Structure-Function Relationships, In Vivo Mutability and Gene Amplification in Human Cholinesterases, Targets for Organophosphorous Poisons

The human Cholinesterase genes and their protein products have been the focus of intensive research for many years (for comprehensive reviews see Whittaker, 1986; 1Rakonczay and Brimijoin, 1988; and Soreq and Zakut, 1990) because of the physiological function attributed to these enzymes, which are both capable of hydrolyzing the neurotransmitter acetylcholine. Genetic linkage evidence indicated that two distinct genes, designated ACHE and CHE, encode the two principal forms of cholinesterases, acetylcholinesterase (acetylcholine acetyl hydrolase, AChE, EC 3.1.1.7) and butyrylcholinesterase (acylcholine acylhydrolase, BuChE, EC 3.1.1.8) which differ in their substrate specificities and sensitivities to selective inhibitors. The toxic effects of organophosphorous (OP) poisons, such as common insecticides or nerve gases, are generally attributed to their specific inhibition of cholinesterases, interfering with cholinergic neurotransmission. OP inhibition of cholinesterases occurs through a covalent interaction of the OP compounds with a serine residue in the active esteratic site (Koelle, 1972). However, detailed structure-function relationships in this family of enzymes have been hampered by the difficulties in purifying mammalian cholinesterases.