Structural Study of the Complex Stereoselectivity of Human Butyrylcholinesterase for the Neurotoxic V-agents

Abstract

Nerve agents are chiral organophosphate compounds (OPs) that exert their acute toxicity by phosphorylating the catalytic serine of acetylcholinesterase (AChE). The inhibited cholinesterases can be reactivated using oximes, but a spontaneous timedependent process called aging alters the adduct, leading to resistance toward oxime reactivation. Human butyrylcholinesterase (BChE) functions as a bioscavenger, protecting the cholinergic system against OPs. The stereoselectivity of BChE is an important parameter for its efficiency at scavenging the most toxic OPs enantiomer for AChE. Crystals of BChE inhibited in solution or in cristallo with racemic V-agents (VX, Russian VX, and Chinese VX) systematically show the formation of the P S adduct. In this configuration, no catalysis of aging seems possible as confirmed by the three-dimensional structures of the three conjugates incubated over a period exceeding a week. Crystals of BChE soaked in optically pure VX R -(؉) and VX S -(؊) solutions lead to the formation of the P S and P R adduct, respectively. These structural data support an in-line phosphonylation mechanism. Additionally, they show that BChE reacts with VX R -(؉) in the presence of racemic mixture of V-agents, at odds with earlier kinetic results showing a moderate higher inhibition rate for VX S -(؊). These combined results suggest that the simultaneous presence of both enantiomers alters the enzyme stereoselectivity. In summary, the three-dimensional data show that BChE reacts preferentially with P R enantiomer of V-agents and does not age, in complete contrast to AChE, which is selectively inhibited by the P S enantiomer and ages.

Effects of viscosity and osmotic stress on the reaction of human butyrylcholinesterase with cresyl saligenin phosphate, a toxicant related to aerotoxic syndrome: kinetic and molecular dynamics studies

“…k i for inhibition of human BChE by potent OP nerve agents are fast; for instance, 1.1 × 10 7 M − 1 · min − 1 for VX S ( − ) [34] and 3.8 × 10 8 M − 1 · min − 1 for cyclohexylsarin [35]. Values of k i and k i for inhibition of BChE by CSP are comparable and are thus among the highest values for reaction of OP agents with ChEs, making CSP one of the most potent irreversible inhibitors of human BChE that is known.…”

Decline in Serum Cholinesterase Activities Predicts 2-Year Major Adverse Cardiac Events

“…The crystalographic structure PDB file of recombinant human acethylcholinesterase in complex with donepezil (PDB ID: 4EY7 [26]) and the X-ray structure PDB file of human butyrylcholinesterase (PDB ID: 2XQG [27]) were obtained from the RCSB Protein Data Bank (www.pdb.org) (28). One of the monomers in the crystalographic structure of human BChE and all water and ligand molecules besides donepezil were extracted from the PDB files using the PyMOL Molecular Graphics System, Version 1.3 (Schrödinger LLC, New York, NY, USA).…”

Assessment of Potential Long Term Health Effects on Army Human Test Subjects of Relevant Biological and Chemical Agents, Drugs, Medications and Substances

“…253 One month after intoxication, mnemonic cognitive performances of the LWL group were similar to controls while the HWL group did not exhibit any learning skill. 253 Three months after poisoning, compared to controls, the LWL group showed similar mnemonic performances in the maze test but a mild deficit in the Morris water maze task. At the same time, learning skills slightly recovered in the HWL group.…”

“…252 Soman exposure can also impair fear conditioning in rats, with soman-exposed animals spending less time freezing than controls, possibly due to the neuropathy observed in the hippocampus, amygdala, and thalamus. 253 Filliat and colleagues found that mice exposed to 1.2 LD50 of soman (110 mg/kg in 200 ml of saline solution) could be divided into high-weight loss (HWL) and low-weight loss (LWL) groups, and that this grouping was predictive of neuropathological damage to the hippocampus. 254 Initially, both groups of mice showed a decrease in their motor performance subsequent to an acute soman toxicity phase.…”