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Gene Review

Thop1  -  thimet oligopeptidase 1

Rattus norvegicus

Synonyms: Endo-oligopeptidase A, Endopeptidase 24.15, PZ-peptidase, Soluble metallo-endopeptidase, Thimet oligopeptidase
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Disease relevance of Thop1


High impact information on Thop1

  • Novel natural peptide substrates for endopeptidase 24.15, neurolysin, and angiotensin-converting enzyme [6].
  • The active site of EP24.15 exhibits an HEXXH motif, a common feature of zinc metalloenzymes [7].
  • In studying the structure and function of EP24.15, we have employed in vitro mutagenesis and subsequent protein expression to genetically dissect the enzyme and allow us to glean insight into the mechanism of substrate binding and catalysis [7].
  • Endopeptidase EC (EP24.15) is a zinc metalloendopeptidase that is broadly distributed within the brain, pituitary, and gonads [7].
  • The formation and disruption of disulfide bonds involving these cysteine residues may be a mechanism by which EP24.15 activity is regulated through changes in intra- and extracellular redox potential [8].

Biological context of Thop1


Anatomical context of Thop1


Associations of Thop1 with chemical compounds

  • We term the enzyme oligopeptidase M. Oligopeptidase M acts similarly to thimet oligopeptidase (EC on bradykinin and several other peptides, but hydrolyzes neurotensin exclusively at the -Pro+Tyr- bond (the symbol + is used to indicate a scissile peptide bond) rather than the -Arg+Arg- bond [16].
  • Moreover, the rat protein is recognized by a monoclonal antibody against rabbit soluble angiotensin II-binding protein, all of which is consistent with these proteins being species variants of a single protein that is a homologue of thimet oligopeptidase [16].
  • The enzyme is inhibited by chelating agents and some thiol-blocking compounds, but differs from thimet oligopeptidase in not being activated by thiol compounds [16].
  • The peptidase is inhibited by Pro-Ile, unlike thimet oligopeptidase, and the two enzymes are separable in chromatography on hydroxyapatite [16].
  • We also mapped the positions of three cysteine residues believed to be responsible for multimerization of thimet oligopeptidase, a process that inactivates the enzyme [10].

Other interactions of Thop1

  • In the present study, we examined the involvement of prolyl oligopeptidase (POP), thimet oligopeptidase/neurolysin (EP 24.15/16) and glial proteins in PTZ-treated rat brain regions, and the suppressive effect of MK-801, a non-competitive NMDA receptor antagonist, pretreatment for their proteins [17].
  • Species-independent distinctions are the exclusive action of endopeptidase 24.16 on acetylneurotensin-(8-13) and liberation of free Phe from somatostatin only by endopeptidase 24.15 [18].
  • Endopeptidase 24.15 from rat testes. Isolation of the enzyme and its specificity toward synthetic and natural peptides, including enkephalin-containing peptides [19].
  • The generation of Ang-(1-7) is under the control of at least three enzymes, which include neprilysin, thimet oligopeptidase, and prolyl oligopeptidase depending on the tissue compartment [20].
  • Aminopeptidase M, DAP IV, and endopeptidase 24.15 were detected in utero, and their specific activities did not significantly vary until adulthood [21].

Analytical, diagnostic and therapeutic context of Thop1

  • Two putative calcium-binding sites on EP24.15 (D93 and D159) were altered by site-directed mutagenesis to investigate their possible contribution to binding of the enzyme at the cell surface [1].
  • Comparison of the sequence of EP24.15 with bacterial homologues previously solved by x-ray crystallography and used as models for mammalian metalloendopeptidases, indicates conserved residues [7].
  • We now report that intravenous infusion of N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate, a specific active site-directed inhibitor of endopeptidase-24.15, produces an immediate drop in mean arterial pressure of as much as 50 mm Hg in pentobarbital-anesthetized, normotensive rats [22].
  • At 48h after ligation, a significant amount of the axonal transport of EP24.15 activity was found in the proximal segment, while axonal transport of deamidase activity, a lysosomal enzyme, increased in both proximal and distal segments [23].
  • In addition the concentrations of soluble protein and hydroxyproline and the activities of lactate dehydrogenase, PZ peptidase and collagenase in lavage fluid supernatants were measured and an assessment of the hydroxyproline content of recovered cells was made [15].


