a. Acetylcholinesterase exists as a large, complex molecule. The active centre has been suggested to comprise:
(1) A negatively charged or anionic sub-site.
(2) An esteratic sub-site.
b. The current model for the binding group at the esteratic site is an hydroxyl group of a serine molecule of the enzyme. This group binds to the acyl carbon atom of acetylcholine. The sequence of reactions taking place during the hydrolysis of ACh is shown in Figure A-I.
1. Acetylcholine molecule and active site of enzyme shown together but not having undergone any interaction.
2. Acetylcholine combined with enzyme to form a substrate-enzyme intermediate (short lived).
3. The ester link in the acetylcholine has been broken and free choline has been formed.
4. The acyl group has become detached from the enzyme leaving: choline, acetic acid, and the enzyme returned to its original state.
c. The overall reaction could be represented by Figure A-II.
d. The choline is taken up by the pre-synaptic or pre-junctional nerve terminals and recycled by combination with acetyl CoA catalysed by the enzyme choline acetyltransferase to form more acetylcholine.
e. The destruction of acetylcholine by Ache is a very rapid reaction. Organophosphorus compounds (including sarin) act by combining essentially irreversibly with acetylcholinesterase molecules and preventing their activity. The combination of Sarin with AChE is shown in the series of reactions in Figure A-III.
f. Unlike the hydrolysis of acetylcholine, however, this series of reactions is slow as a result of the very slow, and rate limiting, final step (3-4) in Figure A-II. This stage takes place so slowly that in practical terms no regeneration of enzyme takes place and if the dose of sarin is sufficiently large the patient dies.
g. Another reaction may be added to the above series: the reaction describing the process of AGING 11:
h. This loss of an alkyl group produces a very stable sarin-enzyme complex which is then resistant to spontaneous hydrolysis and reactivation by oximes. The rate of aging is dependent on the nature of the alkyl group and is fairly slow (minutes - hours) in the case of sarin or VX but is very rapid (seconds - minutes) in the case of soman.
Taken from US military NBC papers. (references)
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