The cholinesterases: from genes to proteins.

Linkages between cholinesterases and the pharmacological sciences extend back to the mid-nineteenth century when the first organophosphate was synthesized (1) and physostigmine was recognized in the western world for possessing pharmacological activity (2). However, not until Sir Henry Dale (3) delineated two components of the cholinergic nervous system was the suggestion made that physostigmine inhibited an enzyme that catalyzed the breakdown of choline esters. Dale's and later Loewi & Navratil's (4) studies established a role for acetylcholine as a labile neurotransmitter. The high turnover number of acetylcholinesterase (AChE), the specificity of its inhibitors, and the selectivity of thiocholine-metal ion interactions provided the bases for sensitive in vitro and in situ assay systems (5-7). Several cholinesterase inhibitors remain of value as medicinal agents and insecticides, but others possess the potential for insidious use as chemical warfare agents (8). Despite this long history of study, less than a decade has passed since the primary structure of a cholinesterase was determined (9), and only in 1991 was its crystal structure solved (10). Clearly, these recent events have added a new perspective to cholinesterase research wherein all facets of gene expression become amenable to study and structure-function relation­ ships within this family of enzymes can be approached at an atomic level