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CHEMICAL BIOLOGY
Protein engineering of an enzyme that catalytically detoxifies organophosphate compounds in the body opens up fresh opportunities in the search for therapeutic protection against nerve agents used in chemical warfare.
Organophosphates are among the most toxic compounds that have been chemically synthesized. Since the discovery of their biological activity in the 1930s, these compounds have found use as broad-spectrum insecticides for agricultural and domestic applications. But organophosphates have also been developed as chemical-warfare agents, including VX and the 'G-agents' (such as sarin, soman and cyclosarin). Because these compounds are relatively easy to synthesize, their use by international terrorist groups is a serious threat. Current protocols for the prevention and treatment of organophosphate poisoning are largely ineffective, and so new strategies are desperately needed. Reporting in Nature Chemical Biology, Gupta et al.1 describe an approach that might one day find use in preventing organophosphate poisoning.
Organophosphates are highly toxic because they rapidly inactivate acetylcholinesterase (AChE), an enzyme required for nerve function (Fig. 1). AChE breaks down (hydrolyses) acetylcholine, a neurotransmitter that relays nerve impulses to muscles and other organs. Organophosphates form a covalent bond to a serine amino-acid residue in the active site of AChE, stopping the enzyme from functioning. The subsequent build-up of acetylcholine blocks cholinergic nerve impulses, leading to paralysis, suffocation and death.
Various prophylactic approaches have been developed to diminish the toxic effect of organophosphates. Atropine, for example, is a competitive antagonist for muscarinic acetylcholine receptors - it blocks the action of acetylcholine, thereby reducing the effective concentration of the neurotransmitter. Alternatively, chemicals such as pralidoxime react with AChE-organophosphate adducts to regenerate catalytically active AChE.
A relatively new approach for reducing the concentration of organophosphates in the blood is to inject human butyrylcholin esterase (BChE) directly into the bloodstream of a poisoned individual2. This enzyme reacts with organophosphates in the same way...