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Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides

Abstract

ENDOGENOUS neuromodulatory molecules are commonly coupled to specific metabolic enzymes to ensure rapid signal inactivation. Thus, acetylcholine is hydrolysed by acetylcholine esterase1 and tryptamine neurotransmitters like serotonin are degraded by monoamine oxidases2. Previously, we reported the structure and sleep-inducing properties of cis-9-octadecenamide, a lipid isolated from the cerebrospinal fluid of sleep-deprived cats3, cis-9-Octadecenamide, or oleamide, has since been shown to affect serotonergic systems4 and block gap-junction communication in glial cells (our unpublished results). We also identified a membrane-bound enzyme activity that hydrolyses oleamide to its inactive acid, oleic acid3. We now report the mechanism-based isolation, cloning and expression of this enzyme activity, originally named oleamide hydrolase5, from rat liver plasma mem-branes. We also show that oleamide hydrolase converts anandamide, a fatty-acid amide identified as the endogenous ligand for the cannabinoid receptor6, to arachidonic acid, indi-cating that oleamide hydrolase may serve as the general inactivating enzyme for a growing family of bioactive signalling molecules, the fatty-acid amides6–8. Therefore we will hereafter refer to oleamide hydrolase as fatty-acid amide hydrolase, in recognition of the plurality of fatty-acid amides that the enzyme can accept as substrates.

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References

  1. MacPhee-Quigley, K., Taylor, P. & Taylor, S. J. Biol. Chem. 260, 12185–12189 (1985).

    CAS  PubMed  Google Scholar 

  2. Singer, T. P. & Ramsay, R. R. FASEB J. 9, 605–610 (1995).

    Article  CAS  Google Scholar 

  3. Cravatt, B. F. et al. Science 268, 1506–1509 (1995).

    Article  ADS  CAS  Google Scholar 

  4. Huidobro-Toro, J. P. & Harris, R. A. Proc. Natl Acad. Sci. USA 93, 8078–8082 (1996).

    Article  ADS  CAS  Google Scholar 

  5. Patterson, J. E. et al. J. Am. Chem. Soc. 118, 5938–5945 (1996).

    Article  CAS  Google Scholar 

  6. Devane, W. A. et al. Science 258, 1946–1949 (1992).

    Article  ADS  CAS  Google Scholar 

  7. Wakamatsu, K. et al. Biochem. Biophys. Res. Commun. 168, 423–429 (1990).

    Article  CAS  Google Scholar 

  8. Facci, L. et al. Proc. Natl Acad. Sci. USA 92, 3376–3380 (1995).

    Article  ADS  CAS  Google Scholar 

  9. Klee, H. et al. Proc. Natl Acad. Sci. USA 81, 1728–1732 (1984).

    Article  ADS  CAS  Google Scholar 

  10. Yamada, T., Palm, C. J., Brooks, B. & Kosuge, T. Proc. Natl Acad. Sci. USA 82, 6522–6526 (1985).

    Article  ADS  CAS  Google Scholar 

  11. Corrick, C. M., Twomey, A. P. & Hynes, M. J. Gene 53, 63–71 (1987).

    Article  CAS  Google Scholar 

  12. Chang, T.-H. & Abelson, J. Nucleic Acids Res. 18, 7180 (1990).

    Article  CAS  Google Scholar 

  13. Wilson, R. et al. Nature 368, 32–38 (1994).

    Article  ADS  CAS  Google Scholar 

  14. Ettinger, R. A. & DeLuca, H. F. Arch. Biochem. Biophys. 316, 14–19 (1995).

    Article  CAS  Google Scholar 

  15. Mayaux, J.-F. et al. J. Bacteriol. 172, 6764–6773 (1990).

    Article  CAS  Google Scholar 

  16. Feng, S., Chen, J. K., Yu, H., Simon, J. A. & Schreiber, S. L. Science 266, 1241–1246 (1994).

    Article  ADS  CAS  Google Scholar 

  17. Pawson, T. Nature 373, 573–580 (1995).

    Article  ADS  CAS  Google Scholar 

  18. Rotin, D. et al. EMBO J. 13, 4440–4450 (1994).

    Article  CAS  Google Scholar 

  19. Maurelli, S. et al. FEBS Lett. 377, 82–86 (1995).

    Article  CAS  Google Scholar 

  20. Ueda, N., Kurahashi, Y., Yamamoto, S. & Tokunaga, T. J. Biol. Chem. 270, 23823–23827 (1995).

    Article  CAS  Google Scholar 

  21. Desarnaud, F., Cadas, H. & Piomelli, D. J. Biol. Chem. 270, 6030–6035 (1995).

    Article  CAS  Google Scholar 

  22. Deutsch, D. G. & Chin, S. A. Biochem. Pharmacol. 46, 791–796 (1993).

    Article  CAS  Google Scholar 

  23. Cravatt, B. F., Lerner, R. A. & Boger, D. L. J. Am. Chem. Soc. 118, 580–590 (1996).

    Article  CAS  Google Scholar 

  24. Boivin, J., El Kaim, L. & Zard, S. Z. Tetrahedron Lett. 33, 1285–1288 (1992).

    Article  CAS  Google Scholar 

  25. Falk, M. M., Kumar, N. M. & Gilula, N. B. J. Cell Biol. 127, 343–355 (1994).

    Article  CAS  Google Scholar 

  26. Fernandez, J., Andrews, L. & Mische, S. M. Anal. Biochem. 218, 112–117 (1994).

    Article  CAS  Google Scholar 

  27. Abdel-Aal, Y. A. I. & Hammock, B. D. Science 233, 1073–1076 (1986).

    Article  ADS  CAS  Google Scholar 

  28. Imperiali, B. & Abeles, R. H. Biochemistry 25, 3760–3767 (1986).

    Article  CAS  Google Scholar 

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Cravatt, B., Giang, D., Mayfield, S. et al. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384, 83–87 (1996). https://doi.org/10.1038/384083a0

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