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Originally published In Press as doi:10.1074/jbc.M200330200 on April 1, 2002

J. Biol. Chem., Vol. 277, Issue 23, 20942-20948, June 7, 2002
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Human Neuropathy Target Esterase Catalyzes Hydrolysis of Membrane Lipids*

Marianne van TienhovenDagger , Jane AtkinsDagger §, Yong Li, and Paul Glynn

From the MRC Toxicology Unit, University of Leicester, Leicester LE1 9HN, United Kingdom

A neuronal membrane protein, neuropathy target esterase (NTE), reacts with those organophosphates that initiate a syndrome of axonal degeneration. NTE has homologues in Drosophila and yeast and is detected in vitro by assays with a non-physiological ester substrate, phenyl valerate. We report that NEST, the recombinant esterase domain of NTE (residues 727-1216) purified from bacterial lysates, can catalyze hydrolysis of several naturally occurring membrane-associated lipids. The active site regions of NEST and calcium-independent phospholipase A2 (iPLA2) share sequence similarity, and the phenyl valerate hydrolase activity of NEST is inhibited by low concentrations of iPLA2 inhibitors. However, on incubation with NEST, fatty acid was liberated only extremely slowly from the sn-2 position of phospholipids (Vmax ~0.01 µmol/min/mg and Km ~0.4 mM for 1-palmitoyl, 2-oleoylphosphatidylcholine). Comparison of the NEST-mediated generation of 14C-labeled products from two differentially labeled 14C-phospholipid substrates suggested that a rate-limiting sn-2 cleavage was followed very rapidly by hydrolysis of the resulting lysophospholipid. Among the various naturally occurring lipids tested with NEST, lysophospholipids were by far the most avidly hydrolyzed substrates (Vmax ~20 µmol/min/mg and Km ~0.05 mM for 1-palmitoyl-lysophosphatidylcholine). NEST also catalyzed the hydrolysis of monoacylglycerols, preferring the 1-acyl to the 2-acyl isomer (Vmax ~1 µmol/min/mg and Km ~0.4 mM for 1-palmitoylglycerol). NEST did not catalyze hydrolysis of di- or triacylglycerols or fatty acid amides. This demonstration that membrane lipids are its putative cellular substrates raises the possibility that NTE and its homologues may be involved in intracellular membrane trafficking.

* This work was supported by the MRC, a studentship from the MRC (to J. A.), and a scholarship from the Leonardo da Vinci fund (to M. v. T.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Both authors contributed equally to this work.

§ Present address: Adprotech, Chesterford Research Park, Little Chesterford, Saffron Walden, Essex CB10 1XL, UK.

To whom correspondence should be addressed. Tel.: 44 116 252 5598; Fax: 44 116 252 5616; E-mail: pg8@le.ac.uk.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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