Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.5 (neuropathy target esterase)
 1,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The possibility that organophosphorus (OP) compounds contribute to motor neuron disease (MND) is supported by association of paraoxonase 1 polymorphisms with amyotrophic lateral sclerosis (ALS) and the occurrence of MND in OP compound-induced delayed neuropathy (OPIDN), in which neuropathy target esterase (NTE) is inhibited by organophosphorylation. We evaluated a consanguineous kindred and a genetically unrelated nonconsanguineous kindred in which affected subjects exhibited progressive spastic paraplegia and distal muscle wasting. Affected subjects resembled those with OPIDN and those with Troyer Syndrome due to SPG20/spartin gene mutation (excluded by genetic linkage and SPG20/spartin sequence analysis). Genome-wide analysis suggested linkage to a 22 cM homozygous locus (D19S565 to D19S884, maximum multipoint LOD score 3.28) on chromosome 19p13 to which NTE had been mapped (GenBank AJ004832). NTE was a candidate because of its role in OPIDN and the similarity of our patients to those with OPIDN. Affected subjects in the consanguineous kindred were homozygous for disease-specific NTE mutation c.3034A-->G that disrupted an interspecies conserved residue (M1012V) in NTE's catalytic domain. Affected subjects in the nonconsanguineous family were compound heterozygotes: one allele had c.2669G-->A mutation, which disrupts an interspecies conserved residue in NTE's catalytic domain (R890H), and the other allele had an insertion (c.2946_2947insCAGC) causing frameshift and protein truncation (p.S982fs1019). Disease-specific, nonconserved NTE mutations in unrelated MND patients indicates NTE's importance in maintaining axonal integrity, raises the possibility that NTE pathway disturbances contribute to other MNDs including ALS, and supports the role of NTE abnormalities in axonopathy produced by neuropathic OP compounds.
 ...
PMID:Neuropathy target esterase gene mutations cause motor neuron disease. 1831 24

Neuropathy target esterase (NTE) is an integral membrane protein localized in the endoplasmic reticulum in neurons. Irreversible inhibition of NTE by certain organophosphorus compounds produces a paralysis known as organophosphorus compound-induced delayed neuropathy. In vitro, NTE has phospholipase/lysophospholipase activity that hydrolyses exogenously added single-chain lysophospholipids in preference to dual-chain phospholipids, and NTE mutations have been associated with motor neuron disease. NTE's physiological role is not well understood, although recent studies suggest that it may control the cytotoxic accumulation of lysophospholipids in membranes. We used the NTE catalytic domain (NEST) to hydrolyze palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine (p-lysoPC) to palmitic acid in bilayer membranes comprising 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and the fluorophore 1-oleoyl-2-[12-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]dodecanoyl]-sn-glycero-3-phosphocholine (NBD-PC). Translational diffusion coefficients (D(L)) in supported bilayer membranes were measured by fluorescence recovery after pattern photobleaching (FRAPP). The average D(L) for DOPC/p-lysoPC membranes without NEST was 2.44 microm(2)s(-1)+/-0.09; the D(L) for DOPC/p-lysoPC membranes containing NEST and diisopropylphosphorofluoridate, an inhibitor, was nearly identical at 2.45+/-0.08. By contrast, the D(L) for membranes comprising NEST, DOPC, and p-lysoPC was 2.28+/-0.07, significantly different from the system with inhibited NEST, due to NEST hydrolysis. Likewise, a system without NEST containing the amount of palmitic acid that would have been produced by NEST hydrolysis of p-lysoPC was identical at 2.26+/-0.06. These results indicate that NTE's catalytic activity can alter membrane fluidity.
 ...
PMID:Influence of lysophospholipid hydrolysis by the catalytic domain of neuropathy target esterase on the fluidity of bilayer lipid membranes. 2034 13

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.
 ...
PMID:Constructs of human neuropathy target esterase catalytic domain containing mutations related to motor neuron disease have altered enzymatic properties. 2038 9

Recently, we identified neuropathy target esterase (NTE) mutation as the cause of an autosomal recessive motor neuron disease (NTE-MND). Subsequently, we showed that NTE-MND mutations reduced specific activity (SA) and altered inhibitory kinetics of NTE catalytic domain constructs. Recent preliminary results showed that NTE is expressed in cultured human skin fibroblasts, and others have used mutant forms of neuronal proteins expressed in fibroblasts as biomarkers of neurogenetic diseases. Therefore, the present study was carried out to test the hypothesis that NTE in cultured skin fibroblasts from NTE-MND subjects also exhibit altered enzymological properties assessed by SA and IC(50) values of mipafox (MIP) and chlorpyrifos oxon (CPO). NTE SA was reduced to 65% of control (wild-type NTE from commercially obtained fibroblasts) in homozygous M1012V fibroblasts and 59-61% of control in compound heterozygous R890H/c2946_2947InsCAGC fibroblasts. MIP IC(50) values were unaffected by the NTE mutations, but the CPO IC(50) increased 4.5-fold in homozygous M1012V fibroblasts. Interestingly, markedly reduced NTE SAs (40-43% of control) were observed in fibroblasts from asymptomatic subjects heterozygous for NTE insertion c2946_2947InsCAGC. This insertion is predicted to produce truncated NTE missing the last 235 residues of its catalytic domain. These observations confirm that NTE-MND mutations reduce NTE SA in vitro. Moreover, to the extent observations made in cultured fibroblasts may be generalized to events in the nervous system, lack of correlation between reduced fibroblast NTE SA and the occurrence of NTE-MND in NTE insertion mutation heterozygotes indicates that reduction of NTE SA alone is insufficient to cause MND.
 ...
PMID:Motor neuron disease due to neuropathy target esterase mutation: enzyme analysis of fibroblasts from human subjects yields insights into pathogenesis. 2060 2

Recently, we reported that mutations in the neuropathy target esterase (NTE) gene cause autosomal recessive motor neuron disease (NTE-MND). We describe clinical, neurophysiologic, and neuroimaging features of affected subjects in the index families. NTE-MND subjects exhibited progressive lower extremity spastic weakness that began in childhood and was later associated with atrophy of distal leg and intrinsic hand muscles. NTE-MND resembles Troyer syndrome, except that short stature, cognitive impairment, and dysmorphic features, which often accompany Troyer syndrome, are not features of NTE-MND. Early onset, symmetry, and slow progression distinguish NTE-MND from typical amyotrophic lateral sclerosis. NTE is implicated in organophosphorus compound-induced delayed neurotoxicity (OPIDN). NTE-MND patients have upper and lower motor neuron deficits that are similar to OPIDN. Motor neuron degeneration in subjects with NTE mutations supports the role of NTE and its biochemical cascade in the molecular pathogenesis of OPIDN and possibly other degenerative neurologic disorders.
 ...
PMID:Motor neuron disease due to neuropathy target esterase gene mutation: clinical features of the index families. 2117 Oct 93