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

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Abstract
2‐Octyl‐4H‐1,3,2‐benzodioxaphosphorin 2‐oxide (octyl‐BDPO) is one of the most potent inhibitors known for neuropathy target esterase (NTE) of hen brain with 50% inhibition at 0.2 nM. Two NTE‐like proteins, i.e., resistant to paraoxon and sensitive to mipafox, of ∼155 and ∼119 kDa (designated NTE‐155 and NTE‐119, respectively) are labeled by [octyl‐3H]octyl‐BDPO and separated by sodium dodecyl sulfate‐polyacrylamide gel electrophoresis. Labeling with [aryl‐3H]octyl‐BDPO is only ∼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”). 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 totalling at least 0.44–1.2 µg of NTE protein/g of brain. Structure‐activity investigations involving 17 combinations of organophosphorus (OP) compounds of varied chemical type, stereo‐chemistry, and concentration establish an excellent correlation (r = 0.95) between inhibition of NTE activity and protein labeling and thereby the toxicological relevance of these assays, which equally implicate NTE‐155 and NTE‐119 (probably an autolysis product of NTE‐155) as targets in OP‐induced delayed neuropathy. [octyl‐3H]‐Octyl‐BDPO is an improved probe for NTE in terms of its potency, reactivity, selectivity, and the formation of 3H‐labeled NTE with a stable phosphorus‐carbon bond.

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