Acetylcholinesterase (AChE)

Acetylcholinesterase (AChE; EC 3.1.1.7) is a serine hydrolase enzyme that catalyzes the rapid breakdown of the neurotransmitter acetylcholine into choline and acetate, terminating cholinergic signaling at synapses and neuromuscular junctions. Its catalytic machinery sits at the base of a deep, narrow active-site gorge lined by aromatic residues, with a catalytic triad at one end and a peripheral anionic site at the gorge mouth — an architecture that gives the enzyme both extraordinary turnover speed and two spatially distinct pockets that inhibitors can be designed to occupy. The protein is expressed in cholinergic neurons, at motor endplates, and on erythrocyte membranes, where it also carries the Yt blood group antigen; red blood cell AChE activity is used clinically as a marker of cholinesterase status. Beyond hydrolysis, AChE has been implicated in non-catalytic roles including cell adhesion, neurite outgrowth, and responses to oxidative stress and apoptotic signaling.

Pharmacologically, AChE is a central drug target. Inhibiting it raises synaptic acetylcholine levels, the mechanism behind cholinergic therapy for Alzheimer's disease with agents such as donepezil, and much current medicinal chemistry — coumarin carboxamides, flavonoids and biflavonoids, and other plant-derived scaffolds such as chrysin, apigenin, naringenin, hesperidin, and rosmarinic acid — is screened for AChE inhibition alongside the closely related butyrylcholinesterase, which hydrolyzes a broader range of esters and becomes proportionally more important as AChE activity declines in the aging brain. Because such compounds must reach the central nervous system, blood–brain barrier permeability is a routine consideration in their evaluation, often alongside docking, molecular dynamics, and QSAR modeling. AChE inhibition is frequently studied together with other Alzheimer's-relevant targets including beta-secretase 1, glycogen synthase kinase 3β, and amyloid beta, and with markers of oxidative stress and neuroinflammation such as superoxide dismutase, catalase, glutathione, reactive oxygen species, Tnf-α, IL-1β, and COX-2 — a combination that links AChE to work on diabetes-associated neurodegeneration, where insulin resistance and hyperglycemia accompany cholinergic and hippocampal damage and where dual-acting agents such as SGLT2 inhibitors have been examined. Conversely, irreversible inhibition of AChE by organophosphate pesticides and nerve agents causes acetylcholine accumulation and the cholinergic toxidrome, and the enzyme's sensitivity to these compounds is itself exploited in biosensors that detect organophosphate residues.