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PNPLA6  -  patatin-like phospholipase domain...

Gallus gallus

 
 
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Disease relevance of PNPLA6

  • Considerable evidence exists suggesting that the so-called neuropathy target esterase (NTE) is involved in the mechanisms responsible for organophosphorus-induced delayed polyneuropathy (OPIDP) [1].
  • Furthermore we suggest that NTE inhibition should also be measured in the peripheral nerve in the standard toxicity testing for organophosphate-induced delayed neurotoxicity [2].
  • It is concluded that the peripheral neurological effects of local dosing correlate with the specific modification of NTE in a segment of sciatic nerve and that the axon is a more likely target than the perikaryon or nerve terminal in the triggering mechanism of this axonopathy [3].
  • Earlier histochemical immunoreactivity or esterase assays localized NTE in areas of the brain and spinal cord rich in neuronal cell bodies and in the dorsal root ganglion [4].
  • The posthatching paresis and abnormal gait are not determined solely by either AChE inhibition of NTE inhibition, since they occur in the absence of the latter and are not invariably seen in the presence of the former (Toxicology 49: 253-261; 1988) [5].
 

Psychiatry related information on PNPLA6

  • The organophosphate compound (OP) induced an initial reduction in the activity of NTE, TE and AchE which was reestablished 48 h later, except for brain TE which increased slowly during the latency period [6].
 

High impact information on PNPLA6

  • Gel filtration chromatography with Sephacryl S-300 of the soluble fraction from spinal cord showed two PVase peaks containing NTE activity (S-NTE1 and S-NTE2) [7].
  • Neuropathy target esterase (NTE) activity is defined operatively as the paraoxon-resistant mipafox-sensitive phenyl valerate esterase activity [8].
  • Purification and characterization of naturally soluble neuropathy target esterase from chicken sciatic nerve by HPLC and western blot [8].
  • NTE-155 and NTE-119 have the same kinetic constants and maximal number of phosphorylation sites, equivalent for each of them to 26 fmol/mg of protein and totaling at least 0.44-1.2 micrograms of NTE protein/g of brain [9].
  • Labeling with [aryl-3H]octyl-BDPO is only approximately 15% of that with [octyl-3H]octyl-BDPO, indicating that the majority of the phosphorylated NTE undergoes aging with only a small proportion of nonaged target or intramolecular group transfer ("alkylation") [9].
 

Chemical compound and disease context of PNPLA6

  • The relationship among inhibition of acetylcholinesterase (AChE), inhibition of neuropathy target enzyme (NTE), and developmental toxicity of the organophosphorus ester desbromoleptophos (DBL) was evaluated in chicks exposed on day 3 or day 15 of incubation or 10 days posthatching [5].
  • Dosages of mipafox (30 mg/kg i.p.), TOTP (500 mg/kg p.o.), phenyl saligenin phosphate (2.5 mg/kg i.m.) and DFP (1 mg/kg s.c.) that were capable of inhibiting NTE > 80% in both brain and spinal cord preceded ataxia which reached maximal levels (scores of 7-8), and development of lesions scored as 4 [10].
  • Hens were notably impaired (ataxia scores of 3-4) 21 days after administration of dosages of mipafox (3 and 6 mg/kg), TOTP (90 mg/kg), phenyl saligenin phosphate (0.1 and 0.2 mg/kg), and DFP (0.4 mg/kg) when spinal cord NTE was inhibited 40-75% [10].
  • In order to account for these differences with OPIDP, it was suggested that TPP neuropathy results from the combination of two independent mechanisms of toxicity: typical OPIDP due to inhibition of neuropathy target esterase (NTE) plus a second neurotoxicity related with other target(s) [11].
  • Because of the commercial unavailability and high toxicity of mipafox, which is usually used as the selective inhibitor for assaying NTE, leptophosoxon was used as an alternative to mipafox [12].
 

Biological context of PNPLA6

  • However, according to first-order kinetics, concentrations of inhibitor greater than 6 X I50 should inhibit NTE greater than 98% and for 19 out of 26 compounds a residue greater than 3% (limit of precision) was found under these conditions: in nearly every case the quantity was 3-5% [13].
  • Similar NTE inhibition in 40-day-old or younger chicks however is not followed by changes in retrograde axonal transport nor by OPIDP [14].
  • They protect from neuropathy by preventing the binding of neuropathic inhibitors to NTE catalytic site [15].
  • Promotion was also obtained with phenyl N-methyl N-benzyl carbamate (40 mg/kg iv) but not with non-NTE inhibitors in vivo such as paraoxon or benzenesulfonyl fluoride when given at maximum tolerated doses [16].
  • DBL induced prolonged inhibition of AChE and NTE when administered either early or late in incubation, structural malformations if administered before organogenesis, posthatching paresis if administered after organogenesis, and delayed deficits of gait if administered after hatching [5].
 

