A, a potential agent for therapy in Alzheimer's disease and for prophylaxis of organophosphate toxicity, has recently been characterized as a reversible inhibitor of cholinesterases. To examine the specificity of this novel compound in more detail, we have examined the interaction of the 2 stereoisomers of Huperzine A with cholinesterases and site-specific mutants that detail the involvement of specific amino acid residues. Inhibition of fetal bovine serum acetylcholinesterase by (-)-Huperzine A was 35-fold more potent than (+)-Huperzine A, with K , values of 6.2 nM and 210 nM, respectively. In addition, (-)-Huperzine A was 88-fold more potent in inhibiting Torpedo acetylcholinesterase than (+)-Huperzine A, with K , values of 0.25 pM and 22 pM, respectively. Far larger K , values that did not differ between the 2 stereoisomers were observed with horse and human serum butyrylcholinesterases. Mammalian acetylcholinesterase, Torpedo acetylcholinesterase, and mammalian butyrylcholinesterase can be distinguished by the amino acid Tyr, Phe, or Ala in the 330 position, respectively. Studies with mouse acetylcholinesterase mutants, Tyr 337(330) Phe and Tyr 337(330) Ala yielded a difference in reactivity that closely mimicked the native enzymes. In contrast, mutation of the conserved Glu 199 residue to Gln in Torpedo acetylcholinesterase produced only a 3-fold increase in K , value for the binding of Huperzine A. Molecular mechanics energy minimization of the complexes formed between each of the 2 stereoisomers of Huperzine A and fetal bovine serum acetylcholinesterase, Torpedo acetylcholinesterase, or human butyrylcholinesterase also revealed that (-)-Huperzine A gave a better fit than (+)-Huperzine A and implicated Tyr 337(330) in the stereoselectivity of Huperzine A.

show abstract

Section: Discussionmentioning

confidence: 99%

Identification of amino acid residues involved in the binding of Huperzine A to cholinesterases

et al. 1994

Self Cite

View full text Add to dashboard Cite

show abstract

“…Besides, various non-covalent forces stabilize the aged complex: interactions among the OPC and the oxyanion hole, the acyl pocket and the histidine at the active site either stabilize the aged complex, either limit the dephosphylation by blocking the access of water or other nucleophiles to the phosphorus atom. [98][99][100][101][102] Another factor that may contribute to the resistance of aged enzymes for reactivation is the conformational changes that they suffer after aging, making the OPC less exposed to nucleophilic attacks. 96 Finally, at least in the case of the nerve agent soman, it has been proposed the existence of a "push-pull" electrostatic mechanism, involving residues Glu-199, His-440, Trp-84 and the oxyanion hole in TcAChE, which would stabilize the carbenium formed during aging and favor a methyl migration that would transform a secondary carbenium in a tertiary one.…”

Section: Mechanism Of Action Of Opcsmentioning

confidence: 99%

“…It is believed that the rapid aging of soman is due to the formation of a tertiary carbenium (which later rearranges itself in neutral compounds) by a methyl migration in the secondary pinacolyl carbenium aided by a 'push-pull' mechanism, as shown in Figure 10. 97,99,103,104 Table 4 compiles data of rate constants for inhibition of HuAChE by racemic mixtures of several nerve agents, and also presents rate constants for aging and spontaneous reactivation of the phosphylated enzyme in each case.…”

Section: Opcs As Chemical Warfare Agentsmentioning

confidence: 99%

“…96 Finally, at least in the case of the nerve agent soman, it has been proposed the existence of a "push-pull" electrostatic mechanism, involving residues Glu-199, His-440, Trp-84 and the oxyanion hole in TcAChE, which would stabilize the carbenium formed during aging and favor a methyl migration that would transform a secondary carbenium in a tertiary one. 97,99,103,104 Spontaneous reactivation rates of phosphylated cholinesterases are determined by the structure of the phosphyl-enzyme. Except for the nerve agents, spontaneous reactivation occurs at clinically significant rates with the majority of the OPCs, but it is always slower than the deacetylation that happens in the hydrolysis of the natural substrate: Deacetylation of AChE occurs in microseconds, but dephosphylation in hours to days.…”

