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Serine hydrolase KIAA1363: Toxicological and structural features with emphasis on organophosphate interactions

Academic Article
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Overview

related to degree

  • Chiang, Kyle Ping, Ph.D. in Macromolecular and Cellular Structure and Chemistry, Scripps Research 2001 - 2006

authors

  • Nomura, D. K.
  • Durkin, K. A.
  • Chiang, Kyle Ping
  • Quistad, G. B.
  • Cravatt, Benjamin
  • Casida, J. E.

publication date

  • September 2006

journal

  • Chemical Research in Toxicology  Journal

abstract

  • Serine hydrolase KIAA1363 is highly expressed in invasive cancer cells and is the major protein in mouse brain diethylphosphorylated by and hydrolyzing low levels of chlorpyrifos oxon (CPO) (the activated metabolite of a major insecticide). It is also the primary CPO-hydrolyzing enzyme in spinal cord, kidney, heart, lung, testis, and muscle but not liver, a pattern of tissue expression confirmed by fluorophosphonate-rhodamine labeling. KIAA1363 gene deletion using homologous recombination reduces CPO binding, hydrolysis, and metabolism 3-29-fold on incubation with brain membranes and homogenates determined with 1 nM [(3)H-ethyl]CPO and the inhibitory potency for residual CPO with butyrylcholinesterase as a biomarker. Studies with knockout mice further show that KIAA1363 partially protects brain AChE and monoacylglycerol lipase from CPO-induced in vivo inhibition. Surprisingly, mouse brain KIAA1363 and AChE are similar in in vitro sensitivity to seven methyl, ethyl, and propyl but not higher alkyl OP insecticides and analogues, prompting structural comparisons of the active sites of KIAA1363 and AChE relative to OP potency and selectivity. Homology modeling based largely on the Archaeoglobus fulgidus esterase crystal structure indicates that KIAA1363 has a catalytic triad of S191, D348, and H378, a GDSAG motif, and an oxyanion hole of H113, G114, G115, and G116. Excellent selectivity for KIAA1363 is achieved on OP structure optimization with long alkyl chain substituents suggesting that KIAA1363 has larger acyl and leaving group pockets than those of AChE. KIAA1363 reactivates faster than AChE presumably due to differences in the uncoupling of the catalytic triad His upon phosphorylation. The structural modeling of KIAA1363 helps us understand OP structure-activity relationships and the toxicological relevance of this detoxifying enzyme.

subject areas

  • Animals
  • Binding Sites
  • Chlorpyrifos
  • Enzyme Inhibitors
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Organophosphorus Compounds
  • Serine Endopeptidases
  • Serine Proteases
  • Serine Proteinase Inhibitors
  • Sterol Esterase
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Identity

PubMed Central ID

  • PMC2512971

International Standard Serial Number (ISSN)

  • 0893-228X

Digital Object Identifier (DOI)

  • 10.1021/tx060117m

PubMed ID

  • 16978018
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Additional Document Info

start page

  • 1142

end page

  • 1150

volume

  • 19

issue

  • 9

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