Anatomical context of PNPLA6

  • We have recently found that there is a proximo-distal delay in the recovery of neurotoxic esterase (NTE) following inhibition along the sciatic nerve of the hen [17].
  • Incubation of S9B with brain microsomes led to specific covalent labelling of NTE as determined by detection of a biotinylated 155 kDa polypeptide on Western blots [18].
  • By contrast, phenylmethylsulfonyl fluoride (30 mg/kg s.c.), an agent that prevents the development of OP neuropathy by inhibiting NTE without the "aging" reaction, had no effect on axon transport, nerve fiber integrity, or clinical status and, when administered prior to a neurotoxic dose of DBDCVP (1.00 mg/kg s.c.), prevented DBDCVP effects [19].
  • The resistance might be explained by a more efficient repair mechanism, as suggested by the faster recovery of peripheral nerve NTE activity [14].
  • Neurotoxic esterase (NTE) is a membrane-bound protein found in highest concentration in brain and lymphocytes [20].
 

Associations of PNPLA6 with chemical compounds

  • At 25 degrees C, the Km of NTE for phenyl valerate was determined to be about 2.4 X 10(-3) M [21].
  • For the purpose of assessing the neurotoxic potential of organophosphorus compounds, it has been determined that paraoxon-preinhibited hen brain has both neurotoxicant (mipafox)-sensitive (neurotoxic esterase; NTE) and -insensitive esterase components [21].
  • The induction of central-peripheral distal axonopathy in hens singly dosed with some organophosphorus (OP) compounds, such as di-n-butyl-2,2-dichlorovinyl phosphate (DBDCVP), requires greater than 80% organophosphorylation and subsequent intramolecular rearrangement ("aging") of a protein [neuropathy target esterase (NTE)] in the axon [19].
  • However, the half-life of reappearance of active NTE was 2.07 days +/- 0.13 (SD, n = 6) for brain and 3.62 days +/- 0.23 (SD, n = 6) for spinal cord--shorter than after dosing with phenylmethylsulphonyl fluoride [22].
  • At 37 degrees C, the Km values of NTE for phenyl valerate and phenyl phenylacetate were found to be about 1.4 X 10(-3) and 1.6 X 10(-4) M respectively [21].
 

Analytical, diagnostic and therapeutic context of PNPLA6

  • To determine whether this delay could be due to a requirement for the transport of newly synthesized NTE from the cell body, we investigated the transport of NTE by measuring the rate of accumulation of activity at either one or two ligations [17].
  • Essentially pure NTE was obtained after separation from two endogenous biotinylated polypeptides (120 and 70 kDa) in avidin-Sepharose eluates by preparative SDS/PAGE [18].
  • When the pH during the centrifugation was increased from 6.4 to 11, recovered P-NTE activity decreased from 1,750 to 118 nmol/min/g tissue for brain and from 31 to 12 nmol/min/g for sciatic nerve [23].
  • Sciatic nerve NTE was separated into particulate (P-NTE) and soluble (S-NTE) fractions by ultracentrifugation at 100,000 g for 1 h in 0.32 M sucrose and compared with the corresponding brain extract [23].
  • Considering the exceptional potencies of ethyl and 2-iodoethyl octylphosphonofluoridates (I50s of 0.04 and 0.09 nM, respectively), it is not surprising that at ip doses of 10-30 mg/kg they inhibit brain NTE by 82-97% 48 h after treatment [24].