Section: Mechanism Of Action Of Opcsmentioning

confidence: 99%

See 1 more Smart Citation

Organophosphorus compounds as chemical warfare agents: a review

Delfino¹,

Ribeiro²,

Figueroa‐Villar³

2009

J. Braz. Chem. Soc.

231

178

View full text Add to dashboard Cite

Os agentes de guerra química constituem uma das maiores ameaças do mundo moderno. Dentre estes, destacam-se os agentes neurotóxicos, em virtude de sua alta letalidade e periculosidade. Eles são compostos organofosforados que atuam pela inibição da enzima acetilcolinesterase, a qual é fundamental no processo de transmissão de impulsos nervosos. Existem várias formas de tratamento para a intoxicação por organofosforados, mas nenhuma delas é eficaz contra todos os agentes conhecidos ou contra todos os seus efeitos. Esta revisão tem como foco o uso de compostos organofosforados como agentes neurotóxicos de guerra química. Após uma breve introdução histórica, será feita uma discussão sobre as principais características estruturais e biológicas da acetilcolinesterase, seguida por uma revisão das propriedades dos compostos organofosforados e da sua aplicação como agentes de guerra química. Por fim, serão discutidas as formas de tratamento contra estes agentes, com ênfase nas oximas usadas para reativar a acetilcolinesterase inibida.Chemical warfare agents constitute one of the greatest threats in the modern world. Among them, the neurotoxic agents are of special interest due to their high lethality and danger. Neurotoxic agents are organophosphorus compounds that act by inhibiting the enzyme acetylcholinesterase, which is fundamental for the control of transmission of nervous impulses. There are several ways of treating intoxication by organophosphorus compounds, but none of them is efficient against all the known neurotoxic agents or against all of their effects. This review focus on the use of organophosphorus compounds as neurotoxic chemical warfare agents. After a brief historical introduction, it will be done a discussion about the structural and biological characteristics of acetylcholinesterase, followed by a review of the properties of organophosphorus compounds and their application as chemical warfare agents. Finally, the ways of treatment against intoxication with these agents will be discussed, with emphasis on the oximes used for reactivating the inhibited acetylcholinesterase.

show abstract

“…The interactions that occur in covalently linked tetracoordinate [6][7][8][9][10] and pentacoordinate [11] fragments that mimic transients in the reaction of the natural substrate, ACh, and that are constituents of inhibitors, were computed in this laboratory using molecular mechanics calculations. Interactions with key active-site residues were characterized for tetracoordinate phosphonate and carboxylate fragments [6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics study of active-site interactions with tetracoordinate transients in acetylcholinesterase and its mutants

Enyedy

Kovach

Bencsura

2001

Biochemical Journal

Self Cite

View full text Add to dashboard Cite

The role of active-site residues in the dealkylation reaction in the P S C S diastereomer of 2-(3,3-dimethylbutyl)methylphosphonofluoridate (soman)-inhibited Torpedo californica acetylcholinesterase (AChE) was investigated by full-scale molecular dynamics simulations using CHARMM : 400 ps equilibration was followed by 150-200 ps production runs with the fully solvated tetracoordinate phosphonate adduct of the wild-type, Trp84Ala and Gly199Gln mutants of AChE. Parallel simulations were carried out with the tetrahedral intermediate formed between serine-200 Oγ of AChE and acetylcholine. We found that the NεH in histidine H + -440 is positioned to protonate the oxygen in choline and thus promote its departure. In contrast, NεH in histidine H + -440 is not aligned for a favourable proton transfer to the pinacolyl O to promote dealkylation, but electrostatic stabilization by histidine H + -440 of the developing anion on the phosphonate monoester occurs. Destabilizing interactions between residues and the alkyl fragment

show abstract

Key active site residues in the inhibition of acetylcholinesterases by soman

Cited by 46 publications

References 20 publications

Identification of amino acid residues involved in the binding of Huperzine A to cholinesterases

Identification of amino acid residues involved in the binding of Huperzine A to cholinesterases

Organophosphorus compounds as chemical warfare agents: a review

Molecular dynamics study of active-site interactions with tetracoordinate transients in acetylcholinesterase and its mutants

Contact Info

Product

Resources

About