Dual roles of brain serine hydrolase KIAA1363 in ether lipid metabolism and organophosphate detoxification.
Serine hydrolase KIAA1363 is an acetyl monoalkylglycerol ether (AcMAGE) hydrolase involved in tumor cell invasiveness. It is also an organophosphate (OP) insecticide-detoxifying enzyme. The key to understanding these dual properties was the use of KIAA1363 +/+ (wildtype) and -/- (gene deficient) mice to define the role of this enzyme in brain and other tissues and its effectiveness in vivo in reducing OP toxicity. KIAA1363 was the primary AcMAGE hydrolase in brain, lung, heart and kidney and was highly sensitive to inactivation by chlorpyrifos oxon (CPO) (IC50 2 nM) [the bioactivated metabolite of the major insecticide chlorpyrifos (CPF)]. Although there was no difference in hydrolysis product monoalkylglycerol ether (MAGE) levels in +/+ and -/- mouse brains in vivo, isopropyl dodecylfluorophosphonate (30 mg/kg) and CPF (100 mg/kg) resulted in 23-51% decrease in brain MAGE levels consistent with inhibition of AcMAGE hydrolase activity. On incubating +/+ and -/- brain membranes with AcMAGE and cytidine-5'-diphosphocholine, the absence of KIAA1363 activity dramatically increased de novo formation of platelet-activating factor (PAF) and lyso-PAF, signifying that metabolically-stabilized AcMAGE can be converted to this bioactive lipid in brain. On considering detoxification, KIAA1363 -/- mice were significantly more sensitive than +/+ mice to ip-administered CPF (100 mg/kg) and parathion (10 mg/kg) with increased tremoring and mortality that correlated for CPF with greater brain acetylcholinesterase inhibition. Docking AcMAGE and CPO in a KIAA1363 active site model showed similar positioning of their acetyl and trichloropyridinyl moieties, respectively. This study establishes the relevance of KIAA1363 in ether lipid metabolism and OP detoxification.
Nomura
Daniel K
DK
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, 115 Wellman Hall, University of California, Berkeley, CA 94720 3112, USA.
Fujioka
Kazutoshi
K
Issa
Roger S
RS
Ward
Anna M
AM
Cravatt
Benjamin F
BF
Casida
John E
JE
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000201:enzymology*; D004390:Chlorpyrifos / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008401:Gas Chromatography-Mass Spectrometry; D008658:Inactivation, Metabolic / Q000235:genetics*; D007306:Insecticides / Q000633:toxicity; D050356:Lipid Metabolism / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology; D010755:Organophosphates / Q000378:metabolism / Q000633:toxicity*; D010278:Parathion / Q000633:toxicity; D010972:Platelet Activating Factor / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics* / Q000502:physiology*; D057057:Serine Proteases; D002787:Sterol Esterase; D014018:Tissue Distribution
D004791:Enzyme Inhibitors; D007306:Insecticides; D010755:Organophosphates; D010972:Platelet Activating Factor; D010278:Parathion; C514712:Nceh1 protein, mouse; D002787:Sterol Esterase; D000110:Acetylcholinesterase; D057057:Serine Proteases; D012697:Serine Endopeptidases; D004390:Chlorpyrifos