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Gene Review

THOP1  -  thimet oligopeptidase 1

Homo sapiens

Synonyms: EP24.15, Endopeptidase 24.15, MEPD_HUMAN, MP78, TOP, ...
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Disease relevance of THOP1

  • A phosphonamide peptide, N-(phenylethylphosphonyl)-Gly-L-Pro-L-aminohexanoic acid, previously shown to block Clostridium histolyticum collagenases, was examined as a putative inhibitor of endopeptidase 24.16 and endopeptidase 24.15 [1].
  • Furthermore, immunoneutralization of EP24.15 resulted in the inhibition of the LHRH-facilitated lordosis but had no inhibitory effects on LHRH-(1-5)-facilitated lordosis [2].
  • The gluzincins, defined by the HEXXH motif and a glutamic acid as the third zinc ligand, include the thermolysin, endopeptidase-24.11, aminopeptidase, angiotensin converting enzyme, endopeptidase-24.15, and tetanus and botulinum neurotoxin families [3].
  • In addition, recombinant h-MP78 purified from E. coli cleaved an APP-derived substrate spanning the beta-secretase site (ISEVKMD1AEFRHDS) at multiple sites, but the beta-site cleavage was only a minor one; cleavage occurred predominantly at K-M and E-F bonds [4].
  • It is suggested that elevated plasma nociceptin level found in Wilson disease patients is due to inhibition of nociceptin-inactivating Zn-metallopeptidases (aminopeptidase N (APN) and endopeptidase 24.15) by the toxic copper deposits in liver and/or brain [5].

High impact information on THOP1


Chemical compound and disease context of THOP1


Biological context of THOP1


Anatomical context of THOP1


Associations of THOP1 with chemical compounds

  • EP24.15 is widely distributed and is known to degrade bioactive peptides such as angiotensin I and II and bradykinin [12].
  • Additionally, drugs which disrupt the classical secretory pathway, such as Brefeldin A and nocodazole, blocked A23187-stimulated EP24.15 release yet had no effect on basal EP24.15 release, suggesting differences in the basal and stimulated pathways of secretion for EP24.15 [18].
  • Experiments with isoleucine-containing analogues of (Gly-Hyp-Leu)4 showed that thimet oligopeptidase preferred to cleave these peptides near the C-terminus [19].
  • EP24.15/16 inhibition by N-[1(R,S)-carboxy-3-phenylpropyl]-Ala-AlalTyr-p-aminobenzoate (cFP) resulted in a 1000-fold increase in B2R sensitivity to BK as measured by inositol phosphate accumulation [20].
  • In addition, the phosphonamide peptide inhibited the hydrolysis of benzoyl (Bz)-Gly-Ala-Ala-Phe-(pAB) p-aminobenzoate and neurotensin by endopeptidase 24.15 with about a 10-fold lower potency (KI values of 5 and 7.5 nM respectively) [1].

