Details

Autor(en) / Beteiligte

• Wijeyesakere, Sanjeeva J.
• Richardson, Rudy J.

Titel

Chapter 67 - Neuropathy Target Esterase

Ist Teil von

• Hayes' Handbook of Pesticide Toxicology, 2010, p.1435-1455

Auflage

Third Edition

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

2010

Beschreibungen/Notizen

• This chapter deals with neuropathy target esterase (NTE). Human NTE is now known as patatin-like phospholipase domain-containing protein-6 because of the homology of its catalytic domain to patatin, a lipid acyl hydrolase found in potatoes and other plants. It is also cataloged as a lysophospholipase due to its hydrolysis of lysophosphatidylcholine to glycerophosphocholine, but its precise physiological and pathogenic roles have not been firmly established. The protein was first identified in hen brain as the target for initiation of OPIDN by neuropathic OP compounds. NTE is commonly assayed as the activity toward the nonphysiological substrate PV that is resistant to preincubation with nonneuropathic paraoxon and sensitive to neuropathic mipafox. Extensive structure–activity relationships demonstrated that NTE inhibitors fell into two functional categories: neuropathic and nonneuropathic. The essential difference between neuropathic and nonneuropathic NTE inhibitors is that neuropathic inhibitors are capable of undergoing the aging reaction, whereby the NTE–OP conjugate undergoes net dealkylation/dearylation or deprotonation to yield a negatively charged phosphyl group covalently bonded to the active site serine. Because initiation of OPIDN appears to require aging of NTE rather than mere inhibition of its activity, it has been thought that aged NTE operates through a toxic gain-of-function mechanism, possibly by acting as a spurious phosphorylation signal to trigger a proactive axonopathic process akin to Wallerian degeneration. Conventional and conditional knockout experiments have shown NTE to be essential for the development and maintenance of various cells and tissues, including large neurons in the hippocampus and cerebellum. Although the model provides an alternative to the toxic gain-of-function hypothesis of aged NTE, further research is needed to decide between the options or to determine that they are not mutually exclusive and that both mechanisms may be operating.