Acetylcholinesterase pathway

Acetylcholine is formed from acetyl CoA (produced as a byproduct of the citric acid and glycolytic pathways) and choline (component of membrane lipids) by the enzyme choline acetyltransferase (ChAT). Following release it is degraded in the extracellular space by the enzyme acetylcholinesterase (AChE) to acetate and choline. The formation of acetylcholine is limited by the intracellular concentration of choline, which is determined by the (re)uptake of choline into the nerve ending (Taylor Brown, 1994). 

Fig. 2. Two reaction pathways of phenyl N-methylcarbamates with acetylcholinesterase the boldfaced arrow indicates an electron pair migration as the driving force of the reaction14) (reproduced with permission from Academic Press, Inc.)...

Mesulam, M. M., Guillozet, A., Shaw, P., Levey, A., Duysen, E. G. and Lockridge, O. (2002) Acetylcholinesterase knockouts establish central cholinergic pathways and can use butyrylcholinesterase to hydrolyze acetylcholine. Neuroscience 110, 627-639. 

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). 

It is well known that organophosphates, carbamates and sulfonates are acid-transfer-inhibitors of serine hydrolases because they transfer the acid moiety of the inhibitor to the serine hydroxyl of the enzyme active site (34). Extensive evidence indicates that the reaction of these inhibitors with acetylcholinesterases (AChE) appears to involve the same reaction pathway as that for the esters of carboxylic acids, i.e. acetylcholine (see (35) for review), and in fact these inhibitors are considered to be poor substrates of AChE (36), especially the carbamic acid esters ("Equation 30 ). 

Such a pathway does, however, exist in insects. In the latter species, parathion and malathion act as prodrugs. They are metabolized by oxidative desulfurization to give the active anticholinesterases which irreversibly bind to the insects acetylcholinesterase enzymes and lead to death. In mammals, the same compounds are metabolized in a different way to give inactive compounds which are then excreted (Fig. 11.59). 

Farris, T. W., Butcher, L. L., Oh, J. D., and Woolf, N. J., Trophic-factor modulation of cortical acetylcholinesterase reappearance following transection of the medial cholinergic pathway in the adult rat, Exp. Neurol., 131, 180, 1995. 

The onset of intoxication symptoms is dependent on the pathway of absorption within a few minutes of inhalation, from 15 min to 1 h after swallowing, and 2-3 h after cutaneous resorption, a toxic concentration will be reached in the blood. With indirect acetylcholinesterase inhibitors, e.g. parathion, symptoms of poisoning occur later. No exact data exist about the extent of bioavaUability in the human body. 

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