Enzymatic interactions of THOP1


Regulatory relationships of THOP1


Other interactions of THOP1


Analytical, diagnostic and therapeutic context of THOP1


  1. Potent inhibition of endopeptidase 24.16 and endopeptidase 24.15 by the phosphonamide peptide N-(phenylethylphosphonyl)-Gly-L-Pro-L-aminohexanoic acid. Barelli, H., Dive, V., Yiotakis, A., Vincent, J.P., Checler, F. Biochem. J. (1992) [Pubmed]
  2. Facilitation of lordosis in rats by a metabolite of luteinizing hormone releasing hormone. Wu, T.J., Glucksman, M.J., Roberts, J.L., Mani, S.K. Endocrinology (2006) [Pubmed]
  3. Families of zinc metalloproteases. Hooper, N.M. FEBS Lett. (1994) [Pubmed]
  4. Expression and characterization of human beta-secretase candidates metalloendopeptidase MP78 and cathepsin D in beta APP-overexpressing cells. Thompson, A., Grueninger-Leitch, F., Huber, G., Malherbe, P. Brain Res. Mol. Brain Res. (1997) [Pubmed]
  5. Elevated plasma nociceptin level in patients with Wilson disease. Hantos, M.B., Szalay, F., Lakatos, P.L., Hegedus, D., Firneisz, G., Reiczigel, J., Török, T., Tekes, K. Brain Res. Bull. (2002) [Pubmed]
  6. Soluble metalloendopeptidases and neuroendocrine signaling. Shrimpton, C.N., Smith, A.I., Lew, R.A. Endocr. Rev. (2002) [Pubmed]
  7. The cytosolic endopeptidase, thimet oligopeptidase, destroys antigenic peptides and limits the extent of MHC class I antigen presentation. York, I.A., Mo, A.X., Lemerise, K., Zeng, W., Shen, Y., Abraham, C.R., Saric, T., Goldberg, A.L., Rock, K.L. Immunity (2003) [Pubmed]
  8. Post-proteasomal antigen processing for major histocompatibility complex class I presentation. Rock, K.L., York, I.A., Goldberg, A.L. Nat. Immunol. (2004) [Pubmed]
  9. Swapping the substrate specificities of the neuropeptidases neurolysin and thimet oligopeptidase. Lim, E.J., Sampath, S., Coll-Rodriguez, J., Schmidt, J., Ray, K., Rodgers, D.W. J. Biol. Chem. (2007) [Pubmed]
  10. The role of neuropeptide processing enzymes in endocrine (prostate) cancer: EC (EP24.15). Swanson, T.A., Kim, S.I., Myers, M., Pabon, A., Philibert, K.D., Wang, M., Glucksman, M.J. Protein Pept. Lett. (2004) [Pubmed]
  11. Human endopeptidase 24.15 (THOP1) is localized on chromosome 19p13.3 and is excluded from the linkage region for late-onset Alzheimer disease. Torres, M.P., Prange, C., Lennon, G. Genomics (1998) [Pubmed]
  12. EP24.15 interacts with the angiotensin II type I receptor and bradykinin B2 receptor. Shivakumar, B.R., Wang, Z., Hammond, T.G., Harris, R.C. Cell Biochem. Funct. (2005) [Pubmed]
  13. Major histocompatibility complex class I-presented antigenic peptides are degraded in cytosolic extracts primarily by thimet oligopeptidase. Saric, T., Beninga, J., Graef, C.I., Akopian, T.N., Rock, K.L., Goldberg, A.L. J. Biol. Chem. (2001) [Pubmed]
  14. Human thimet oligopeptidase. Dando, P.M., Brown, M.A., Barrett, A.J. Biochem. J. (1993) [Pubmed]
  15. Pathway for degradation of peptides generated by proteasomes: a key role for thimet oligopeptidase and other metallopeptidases. Saric, T., Graef, C.I., Goldberg, A.L. J. Biol. Chem. (2004) [Pubmed]
  16. Distribution of thimet oligopeptidase (E.C. in human and rat testes. Pineau, C., McCool, S., Glucksman, M.J., Jégou, B., Pierotti, A.R. J. Cell. Sci. (1999) [Pubmed]
  17. The association of metalloendopeptidase EC at the extracellular surface of the AtT-20 cell plasma membrane. Crack, P.J., Wu, T.J., Cummins, P.M., Ferro, E.S., Tullai, J.W., Glucksman, M.J., Roberts, J.L. Brain Res. (1999) [Pubmed]
  18. Secretion of metalloendopeptidase 24.15 (EC Ferro, E.S., Tullai, J.W., Glucksman, M.J., Roberts, J.L. DNA Cell Biol. (1999) [Pubmed]
  19. Thimet oligopeptidase specificity: evidence of preferential cleavage near the C-terminus and product inhibition from kinetic analysis of peptide hydrolysis. Knight, C.G., Dando, P.M., Barrett, A.J. Biochem. J. (1995) [Pubmed]
  20. Modulation of bradykinin signaling by EP24.15 and EP24.16 in cultured trigeminal ganglia. Jeske, N.A., Berg, K.A., Cousins, J.C., Ferro, E.S., Clarke, W.P., Glucksman, M.J., Roberts, J.L. J. Neurochem. (2006) [Pubmed]
  21. Thimet oligopeptidase cleaves the full-length Alzheimer amyloid precursor protein at a beta-secretase cleavage site in COS cells. Koike, H., Seki, H., Kouchi, Z., Ito, M., Kinouchi, T., Tomioka, S., Sorimachi, H., Saido, T.C., Maruyama, K., Suzuki, K., Ishiura, S. J. Biochem. (1999) [Pubmed]
  22. Thimet oligopeptidase EC is a major liver kininase. Molina, H.M., Carmona, A.K., Kouyoumdjian, M., Borges, D.R. Life Sci. (2000) [Pubmed]
  23. Development and characterization of novel potent and stable inhibitors of endopeptidase EC Shrimpton, C.N., Abbenante, G., Lew, R.A., Smith, I. Biochem. J. (2000) [Pubmed]
  24. Antihypertensive effects of angiotensin-(1-7). Chappell, M.C., Iyer, S.N., Diz, D.I., Ferrario, C.M. Braz. J. Med. Biol. Res. (1998) [Pubmed]
  25. Human endopeptidase (THOP1) is localized on chromosome 19 within the linkage region for the late-onset alzheimer disease AD2 locus. Meckelein, B., de Silva, H.A., Roses, A.D., Rao, P.N., Pettenati, M.J., Xu, P.T., Hodge, R., Glucksman, M.J., Abraham, C.R. Genomics (1996) [Pubmed]
  26. Cloning and functional expression of a metalloendopeptidase from human brain with the ability to cleave a beta-APP substrate peptide. Thompson, A., Huber, G., Malherbe, P. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
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