Toxicological and structural features of KIAA1363: A novel detoxifying enzyme for organophosphorus nerve poisons

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Daniel K. Nomura, DNomura@aol.com1, Kathleen A. Durkin2, Kyle P. Chiang3, Gary B. Quistad4, Benjamin F. Cravatt, cravatt@scripps.edu3, and John E. Casida, ectl@nature.berkeley4. (1) Nutritional Sciences and Toxicology, Molecular Toxicology Graduate Group, University of California, Berkeley, Environmental Chemistry and Toxicology Laboratory, Berkeley, CA 94720-3112, (2) Molecular Graphics Facility, College of Chemistry, University of California, Berkeley, Berkeley, CA 94720-1460, (3) The Skaggs Institute for Chemical Biology and Departments of Chemistry and Cell Biology, The Scripps Research Institute, La Jolla, CA 92037-1000, (4) Department of Environmental Sciences, Policy and Management, University of California, Berkeley, Environmental Chemistry and Toxicology Laboratory, Berkeley, CA 94720-3112
Most organophosphorus (OP) toxicants such as the insecticide metabolite chlorpyrifos oxon (CPO) act by inhibiting acetylcholinesterase (AChE). The primary CPO-detoxifying enzyme is identified as KIAA1363 in mouse brain, spinal cord, kidney, heart, lung, testes and muscle but not liver. KIAA1363 protects AChE and monoacylglycerol lipase from CPO inhibition. KIAA1363 and AChE are similar in sensitivity to seven OP insecticides and analogs, prompting structural comparisons of their active sites relative to OP potency and selectivity. Homology modeling places KIAA1363 in the hormone-sensitive lipase family with a catalytic triad of S191-D348-H378. OP structure optimization and CPO docking suggest that KIAA1363 has a much larger binding pocket than AChE allowing excellent selectivity for KIAA1363 with long chain alkyl phosphates and phosphonates. KIAA1363 reactivates much faster than AChE, possibly because KIAA1363 lacks a mobile catalytic His which is considered to be important in preventing AChE dephosphorylation.
 

General Papers: Young Investigator Session
8:00 AM-12:00 PM, Tuesday, 12 September 2006 Moscone Center -- Room 308, Oral

Sci-Mix
8:00 PM-10:00 PM, Monday, 11 September 2006 Moscone Center -- Hall D, Sci-Mix

Division of Chemical Toxicology

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006