Aging Mechanism of Soman Inhibited Acetylcholinesterase

Abstract

Acetylcholinesterase (AChE) is a crucial enzyme in the cholinergic nervous system that hydrolyses neurotransmitter acetylcholine (ACh) and terminates synaptic signals. The catalytic serine of AChE can be phosphonylated by soman, one of the most potent nerve agents, and subsequently undergo an aging reaction. This phosphonylation and aging process leads to irreversible AChE inhibition, results in accumulation of excess ACh at the synaptic clefts and causes neuromuscular paralysis. By employing Born-Oppenheimer ab initio QM/MM molecular dynamics simulations with umbrella sampling, a state-of-the-art approach to simulate enzyme reactions, we have characterized the aging mechanism of soman phosphonylated AChE and determined its free energy profile. This aging reaction starts with the scission of the O2-Cα bond, which is followed by methyl migration, and results in a tertiary carbenium intermediate. At the transition state, the scissile O2-Cα bond is already cleaved with an average O-C distance of 3.2 ± 0.3 Å and the migrating methyl group is shared between Cα and Cβ carbons with C-C distances of 1.9 ± 0.1 and 1.8 ± 0.1 Å, respectively. The negatively charged phosphonate group is stabilized by a salt bridge with the imidazole ring of the catalytic histidine. A major product of aging, 2,3-dimehtyl-2-butanol can be formed swiftly by the reaction of a water molecule. Our characterized mechanism and simulation results provide new detailed insights into this important biochemical process.

Comparing the Antiseizure and Neuroprotective Efficacy of LY293558, Diazepam, Caramiphen, and LY293558-Caramiphen Combination against Soman in a Rat Model Relevant to the Pediatric Population

“…The primary action of these organophosphorus neurotoxins is the inhibition of acetylcholinesterase (Sirin et al, 2012). Death may ensue due to the peripheral cholinergic crisis that follows acetylcholinesterase inhibition, and/or the prolonged seizures and status epilepticus (SE) which are initiated by excessive accumulation of acetylcholine in neuronal synapses in the brain, and overstimulation of cholinergic receptors.…”

Crystal Structure of Patatin-17 in Complex with Aged and Non-Aged Organophosphorus Compounds

“…Taken together, these observations suggest that the protonated amides in the oxyanion hole of pat17 may play a role in the aging reaction by stabilizing the emerging net negative charge on the alkoxy oxygen during the dealkylation phase of the aging process. This is a similar role to that played by the oxyanion hole in the normal catalytic process and can be contrasted to the previously proposed role for the protonated form of His440 (the general base in the catalytic triad of AChE) in the aging of an OP adduct on the catalytic nucleophile (Ser200) of AChE [27]. As such, the putative preference of pat17 towards the S-enantiomer of MAFP could shield its labile O-methyl group from the residues that form the oxyanion hole of patatin, thus hindering the aging of the (S)-MAFP adduct.…”

Computational Studies of Glycoside, Carboxylic Ester, and Thioester Hydrolase Mechanisms: A Review

“…This is followed by methyl migration, leading to a tertiary carbenium intermediate. 125 A salt bridge with the catalytic histidine residue imidazole ring stabilizes the negatively charged phosphonate group.…”