A phosphorylation site in brain and the delayed neurotoxic effect of some organophosphorus compounds

Johnson, Martin K.

doi:10.1042/bj1110487

Cited by 152 publications

(34 citation statements)

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“…The phosphorylation of an enzyme (neuropathy target esterase; NTE) in nerve tissue is considered to be responsible for the polyneuropathy [72,73]. Neuropathy target esterase is a membrane-bound protein with high esterase catalytic activity whose physiological function is not known.…”

Section: Delayed Polyneuropathymentioning

confidence: 99%

Organophosphorus poisoning and anaesthesia

1999

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SummaryOrganophosphorus compounds, used as insecticides and agents of chemical warfare, are a major global cause of health problems. These irreversible inhibitors of cholinesterase produce three wellrecognised clinical entities: the initial cholinergic phase, which is a medical emergency often requiring management in an intensive care unit; the intermediate syndrome, during which prolonged ventilatory care is necessary; and delayed polyneuropathy. In addition, disturbances of body temperature and endocrine function, electrolyte imbalances, immunological dysfunction and disorders of reproduction have been reported in animals and man. Vocal cord paralysis, pancreatitis, cardiac arrhythmias and a wide range of neuropsychiatric disorders are known to follow acute and chronic exposure to organophosphorus compounds. As a result of the inhibition of plasma cholinesterase, there can be increased sensitivity to drugs hydrolysed by this enzyme, e.g. suxamethonium and mivacurium. The inhibition of acetylcholinesterase causes dysfunction at the neuromuscular junction which can produce altered responses to nondepolarising neuromuscular blockers. Anaesthetists may encounter patients exposed to organophosphorus compounds either following acute poisoning, trauma (warfare) or as patients with a wide range of nonspecific disorders presenting for surgery. The traditional use of oximes and atropine in treatment has failed to reduce the morbidity and mortality associated with poisoning. The roles of agents that have reduced the toxicity of organophosphorus compounds in animal experiments are discussed as potential therapeutic agents. There is an urgent need for accurate information on the problems associated with exposure to organophosphorus compounds. This would best be achieved by collaborative research between technologically advanced countries and developing countries, where organophosphorus compounds are a leading cause of ill health.

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Section: Delayed Polyneuropathymentioning

confidence: 99%

Organophosphorus poisoning and anaesthesia

1999

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“…NTE was originally identified and defined by its ability to both bind a radiolabelled OP and hydrolyse a (non-physiological) ester substrate [7,8]. By the mid-1970s, pioneering work by Johnson showed that inhibition by OPs of NTE's esteratic activity per se did not itself initiate neuropathy ; the latter required a rapid secondary intramolecular change in the neutrally charged covalently bound OP, which left a negatively charged form of the OP still attached to the active-site serine of NTE [9].…”

Section: Introductionmentioning

confidence: 99%

Neuropathy target esterase and a homologous Drosophila neurodegeneration-associated mutant protein contain a novel domain conserved from bacteria to man

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et al. 1998

Biochemical Journal

138

113

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The N-terminal amino acid sequences of proteolytic fragments of neuropathy target esterase (NTE), covalently labelled on its active-site serine by a biotinylated organophosphorus ester, were determined and used to deduce the location of this serine residue and to initiate cloning of its cDNA. A putative NTE clone, isolated from a human foetal brain cDNA library, encoded a 1327 residue polypeptide with no homology to any known serine esterases or proteases. The active-site serine of NTE (Ser-966) lay in the centre of a predicted hydrophobic helix within a 200-amino-acid C-terminal domain with marked similarity to conceptual proteins in bacteria, yeast and nematodes; these proteins may comprise a novel family of potential serine hydrolases. The Swiss Cheese protein which, when mutated, leads to widespread cell death in Drosophilabrain [Kretzschmar, Hasan, Sharma, Heisenberg and Benzer (1997) J. Neurosci. 17, 7425–7432], was strikingly homologous to NTE, suggesting that genetically altered NTE may be involved in human neurodegenerative disease.

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“…Certain fluoro-organophosphorus compounds are known to ,cause deLayed neurotoxicity (1,2,5,12,13). Hexane (20) and other hydrocarbon solvents (8) may also cause ,polyneuropa;thy.…”

Section: Discussionmentioning

confidence: 99%