Abstract
While much progress has been made in the last 50 years in the development of treatments for nerve agent intoxication, the organophosphorus anticholinesterase inhibitors (OPs) remain a chemical warfare threat. In addition, treatments for the large numbers of people are accidentally poisoned by organophosphorus insecticides each year remain inadequate. It is generally accepted that we are approaching the limiting efficacy for pharmacological treatment of this type of intoxication with drugs now in development, so any significant increase of protection without unacceptable side effects must result from new approaches. In recent years it has been shown (Raveh et al. 1989, Broomfield et al., 1991; Broomfield, 1992) that it is possible to protect animals from OPs by prophylactic administration of scavengers that can react with and detoxify the inhibitors before they reach their critical targets. Stoichiometric scavengers (one molecule of scavenger reacts with one molecule of toxin) are effective but require a large amount of material to destroy a small amount of toxin. Catalytic scavengers (enzymes that catalyze the hydrolysis of the toxins) are also effective (Broomfield, 1992) but the enzymes that occur in nature are generally inefficient; they have high Km values and low turnover numbers. Again, a large amount of material is required to afford the desired degree of protection. To remedy this situation, we proposed to construct a more efficient organophosphorus acid anhydride hydrolase (OPAH) by site-directed mutagenesis of the butyrylcholinesterase (BuChE) gene. The rationale for this scheme was based on an hypothesis by J. Jarv (1984) that organophosphates are hemisubstrates for the cholinesterases because they form chiral phosphorylated enzymes. The histidine-bound water molecule that normally displaces the acyl group from the active site serine in the course of normal hydrolysis is prevented sterically from attacking the appropriate face of the tetrahedral phosphorus molecule, thus preventing reactivation of the enzyme. If this hypothesis is correct, we reasoned that it might be possible to introduce a second nucleophilic center into the active site in such a position that it could carry an activated water molecule to the face of the phosphorus moiety opposite the phosphorus-serine bond and thereby reactivate the enzyme. This became possible when the crystal structure of acetylcholinesterase (AcChE) was solved by Sussman, et al. (1991).
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References
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© 1995 Springer Science+Business Media New York
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Broomfield, C.A., Millard, C.B., Lockridge, O., Caviston, T.L. (1995). Mutation of Human Butyrylcholinesterase Glycine 117 to Histidine Preserves Activity but Confers Resistance to Organophosphorus Inhibitors. In: Quinn, D.M., Balasubramanian, A.S., Doctor, B.P., Taylor, P. (eds) Enzymes of the Cholinesterase Family. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-1051-6_35
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DOI: https://doi.org/10.1007/978-1-4899-1051-6_35
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