The cholinesterases.

In 1914 Sir Henry Dale (1) suggested that an enzyme which degrades the esters of choline played a role in neurotransmission within the autonomic and somatic motor nervous systems and that this enzyme, acetylcholinesterase, was the target of action of the drug, physostigmine (eserine). In the intervening 75 years, inhibition of the enzyme has been used to augment both the nicotinic and muscarinic actions of acetylcholine. Cholinesterase inhibitors are frequently used as therapeutic agents and are employed worldwide as insecticides. Over 20 years ago Jean Massoulib and FranCois Reiger uncovered an unusual structural polymorphism in the cholinesterases (2). Subsequent studies have shown that the polymorphism is reflected in multiple modes of attachment of the enzyme to the outside surface of the cell. Accordingly, the precise localization of cholinesterases within synaptic junctions and the high catalytic potential of the enzyme are both critical to the fidelity of cholinergic synaptic function. Within the last 5 years primary structures of several cholinesterases have been determined, and this has enabled investigators to ascertain the structural basis of the polymorphism and the organization of the genes encoding the cholinesterases. Cholinesterases may be classified as acetylcholinesterase (AChE,' EC 3.1.1.7) and butyrylcholinesterase (BuChE, EC 3.1.1.8) on the basis of differential specificity for acetylcholine and butyrylcholine hydrolysis. Several inhibitors have also been shown to be selective for one of the two enzymes. The AChEs are primarily associated with nerve and muscle, typically with localization at synaptic contacts, while BuChE is synthesized in liver with substantial amounts appearing in serum. The physiologic function of BuChE remains obscure; in fact, deficiencies of this enzyme in man only became apparent when succinylcholine was administered to produce neuromuscular blockade (3). The population distribution of BuChE mutations which yield an active enzyme resistant to certain inhibitors suggests a primary role for this enzyme to be in detoxification of plant esters ingested in the diet (4). The characterization of AChE as solely an enzyme of the cholinergic nervous system is an oversimplification. First, BuChE is often found in the developing nervous system while AChE appears at later stages of development. Second, both AChE and BuChE are found in hematopoietic cells, and their presence can be correlated with cell differentiation. Finally, AChE carries novel cell surface antigens which could play a role in cell-cell communication ( 5 ) .