Acetylcholinesterase phosphylated

E. Elhanany, A. Ordentlich, O. Dgany, D. Kaplan, Y. Segall, R. Barak, B. Velan and A. Shafferman, Resolving pathways of interaction of covalent inhibitors with the active site of acetylcholinesterases MALDI-TOF/MS analysis of various nerve agent phosphyl adducts, Chem. Res. Toxicol., 14, 912-918 (2001). 

Phosphylation of the OH moiety of the serine residue, being part of the catalytic triad in the esteratic center of acetylcholinesterase (AChE), represents the pathophysio-logically most important reaction resulting in enzyme deactivation. Inhibition of AChE was proven to be the predominant major reaction in vivo that causes death... 

Shafferman, A., Ordentlich, A., Barak, D., Stein, D., Ariel, N., Velan, B. (1996). Aging of phosphylated human acetylcholinesterase catal dic processes mediated by aromatic and polar residues of the active site. Biochem. J. 318 833 0. 

Hanke, D.W. and Overton, M.A. 1991, Phosphylation kinetic constants and oxime-induced reactivation in acetylcholinesterase from fetal bovine serum, bovine caudate nucleus, and electric eel, J. Toxicol Environ. Health, vol. 34, no. 1, pp. 141-156. 

Some useful relationships can then be derived, e.g. k = ki/Kn (Main and Iverson, 1966). In addition, k, = In 2//50 (Aldridge, 1950) which allows easy estimation of, (The I50 is the concentration of inhibitor, which inhibits the enzyme by 50%). These constants have been measured for many OP chemical warfare agents and also pesticides (e.g. Gray and Dawson, 1987). The hydrolysis reaction for acetylated acetylcholinesterase is fast (Koelle, 1992), in the region of 100 ps (Lawler, 1961 O Brien, 1976). The key to the powerful anticholinesterase effects of OPs is what happens after inhibition by these compounds. In the case of OPs, hydrolysis of the phosphylated serine residue is much slower2 than the acetylated analogue. 

Milatovic, D., and Vorkapic-Furac, J., 1989. Synthesis of three pyridoxal oxime derivatives and their reactivating potency against phosphylated acetylcholinesterase. Acta Pharmaceutica Jugoslavia. 39 281-287. 

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