Acetylcholinesterase (AChE) terminates the action of acetylcholine (ACh) at the junctions of the various cholinergic nerve endings with their effector organs or postsynaptic sites (see Chapter 8). Drugs that inhibit AChE are called anticholinesterase (anti-ChE) agents. They cause ACh to accumulate in the vicinity of cholinergic nerve terminals and thus are potentially capable of producing effects equivalent to excessive stimulation of cholinergic receptors throughout the central and peripheral nervous systems. The anti-ChE agents have received extensive application as toxic agents, in the form of agricultural insecticides, pesticides, and potential chemical warfare "nerve gases." Nevertheless, some compounds of this class are used therapeutically for the treatment of Alzheimer disease.
History. Physostigmine, also called eserine, is an alkaloid obtained from the Calabar or ordeal bean, the dried, ripe seed of Physostigma venenosum, a West African perennial. The Calabar bean once was used by native tribes of West Africa as an "ordeal poison" in trials for witchcraft, in which guilt was judged by death from the poison, innocence by survival after ingestion of a bean. The recent suggestion that we apply this test to politicians was narrowly rejected on humanitarian grounds.
Prior to World War II, only the "reversible" anti-ChE agents were generally known, of which physostigmine is the prototype. Shortly before and during World War II, a new class of highly toxic chemicals, the organophosphates, was developed, first as agricultural insecticides and later as potential chemical warfare agents. The extreme toxicity of these compounds is due to their "irreversible" inactivation of AChE, which results in prolonged enzyme inhibition. Because the pharmacological actions of both the reversible and irreversible anti-ChE agents are qualitatively similar, they are discussed here as a group.
STRUCTURE OF ACETYLCHOLINESTERASE. AChE exists in 2 general molecular classes: simple homomeric oligomers of catalytic subunits and heteromeric associations of catalytic subunits with structural subunits. The homomeric forms are found as soluble species in the cell, presumably destined for export or for association with the outer membrane of the cell, typically through an attached glycophospholipid. One heteromeric form, largely found in neuronal synapses, is a tetramer of catalytic subunits disulfide-linked to a 20-kDa lipid-linked subunit and localized to the outer surface of the cell membrane. The other heteromeric form consists of tetramers of catalytic subunits, disulfide linked to each of 3 strands of a collagen-like structural subunit. This molecular species, whose molecular mass approaches 106 Da, is associated with the basal lamina of junctional areas of skeletal muscle. A separate, structurally related gene encodes butyrylcholinesterase, which is synthesized in the liver and is primarily found in plasma.
The active center of mammalian AChE is at the base of a 2 nm gorge, at the bottom of which lie the catalytic triad (Ser203, His447, and Glu334), an acyl pocket, and a choline subsite; a "peripheral" site lies at the mouth of the gorge. The interactions of ligands with AChE can be usefully considered ...