MECHANISMS OF PREDICTION AND POTENTIAL CAUSATION OF ORGANOPHOSPHATE INDUCED DELAYED NEUROTOXICITY by Nichole

Serine esterases are inhibited by dialkyl fluorinated aminophosphonate (FAP) compounds of general formula, (RO)2P(O)C(CF3)2NHS(O)2C6H5, where R = alkyl. It has been hypothesized that the active site serine of the esterase covalently attaches to the phosphoryl moiety of the FAP compound, resulting in formation of a dialkyl phosphate adduct that can age by net loss of an R-group. However, this mechanism would require an unusual inhibition reaction involving scission of a P—C bond. The present work tested this hypothesis by using FAP compounds with R-groups of varying length and branching, and identifying adducts on treated horse serum butyrylcholinesterase using peptide mass mapping with surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. Observed and predicted mass shifts were statistically identical for inhibited and protonated aged adducts, respectively. The results support the hypothesis that FAP compounds inhibit serine esterases by scission of the P—C bond, in agreement with