Calcium-activated butyrylcholinesterase in human skin protects acetylcholinesterase against suicide inhibition by neurotoxic organophosphates

• Published in: Biochemical and biophysical research communications Vol. 355; no. 4; pp. 1069 - 1074
• Main Authors: Schallreuter, Karin U., Gibbons, Nicholas C.J., Elwary, Souna M., Parkin, Susan M., Wood, John M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.04.2007
• Subjects: 60 APPLIED LIFE SCIENCES; ACETYLCHOLINE; Acetylcholinesterase; Acetylcholinesterase - metabolism; Amino Acid Sequence; Binding Sites; Butyrylcholinesterase; Butyrylcholinesterase - chemistry; Butyrylcholinesterase - metabolism; CALCIUM; Calcium - pharmacology; CELL MEMBRANES; Cholinesterase Inhibitors; Computer Simulation; COMPUTERIZED SIMULATION; EF Hand Motifs; EF-hand; Enzyme Activation - drug effects; EPIDERMIS; Human epidermis; Humans; HYDROGEN PEROXIDE; Hydrogen Peroxide - pharmacology; HYDROLYSIS; INHIBITION; LABELLING; Models, Molecular; Neurotoxins - pharmacology; Organophosphates; Organophosphates - pharmacology; OXIDATION; Oxidation-Reduction; Protein Binding; Protein Structure, Tertiary; Protein Subunits - chemistry; Protein Subunits - metabolism; Skin - drug effects; Skin - enzymology; Hydrogen peroxide; Calcium; EF-hand; Human epidermis; Butyrylcholinesterase; Acetylcholinesterase; Organophosphates
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2007.02.078

The human epidermis holds an autocrine acetylcholine production and degradation including functioning membrane integrated and cytosolic butyrylcholinesterase (BuchE). Here we show that BuchE activities increase 9-fold in the presence of calcium (0.5 × 10 -3 M) via a specific EF-hand calcium binding site, whereas acetylcholinesterase (AchE) is not affected. 45Calcium labelling and computer simulation confirmed the presence of one EF-hand binding site per subunit which is disrupted by H 2O 2-mediated oxidation. Moreover, we confirmed the faster hydrolysis by calcium-activated BuchE using the neurotoxic organophosphate O-ethyl- O-(4-nitrophenyl)-phenylphosphonothioate (EPN). Considering the large size of the human skin with 1.8 m 2 surface area with its calcium gradient in the 10 −3 M range, our results implicate calcium-activated BuchE as a major protective mechanism against suicide inhibition of AchE by organophosphates in this non-neuronal tissue.