Calcium-activated butyrylcholinesterase in human skin protects acetylcholinesterase against suicide inhibition by neurotoxic organophosphates.
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.
Schallreuter
Karin U
KU
Clinical and Experimental Dermatology, Department of Biomedical Sciences, University of Bradford, Bradford BD7 1DP, West Yorkshire, UK. K.Schallreuter@bradford.ac.uk
Gibbons
Nicholas C J
NC
Elwary
Souna M
SM
Parkin
Susan M
SM
Wood
John M
JM
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*
D002800:Cholinesterase Inhibitors; D009498:Neurotoxins; D010755:Organophosphates; D021122:Protein Subunits; D006861:Hydrogen Peroxide; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D002118:Calcium