Acetylcholinesterase (AChE) is an enzyme that catalyses the hydrolysis of the neurotransmitter acetylcholine (ACh) to acetate and choline, and plays a crucial role in terminating the nerve impulse at cholinergic synapses. Reversible inhibitors of AChE are used to treat diseases such as Alzheimer’s disease (AD) and Parkinson’s disease. Conversely, irreversible inhibition of AChE by organophosphates (OP), such as soman, can lead to death. In this process, the OP covalently attaches to a in the active site to generate a phosphorylated enzyme. Subsequently, the OP is dealkylated, a process that is termed aging, generating a form of the enzyme that cannot be reactivated by antidotes, such as pralidoxime (2-PAM). Recently, the structures of Torpedo californica (Tc) AChE conjugated with soman, in both the non-aged and aged forms, and 2-PAM have been solved. From these structures, it is clear that a structural reorientation of His440, a component of the active site, occurs during the aging process. Additionally, the structure of the ternary complex of the aged AChE complex with 2-PAM, revealed that the oxime functional group is not optimally positioned for nucleophilic attack on the phosphorous atom.
