title: Calcium-activated butyrylcholinesterase in human skin protects acetylcholinesterase against suicide inhibition by neurotoxic organophosphates.
abstract: 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 (0.5x10(-3)M) via a specific EF-hand calcium binding site, whereas acetylcholinesterase (AchE) is not affected. (45)Calcium labelling and computer simulation confirmed the presence of one EF-hand binding site per subunit which is disrupted by H(2)O(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 1.8m(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.
authors.affiliation: Clinical and Experimental Dermatology, Department of Biomedical Sciences, University of Bradford, Bradford BD7 1DP, West Yorkshire, UK. K.Schallreuter@bradford.ac.uk
authors.forename: Karin U
authors.initials: KU
authors.lastname: Schallreuter
authors.forename: Nicholas C J
authors.initials: NC
authors.lastname: Gibbons
authors.forename: Souna M
authors.initials: SM
authors.lastname: Elwary
authors.forename: Susan M
authors.initials: SM
authors.lastname: Parkin
authors.forename: John M
authors.initials: JM
authors.lastname: Wood
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000595:Amino Acid Sequence; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D002118:Calcium / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors; D003198:Computer Simulation; D020832:EF Hand Motifs; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006868:Hydrolysis; D008958:Models, Molecular; D009498:Neurotoxins / Q000494:pharmacology*; D010755:Organophosphates / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D012867:Skin / Q000187:drug effects* / Q000201:enzymology*
chemical_list: D002800:Cholinesterase Inhibitors; D009498:Neurotoxins; D010755:Organophosphates; D021122:Protein Subunits; D006861:Hydrogen Peroxide; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D002118:Calcium