title: Neural development and neurodegeneration: two faces of neuropathy target esterase.
abstract: Neuropathy target esterase (NTE) is an integral membrane protein in vertebrate neurons. Recent evidence suggests that NTE plays an important role in neural development, possibly via involvement in a signalling pathway between neurons and glial cells. NTE is a member of a novel protein family, represented in organisms from bacteria to man. NTE comprises an N-terminal regulatory domain (with some sequence similarity to cyclic nucleotide-binding proteins) and a C-terminal catalytic domain: the latter has three predicted transmembrane segments and requires membrane-association for activity. In vitro, NTE potently catalyses hydrolysis of phenyl valerate: however, its physiological substrate is likely to be a metabolite of a much longer chain carboxylic acid, possibly associated with cell membranes. NTE was discovered originally as the primary target for those organophosphorus esters (OPs) which cause a delayed neuropathy with degeneration of long axons in peripheral nerves and spinal cord. Paradoxically, NTE's catalytic activity appears redundant in adult vertebrates. Neuropathic OPs react covalently with NTE in a rapid two-step process which not only inhibits catalytic activity but also leaves a negatively-charged OP group attached to the active site serine. The latter event is proposed to induce a toxic gain of function in NTE. OP-modified NTE somehow engenders a "chemical transection of the axon". In turn, this leads to calcium entry, elevation of axonal calpain activity and Wallerian-type degeneration. The net damage to peripheral nerve axons is a balance between ongoing degenerative and repair processes: the latter involve serine hydrolases which can be inhibited by the same OPs used to modify NTE.
authors.affiliation: MRC Toxicology Unit, University of Leicester, UK. pg8@le.ac.uk
authors.forename: P
authors.initials: P
authors.lastname: Glynn
mesh_terms: D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D006801:Humans; D009410:Nerve Degeneration / Q000378:metabolism*; D009420:Nervous System / Q000201:enzymology* / Q000503:physiopathology*; D010523:Peripheral Nervous System Diseases / Q000378:metabolism* / Q000503:physiopathology*
chemical_list: D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase