Human Neutral Endopeptidase 24.11 (NEP, Enkephalinase) ; Function, Distribution and Release

  • Ervin G. Erdös
  • Randal A. Skidgel
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 240)


Neutral endopeptidase 24.11 (NEP), although discovered in 1974 (1), received much attention recently because of its very wide distribution and many potential functions in the body (2). NEP is also known as enkephalinase (3). This name wrongfully indicates that it only cleaves enkephalins, whereas it actually hydrolyzes a variety of vaso- and CNS-active peptides (2-7). NEP, a metalloendopeptidase, was first detected in the brush border of animal kidney by Kerr and Kenny (1), who used the B-chain of insulin as substrate. The name “enkephalinase” was given later to an enzyme present in brain which cleaved enkephalins at the same bond as the angiotensin I converting enzyme (kininase II or ACE) (8). Schwartz et al (3) suggested that this “enkephalinase” was a second peptidyl dipeptidase present in the striatum of mouse brain. Because the Km of enkephalins with the latter enzyme was lower than with ACE, the second peptidyl dipeptidase was named the true “enkephalinase”. Both enzymes are membranebound and contain zinc as a cofactor, but human NEP is not a second peptidyl dipeptidase. It differs from ACE in its substrate specificity; for example, it releases a tetrapeptide from angiotensin II and inactivates angiotensin I by cleaving the C-terminal tripieptide instead of activating it as ACE does by releasing His-Leu (4,7). It does not crossreact with antiserum to human ACE (9), and is inhibited by phosphoramidon and thiorphan (2,5) but not by captopril or enalapril. Human NEP can be classified as a thermolysin-type metalloendopeptidase (2,10,11).


