Neuropathy Target Esterase (NTE)
Neuropathy target esterase (NTE) is an integral membrane phospholipase that is anchored to the endoplasmic reticulum (ER). NTE (also known as PNPLA6) is a member of a broad class of related proteins called the patatin-like phospholipase domain-containing proteins (PNPLAs). 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 ‘aging’ of the OP adduct. Aging is a post-inhibitory reaction wherein the NTE-OP conjugate gains a net negative charge. In most cases this occurs through 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.
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.
Figure 1: Domain organization of NTE showing its N-terminal transmembrane domain (TMD), three cyclic nucleotide (CNP) binding domains (CNP1, CNP2 and CNP3) and C-terminal catalytic (patatin-homology) domain (PNTE).
PNTE: The catalytic domain of NTE
While experimentally-derived structures for NTE or PNTE (its catalytic domain) are currently unavailable, we have developed a homology model for the catalytic domain of NTE (residues 933-1099) based on the crystal structure of patatin-17 (PDB ID 1OXW). The article detailing the modeling process together with a structural analysis of the resulting model has been published in the Protein Journal (Wijeyesakere et al., 2007).
Figure 2: Homology model of the catalytic (patatin-like) domain of NTE (PNTE) showing its modified alpha/beta hydrolase fold and Ser966-Asp1086 catalytic dyad (rendered as sticks with carbons colored blue and oxygens colored red).
Model of PNTE
This is our model of PNTE that was built using the crystal structure of Patatin-17 (PDB ID 1oxw) as a template. This model is rendered using GLmol (a WebGL-based PDB viewer). If you have trouble viewing the model, please check the help and support section of my website.
Biochemical data on NTE
Alternate name: PNPLA6
Proteomic data calculated using ProtParam:
Molecular weight: 146.3 kDa
Number of amino Acids: 1327
Isoelectric point (pI): 8.04
External Resources of Interest:
- Richardson, R.J. (2005). Organophosphate poisoning, delayed neurotoxicity. In Encyclopedia of Toxicology (2nd ed), Vol. 2 (P. Wexler, ed.), pp. 302-306.
- Wijeyesakere, S.J., Richardson, R.J., and Stuckey J.A. (2007). Modeling the Patatin Domain of Neuropathy Target Esterase. Protein J. 26, 165-172.
- Wijeyesakere, S.J. and Richardson, R.J. (2010). Neuropathy target esterase. In The Hayes Handbook of Pesticide Toxicity (3rd ed). pp 1435-1455.