Journal
TOXICOLOGY LETTERS
Volume 196, Issue 2, Pages 67-73Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2010.03.1120
Keywords
Hereditary spastic paraplegia (HSP); Motor neuron disease (MND); Neuropathy target esterase (NTE); Organophosphorus compound-induced delayed neuropathy (OPIDN)
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Funding
- NIH [GM007767, ES07062, UL1RR024986, NS 053917]
- University of Michigan Center for Structural Biology
- Department of Veterans Affairs
- Spastic Paraplegia Foundation
- Dow Chemical Company
- National Ataxia Foundation
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Neuropathy target esterase (NTE) is a phospholipase/lysophospholipase associated with organophosphorus (OP) compound-induced delayed neurotoxicity (OPIDN). Distal degeneration of motor axons occurs in both OPIDN and the hereditary spastic paraplegias (HSPs). Recently, mutations within the esterase domain of NTE were identified in patients with a novel type of HSP (SPG39) designated NTE-related motor neuron disease (NTE-MND). Two of these mutations, arginine 890 to histidine (R890H) and methionine 1012 to valine (M1012V), were created in human recombinant NTE catalytic domain (NEST) to measure possible changes in catalytic properties. These mutated enzymes had decreased specific activities for hydrolysis of the artificial substrate, phenyl valerate. In addition, the M1012V mutant exhibited a reduced bimolecular rate constant of inhibition (k(i)) for all three inhibitors tested: mipafox, diisopropylphosphorofluoridate, and chlorpyrifos oxon. Finally, while both mutated enzymes inhibited by OP compounds exhibited altered time-dependent loss of their ability to be reactivated by nucleophiles (aging), more pronounced effects were seen with the M1012V mutant. Taken together, the results from specific activity, inhibition, and aging experiments suggest that the mutations found in association with NTE-MND have functional correlates in altered enzymological properties of NTE. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
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