Chronic Obstructive Pulmonary Disease Brush Border Adult Respiratory Distress Syndrome Cardiogenic Pulmonary Edema Neutral Endopeptidase 
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  1. 1.
    M.A. Kerr, and A.J. Kenny, The purification and specificity of a neutral endopeptidase from rabbit kidney brush border, Biochem. J. 137:477 (1974).PubMedGoogle Scholar
  2. 2.
    A.J. Turner, Metabolism of enkephalins, ISI Atlas Sci.; Pharmacol. 1:74 (1987).Google Scholar
  3. 3.
    J.-C. Schwartz, B. Malfroy, and S. De La Baume, Biological inactivation of enkephalins and the role of enkephalin-dipeptidyl-carboxypeptidase (“enkephalinase”) as neuropeptidase, Life Sci. 29:1715 (1981).PubMedCrossRefGoogle Scholar
  4. 4.
    R. Matsas, A.J. Kenny, and A.J. Turner, The metabolism of neuropeptides: The hydrolysis of peptides, including enkephalins, tachykinins and their analogues, by endopeptidase-24.11, Biochem. J. 223:433 (1984).PubMedGoogle Scholar
  5. 5.
    J.T. Gafford, R.A. Skidgel, E.G. ErdÖs, and L.B. Hersh, Human kidney “enkephalinase”, a neutral metalloendopeptidase that cleaves active peptides, Biochemisty 22:3265 (1983).CrossRefGoogle Scholar
  6. 6.
    A.R. Johnson, R.A. Skidgel, J.T. Gafford, and E.G. ErdÖs, Enzymes in placental microvilli: angiotensin I converting enzyme, angiotensinase A, carboxypeptidase, and neutral endopeptidase (“enkephalinase”), Peptides 5:789 (1984).PubMedCrossRefGoogle Scholar
  7. 7.
    R.A. Skidgel, S. Engelbrecht, A.R. Johnson, and E.G. ErdÖs, Hydrolysis of substance P and neurotensin by converting enzyme and neutral endopeptidase, Peptides 5:769 (1984).PubMedCrossRefGoogle Scholar
  8. 8.
    E.G. ErdÖs, A.R. Johnson, and N.T. Boyden, Hydrolysis of enkephalin by cultured human endothelial cells and by purified peptidyl dipeptidase, Biochem. Pharmacol. 27:843 (1978).PubMedCrossRefGoogle Scholar
  9. 9.
    E.G. ErdÖs, W.W. Schulz, J.T. Gafford, and R. Defendini, Neutral metalloendopeptidase in human male genital tract: comparison to angiotensin I-converting enzyme, Lab. Invest. 52:437 (1985).PubMedGoogle Scholar
  10. 10.
    S. Blumberg, Z. Vogel, and M. Altstein, Inhibition of enkephalin-degrading enzymes from rat brain and of thermolysin by amino acid hydroxamates, Life Sci. 28:301 (1981).PubMedCrossRefGoogle Scholar
  11. 11.
    J. Almenoff, S. Wilk, and M. Orlowski, Membrane bound pituitary metalloendopeptidase: apparent identity to enkephalinase, Biochem. Biophys. Res. Commun. 102:206 (1981).PubMedCrossRefGoogle Scholar
  12. 12.
    R.A. Skidgel, W.W. Schulz, L.-T. Tam, and E. G. ErdÖs, Human renal angiotensin I converting enzyme and neutral endopeptidase, Kidney Int. (In press, 1987).Google Scholar
  13. 13.
    R. Matsas, A.J. Kenny, and A.J. Turner, An immunohistochemical study of endopeptidase-24.11 (“enkephalinase”) in the pig nervous system, Neurosci. 18:991 (1986).CrossRefGoogle Scholar
  14. 14.
    A.R. Johnson, J. Ashton, W.W. Schulz, and E.G. ErdÖs, Neutral metalloendopeptidase in human lung tissue and cultured cells, Am. Rev. Respir. Pis. 132:564 (1985).Google Scholar
  15. 15.
    N. Ura, O.A. Carretero, and E.G. ErdÖs, The role of renal endopeptidase 24.11 in kinin metabolism, Kidney Int. (In press).Google Scholar
  16. 16.
    G.M. Olins, K.L. Spear, N.R. Siegel, H.A. Zurcher-Neely, and C.E. Smith, Proteolytic degradation of atriopeptin III by rabbit kidney brush border membranes, Fed. Proc. 45:427 (1986).Google Scholar
  17. 17.
    N.G. Delaney, D.W. Cushman, M.B. Rom, M.M. Asaad, J.L. Bergey, and A.A. Seymour, Neutral endopeptidase cleaves ANP 103-126 to ring-opened products with diminished biological activity, Fed. Proc. 46:1296 (1987).Google Scholar
  18. 18.
    J.-M. Lecomte, J. Costentin, A. Vlaiculescu, P. Chaillet, H. Marcais-Collado, C. Llorens-Cortes, M. Leboyer and J.-C. Schwartz, Pharmacological properties of acetorphan, a parenterally active “enkephalinase” inhibitor, J. Pharmacol. Exper. Therap. 237:937 (1986).Google Scholar
  19. 19.
    J.C. Connelly, R.A. Skidgel, W.W. Schulz, A.R. Johnson, and E.G. ErdÖs, Neutral endopeptidase 24.11 in human neutrophils: Cleavage of chemotactic peptide, Proc. Natl. Acad. Sci. 82:8737 (1985).PubMedCrossRefGoogle Scholar
  20. 20.
    M.A. Bowes, and A.J. Kenny, Endopeptidase-24.11 in pig lymph nodes. Purification and immunocytochemical localization in reticular cells, Biochem. J. 236:801 (1986).PubMedGoogle Scholar
  21. 21.
    J. Almenoff, A.S. Teirstein, J.C. Thornton, and M. Orlowski, Identification of a thermolysin-like metalloendopeptidase in serum: activity in normal subjects and in patients with sarcoidosis, J. Lab. Clin. Med. 103:420 (1984).PubMedGoogle Scholar
  22. 22.
    A.R. Johnson, J.J. Coalson, J. Ashton, M. Larumbide, and E.G. ErdÖs, Neutral endopeptidase in serum samples from patients with adult respiratory distress syndrome: comparison with angiotensin-converting enzyme, Am. Rev. Respir. Pis. 132:1262 (1985).Google Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Ervin G. Erdös
    • 1
  • Randal A. Skidgel
    • 1
  1. 1.Departments of Anesthesiology and PharmacologyUniversity of Illinois College of MedicineChicagoUSA

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