Reactivators, acetylcholinesterase molecule

Musilek, K., Kuca, K., Dohnal, V., Jun, D., Marek, J., Koleckar, V. (2007d). Two step synthesis of non-symmetric reactivator of acetylcholinesterase. Molecules 12 1755-61. 

A two-site immunometric assay of undecapeptide substance P (SP) has been developed. This assay is based on the use of two different antibodies specifically directed against the N- and C-terminal parts of the peptide (95). Affinity-purified polyclonal antibodies raised against the six amino-terminal residues of the molecule were used as capture antibodies. A monoclonal antibody directed against the carboxy terminal part of substance P (SP), covalently coupled to the enzyme acetylcholinesterase, was used as the tracer antibody. The assay is very sensitive, having a detection limit close to 3 pg/mL. The assay is fiiUy specific for SP because cross-reactivity coefficients between 0.01% were observed with other tachykinins, SP derivatives, and SP fragments. The assay can be used to measure the SP content of rat brain extracts. 

All three of these molecules contain highly reactive phosphoryl groups that readily react with the active-site serine of acetylcholinesterase to form a stable derivative. Without active acetylcholinesterase, synaptic transmission at the cholinergic synapses is impossible, resulting in respiratory paralysis. 

For the electrical signal to be completed, one final event is necessary the turning off of the signal. Acteylcholine will bind the cholinesterase receptor reversibly, such that it will bind, activate, then release. However, if the acetylcholine molecule remains intact in the synapse, the space between neuron and muscle fiber, it can reactivate the receptor. To turn the signaling chemical off once and for all, yet another protein, acetylcholinesterase, is found embedded in the membrane of the muscle fiber. Acetylcholinsterase cleaves the molecule into acetate and choline, and puts an end to the activation of the acetylcholine receptor. 

Oximes Oximes are compounds capable of reactivating, in some cases the complex formed by the OP compounds and acetylcholinesterase. Chemically, oximes are mono or bispyridinium compounds which can bind to the OP-AChE complex and cause the nerve agent molecule to separate from the enzyme. Importantly, oximes can reverse the actions of OP at both muscarinic and nicotinic receptors. Thus, unlike atropine, they act at the neuromuscular junction and can thus reduce the degree of paralysis. They have been shown to be effective in the management of OP pesticide poisoning. However, their effectiveness against nerve... 

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