References

  1. Soluble and particulate organophosphorus neuropathy target esterase in brain and sciatic nerve of the hen, cat, rat, and chick. Tormo, N., Gimeno, J.R., Sogorb, M.A., Díaz-Alejo, N., Vilanova, E. J. Neurochem. (1993) [Pubmed]
  2. Intra-arterial injection of diisopropylfluorophosphate or phenylmethanesulphonyl fluoride produces unilateral neuropathy or protection, respectively, in hens. Caroldi, S., Lotti, M., Masutti, A. Biochem. Pharmacol. (1984) [Pubmed]
  3. Local application of neuropathic organophosphorus compounds to hen sciatic nerve: inhibition of neuropathy target esterase and peripheral neurological impairments. Carrera, V., Barril, J., Mauricio, M., Pellín, M., Vilanova, E. Toxicol. Appl. Pharmacol. (1992) [Pubmed]
  4. Localization of [3H]octylphosphonyl-labeled neuropathy target esterase by chicken nervous tissue autoradiography. Kamijima, M., Casida, J.E. Neurosci. Lett. (1999) [Pubmed]
  5. Developmental toxicity of desbromoleptophos in chicks: enzyme inhibition, malformations and functional deficits. Farage-Elawar, M., Duffy, J.S., Francis, B.M. Neurotoxicology and teratology. (1991) [Pubmed]
  6. Study of delayed neurotoxicity caused by fatty acid anilides in hens. Sanz, P., Moreno, E., Blasco, R., Repetto, M. Veterinary and human toxicology. (1990) [Pubmed]
  7. Chromatographic discrimination of soluble neuropathy target esterase isoenzymes and related phenyl valerate esterases from chicken brain, spinal cord, and sciatic nerve. Escudero, M.A., Céspedes, M.V., Vilanova, E. J. Neurochem. (1997) [Pubmed]
  8. Purification and characterization of naturally soluble neuropathy target esterase from chicken sciatic nerve by HPLC and western blot. Escudero, M.A., Vilanova, E. J. Neurochem. (1997) [Pubmed]
  9. Neuropathy target esterase of hen brain: active site reactions with 2-[octyl-3H]octyl-4H-1,3,2-benzodioxaphosphorin 2-oxide and 2-octyl-4H-1,3,2-[aryl-3H]benzodioxaphosphorin 2-oxide. Yoshida, M., Tomizawa, M., Wu, S.Y., Quistad, G.B., Casida, J.E. J. Neurochem. (1995) [Pubmed]
  10. Relationship of neuropathy target esterase inhibition to neuropathology and ataxia in hens given organophosphorus esters. Ehrich, M., Jortner, B.S., Padilla, S. Chem. Biol. Interact. (1993) [Pubmed]
  11. Triphenylphosphite neuropathy in hens. Fioroni, F., Moretto, A., Lotti, M. Arch. Toxicol. (1995) [Pubmed]
  12. Assay of chicken brain neurotoxic esterase activity using leptophosoxon as the selective neurotoxic inhibitor. Soliman, S.A., Curley, A. Journal of analytical toxicology. (1981) [Pubmed]
  13. Sensitivity and selectivity of compounds interacting with neuropathy target esterase. Further structure-activity studies. Johnson, M.K. Biochem. Pharmacol. (1988) [Pubmed]
  14. Age sensitivity to organophosphate-induced delayed polyneuropathy. Biochemical and toxicological studies in developing chicks. Moretto, A., Capodicasa, E., Peraica, M., Lotti, M. Biochem. Pharmacol. (1991) [Pubmed]
  15. The phosphorothioic acid O-(2-chloro-2,3,3-trifluorocyclobutyl) O-ethyl S-propyl ester exacerbates organophosphate polyneuropathy without inhibition of neuropathy target esterase. Moretto, A., Bertolazzi, M., Lotti, M. Toxicol. Appl. Pharmacol. (1994) [Pubmed]
  16. Promotion of organophosphate-induced delayed polyneuropathy by phenylmethanesulfonyl fluoride. Lotti, M., Caroldi, S., Capodicasa, E., Moretto, A. Toxicol. Appl. Pharmacol. (1991) [Pubmed]
  17. Axoplasmic transport and turnaround of neurotoxic esterase in hen sciatic nerve. Carrington, C.D., Abou-Donia, M.B. J. Neurochem. (1985) [Pubmed]
  18. Synthesis and characterization of a biotinylated organophosphorus ester for detection and affinity purification of a brain serine esterase: neuropathy target esterase. Glynn, P., Read, D.J., Guo, R., Wylie, S., Johnson, M.K. Biochem. J. (1994) [Pubmed]
  19. Progressive deficit of retrograde axonal transport is associated with the pathogenesis of di-n-butyl dichlorvos axonopathy. Moretto, A., Lotti, M., Sabri, M.I., Spencer, P.S. J. Neurochem. (1987) [Pubmed]
  20. Neurotoxic esterase: characterization of the solubilized enzyme and the conditions for its solubilization from chicken brain microsomal membranes with ionic, zwitterionic, or nonionic detergents. Davis, C.S., Richardson, R.J. Biochem. Pharmacol. (1987) [Pubmed]
  21. Kinetics of substrate hydrolysis and inhibition by mipafox of paraoxon-preinhibited hen brain esterase activity. Carrington, C.D., Abou-Donia, M.B. Biochem. J. (1986) [Pubmed]
  22. Neuropathy target esterase: rates of turnover in vivo following covalent inhibition with phenyl di-n-pentylphosphinate. Meredith, C., Johnson, M.K. J. Neurochem. (1988) [Pubmed]
  23. Soluble and particulate forms of the organophosphorus neuropathy target esterase in hen sciatic nerve. Vilanova, E., Barril, J., Carrera, V., Pellin, M.C. J. Neurochem. (1990) [Pubmed]
  24. Ethyl octylphosphonofluoridate and analogs: optimized inhibitors of neuropathy target esterase. Wu, S.Y., Casida, J.E. Chem. Res. Toxicol. (1995) [Pubmed]
 
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