  1. Calcium modulates endopeptidase 24.15 (EC membrane association, secondary structure and substrate specificity. Oliveira, V., Garrido, P.A., Rodrigues, C.C., Colquhoun, A., Castro, L.M., Almeida, P.C., Shida, C.S., Juliano, M.A., Juliano, L., Camargo, A.C., Hyslop, S., Roberts, J.L., Grum-Tokars, V., Glucksman, M.J., Ferro, E.S. FEBS J. (2005) [Pubmed]
  2. Rat thimet oligopeptidase: large-scale expression in Escherichia coli and characterization of the recombinant enzyme. McKie, N., Dando, P.M., Brown, M.A., Barrett, A.J. Biochem. J. (1995) [Pubmed]
  3. Enzyme changes during experimental silicotic fibrosis. I. PZ peptidase and collagen deposition in the lungs. Hurych, J., Mirejovská, E., Kobrle, V., Rencová, J. Environmental research. (1981) [Pubmed]
  4. Expression of PZ-peptidases by cultures of several pathogenic fungi. Purification and characterization of a collagenase from Trichophyton schoenleinii. Ibrahim-Granet, O., Hernandez, F.H., Chevrier, G., Dupont, B. J. Med. Vet. Mycol. (1996) [Pubmed]
  5. Hemopressin: a novel bioactive peptide derived from the alpha1-chain of hemoglobin. Dale, C.S., Pagano, R.d.e. .L., Rioli, V. Mem. Inst. Oswaldo Cruz (2005) [Pubmed]
  6. Novel natural peptide substrates for endopeptidase 24.15, neurolysin, and angiotensin-converting enzyme. Rioli, V., Gozzo, F.C., Heimann, A.S., Linardi, A., Krieger, J.E., Shida, C.S., Almeida, P.C., Hyslop, S., Eberlin, M.N., Ferro, E.S. J. Biol. Chem. (2003) [Pubmed]
  7. Zinc coordination and substrate catalysis within the neuropeptide processing enzyme endopeptidase EC Identification of active site histidine and glutamate residues. Cummins, P.M., Pabon, A., Margulies, E.H., Glucksman, M.J. J. Biol. Chem. (1999) [Pubmed]
  8. Thiol activation of endopeptidase EC A novel mechanism for the regulation of catalytic activity. Shrimpton, C.N., Glucksman, M.J., Lew, R.A., Tullai, J.W., Margulies, E.H., Roberts, J.L., Smith, A.I. J. Biol. Chem. (1997) [Pubmed]
  9. Thimet oligopeptidase: similarity to 'soluble angiotensin II-binding protein' and some corrections to the published amino acid sequence of the rat testis enzyme. McKie, N., Dando, P.M., Rawlings, N.D., Barrett, A.J. Biochem. J. (1993) [Pubmed]
  10. Mapping sequence differences between thimet oligopeptidase and neurolysin implicates key residues in substrate recognition. Ray, K., Hines, C.S., Rodgers, D.W. Protein Sci. (2002) [Pubmed]
  11. Thimet oligopeptidase expression is differentially regulated in neuroendocrine and spermatid cell lines by transcription factor binding to SRY (sex-determining region Y), CAAT and CREB (cAMP-response-element-binding protein) promoter consensus sequences. Morrison, L.S., Pierotti, A.R. Biochem. J. (2003) [Pubmed]
  12. Brain endo-oligopeptidase A, a putative enkephalin converting enzyme. Camargo, A.C., Oliveira, E.B., Toffoletto, O., Metters, K.M., Rossier, J. J. Neurochem. (1987) [Pubmed]
  13. Immunohistochemical localization of endopeptidase 24.15 in rat trachea, lung tissue, and alveolar macrophages. Choi, H.S., Lesser, M., Cardozo, C., Orlowski, M. Am. J. Respir. Cell Mol. Biol. (1990) [Pubmed]
  14. The activities of 'Pz-peptidase' and 'endopeptidase 24.15' are due to a single enzyme. Barrett, A.J., Tisljar, U. Biochem. J. (1989) [Pubmed]
  15. Evidence for a dose-dependent inflammatory response to quartz in the rat lung and its significance in early changes in collagen metabolism. Sykes, S.E., Morgan, A., Moores, S.R., Jones, S.T., Holmes, A., Davison, W. Environ. Health Perspect. (1983) [Pubmed]
  16. Characterization of a mitochondrial metallopeptidase reveals neurolysin as a homologue of thimet oligopeptidase. Serizawa, A., Dando, P.M., Barrett, A.J. J. Biol. Chem. (1995) [Pubmed]
  17. Pentylenetetrazol-induced seizures affect the levels of prolyl oligopeptidase, thimet oligopeptidase and glial proteins in rat brain regions, and attenuation by MK-801 pretreatment. Ahmed, M.M., Arif, M., Chikuma, T., Kato, T. Neurochem. Int. (2005) [Pubmed]
  18. Purification of the main somatostatin-degrading proteases from rat and pig brains, their action on other neuropeptides, and their identification as endopeptidases 24.15 and 24.16. Dahms, P., Mentlein, R. Eur. J. Biochem. (1992) [Pubmed]
  19. Endopeptidase 24.15 from rat testes. Isolation of the enzyme and its specificity toward synthetic and natural peptides, including enkephalin-containing peptides. Orlowski, M., Reznik, S., Ayala, J., Pierotti, A.R. Biochem. J. (1989) [Pubmed]
  20. Angiotensin-(1-7): a bioactive fragment of the renin-angiotensin system. Ferrario, C.M., Iyer, S.N. Regul. Pept. (1998) [Pubmed]
  21. A survey of the cerebral regionalization and ontogeny of eight exo- and endopeptidases in murines. Dauch, P., Masuo, Y., Vincent, J.P., Checler, F. Peptides (1993) [Pubmed]
  22. Inhibition of endopeptidase-24.15 decreases blood pressure in normotensive rats. Genden, E.M., Molineaux, C.J. Hypertension (1991) [Pubmed]
  23. Anterograde axonal transport of endopeptidase 24.15 in rat sciatic nerves. Yamamoto, M., Chikuma, T., Yamashita, A., Yamaguchi, M., Hojo, H., Ozeki, Y., Ahmed, M., Kato, T. Neurochem. Int. (2003) [Pubmed]
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