Molecular cloning of neuropathy target esterase (NTE)

Covalent modification of NTE, a neuronal protein with serine esterase activ ity, by certain organophosphates (OP) initiates degeneration of long axons in the peripheral and central nervous system. Simple inhibition of NTE este rase activity does not initiate neuropathy; the latter requires aging of th e OP bound to the catalytic serine residue so that a negatively-charged spe cies is left attached to the active site. This may indicate that a non-este rase function of NTE is important for axonal maintenance. We have recently cloned NTE and shown that it is unrelated to any known serine hydrolases bu t contains a novel C-terminal domain which is conserved from bacteria to ma n. Furthermore, the catalytic serine is located within this domain at the c entre of a helical hydrophobic segment of the polypeptide's secondary struc ture. The integrity of NTE would be severely compromised by the presence of a negatively-charged organophosphate moiety at this site. Implications for possible higher-order structures and functions for NTE are discussed. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.