Neuropathy Target Esterase (NTE) and the Cholinergic System

What is NTE?

Neuropathy target esterase (NTE) is an integral membrane protein that is anchored to the endoplasmic reticulum (ER) and is known to be involved in lipid hydrolysis. Furthermore, NTE is known to be the cellular target for a class of organophosphorus compounds (OPs) termed neuropathic OPs that can, following exposure to a sufficiently toxic dose, initiate a delayed axonopathy. This condition, known as OP-induced delayed neurotoxicity (OPIDN), is understood follow inexorably after the inhibition of >70% of neuronal NTE by neuropathic OPs (such as diisopropyl phosphorofluoridate (DFP) and diisopropyldiamidophosphorofluoridate (Mipafox)), followed by an 'aging' reaction involving the OP adduct. Aging is a post-inhibitory reaction wherein the NTE-OP conjugate gains a net negative charge. In most cases, this occurs via the net loss of an alkyl (R) group from the OP adduct bound to the active site serine residue (Ser966) of NTE. The end result of the aging reaction is a permanently inhibited enzyme that cannot be reactivated via the use of strong nucleophiles like fluoride.

NTE inhibitors
Structures of some common NTE inhibitors

Structure of NTE

While the tertiary structure of NTE is currently unknown, it is known to be a multi-domain serine hydrolase consisting of an N-terminal transmembrane domain (TMD), three cyclic nucleotide binding domains and a C-terminal catalytic domain that is responsible for the lipid hydrolysis activity of the enzyme (Fig. 1). The catalytic domain is known to be similar to the plant protein patatin and we have shown its catalytic center to consist of a Ser966-Asp1086 catalytic dyad, similar to that found in patatin and cytosolic phospholipase A2.