Neuropathy target esterase and phospholipid deacylation.
Certain organophosphates react with the active site serine residue of neuropathy target esterase (NTE) and cause axonal degeneration and paralysis. Cloning of NTE revealed the presence of homologues in eukaryotes from yeast to man and that the protein has both a catalytic and a regulatory domain. The latter contains sequences similar to the regulatory subunit of protein kinase A, suggesting that NTE may bind cyclic AMP. NTE is tethered via an amino-terminal transmembrane segment to the cytoplasmic face of the endoplasmic reticulum. Unlike wild-type yeast, mutants lacking NTE activity cannot deacylate CDP-choline pathway-synthesized phosphatidylcholine (PtdCho) to glycerophosphocholine (GroPCho) and fatty acids. In cultured mammalian cells, GroPCho levels rise and fall, respectively, in response to experimental over-expression, and inhibition, of NTE. A complex of PtdCho and Sec14p, a yeast phospholipid-binding protein, both inhibits the rate-limiting step in PtdCho synthesis and enhances deacylation of PtdCho by NTE. While yeast can maintain PtdCho homeostasis in the absence of NTE, certain post-mitotic metazoan cells may not be able to, and some NTE-null animals have deleterious phenotypes. NTE is not required for cell division in the early mammalian embryo or in larval and pupal forms of Drosophila, but is essential for placenta formation and survival of neurons in the adult. In vertebrates, the relative importance of NTE and calcium-independent phospholipase A2 for homeostatic PtdCho deacylation in particular cell types, possible interactions of NTE with Sec14p homologues and cyclic AMP, and whether deranged phospholipid metabolism underlies organophosphate-induced neuropathy are areas which require further investigation.
Glynn
Paul
P
MRC Toxicology Unit, University of Leicester, Leicester LE1 9HN, UK. pg8@le.ac.uk
D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D010755:Organophosphates / Q000378:metabolism*; D010641:Phenotype; D010713:Phosphatidylcholines / Q000737:chemistry / Q000378:metabolism*; D010767:Phosphorylcholine / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D005227:Fatty Acids; D010755:Organophosphates; D010713:Phosphatidylcholines; D011994:Recombinant Proteins; D010767:Phosphorylcholine; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase