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Molecular Pharmacology

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Research ArticleArticle

Identification of Acylpeptide Hydrolase as a Sensitive Site for Reaction with Organophosphorus Compounds and a Potential Target for Cognitive Enhancing Drugs

Paul G. Richards, Martin K. Johnson and David E. Ray
Molecular Pharmacology September 2000, 58 (3) 577-583; DOI: https://doi.org/10.1124/mol.58.3.577
Paul G. Richards
Medical Research Council Toxicology Unit, University of Leicester, Leicester, United Kingdom
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Martin K. Johnson
Medical Research Council Toxicology Unit, University of Leicester, Leicester, United Kingdom
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David E. Ray
Medical Research Council Toxicology Unit, University of Leicester, Leicester, United Kingdom
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Abstract

We describe here the purification and identification of a previously unrecognized target for organophosphorus compounds. The target, acylpeptide hydrolase, was isolated as a tritiated-diisopropylfluorophosphate-reactive protein from porcine brain and purified to homogeneity using a combination of ion-exchange and gel-filtration chromatography. Biochemical characterization and internal sequence analysis confirmed identity. Acylpeptide hydrolase was found to be potently inhibited by the organophosphorus compounds chlorpyrifosmethyl oxon, dichlorvos, and diisopropylfluorophosphate (20-min IC50 values of 18.3 ± 2.0, 118.7 ± 9.7, and 22.5 ± 1.2 nM, respectively). The in vitro sensitivity of acylpeptide hydrolase toward these compounds is between six and ten times greater than that of acetylcholinesterase (AChE), making it a target of pharmacological and toxicological significance. We show that, in vivo, acylpeptide hydrolase is significantly more sensitive than AChE to inhibition by dichlorvos and that the inhibition is more prolonged after a single dose of inhibitor. Furthermore, using dichlorvos as a progressive inhibitor, it was possible to show that acylpeptide hydrolase is the only enzyme in the brain capable of hydrolyzing the substrateN-acetyl-alanyl-p-nitroanilide. A concentration of 154 ± 27 pmol of acylpeptide hydrolase/gram of fresh rat brain was also deduced by specific labeling with tritiated-diisopropylfluorophosphate. We also suggest that, by comparison of structure-activity relationships, acylpeptide hydrolase may be the target for the cognitive-enhancing effects of certain organophosphorus compounds. Acylpeptide hydrolase cleavesN α-acylated amino acids from small peptides and may be involved in regulation of neuropeptide turnover, which provides a new and plausible mechanism for its proposed cognitive enhancement effect.

Footnotes

    • Received February 23, 2000.
    • Accepted June 12, 2000.
  • Send reprint requests to: Dr. Paul G. Richards, MRC Toxicology Unit, University of Leicester, Leicester, LE1 9HN UK. E-mail: pgr3{at}le.ac.uk

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 58 (3)
Molecular Pharmacology
Vol. 58, Issue 3
1 Sep 2000
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Research ArticleArticle

Identification of Acylpeptide Hydrolase as a Sensitive Site for Reaction with Organophosphorus Compounds and a Potential Target for Cognitive Enhancing Drugs

Paul G. Richards, Martin K. Johnson and David E. Ray
Molecular Pharmacology September 1, 2000, 58 (3) 577-583; DOI: https://doi.org/10.1124/mol.58.3.577

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Research ArticleArticle

Identification of Acylpeptide Hydrolase as a Sensitive Site for Reaction with Organophosphorus Compounds and a Potential Target for Cognitive Enhancing Drugs

Paul G. Richards, Martin K. Johnson and David E. Ray
Molecular Pharmacology September 1, 2000, 58 (3) 577-583; DOI: https://doi.org/10.1124/mol.58.3.577
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