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Gene Review

PREP  -  prolyl endopeptidase

Homo sapiens

Synonyms: PE, PEP, Post-proline cleaving enzyme, Prolyl endopeptidase
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Disease relevance of PREP

  • The prolyl endopeptidase (PEP) gene of human T cells was amplified by the PCR method and cloned in Escherichia coli [1].
  • Compared with a previously reported IL4-PE chimeric protein (IL-PE4E), IL4(38-37)-PE38KDEL bound with higher affinity and was 3-30-fold more cytotoxic to glioblastoma cell lines [2].
  • The activities of neutral collagenolytic enzymes (CE) and neutral proteoglycan-degrading enzymes (PE) in the synovial membranes of osteoarthritis (OA) patients were determined [3].
  • Identification of the novel PE multigene family was an unexpected finding of the genomic sequencing of Mycobacterium tuberculosis [4].
  • Placentae in pre-eclampsia (PE) and intrauterine growth restriction (IUGR) are characterized by morphological variations, apoptosis, and syncytial shedding, features that are linked to inappropriate oxygen and inflammatory cytokines [5].

Psychiatry related information on PREP


High impact information on PREP

  • Pituitary FGF was virtually inactive, brain (Prep A) FGF had a small amount of activity, and brain (Prep B) FGF was highly potent (50% maximal stimulation at 15-30 ng/ml) in stimulating the growth of human umbilical vein endothelial (HUVE) cells [10].
  • Pituitary and one preparation of brain FGF (Prep A) contain a basic mitogenic activity, which migrates to the same position on electrophoresis in acid pH gels as detected by incorporation of [methyl-3H]-thymidine into BALB/c 3T3 cells [10].
  • PREPL is localized in the cytosol and shows homology with prolyl endopeptidase and oligopeptidase B [11].
  • A human serine endopeptidase, purified with respect to activity against a peptide with phosphoserine in the P1' position, is apparently identical with prolyl endopeptidase [12].
  • These data suggest that phosphorylation of a serine residue in the P1' position of at least a few substrates of prolyl endopeptidase will increase the rate of their cleavage [12].

Chemical compound and disease context of PREP

  • Exaggerated cell death was recorded in PE and IUGR explants exposed to TNFalpha and 3% O2 [5].
  • Vitamin E status of Chinese population with different age groups was studied by determining plasma vitamin E levels (PE) and hydrogen peroxide-induced erythrocyte hemolysis (HPEH) [13].
  • The melphalan prodrug was essentially nontoxic to CHO, F9 teratocarcinoma, MCF7 breast adenocarcinoma, and p3U1 mouse myeloma cells up to millimolar concentrations, while prodrug incubation with the engineered prolyl endopeptidase mutant led to a cell killing profile superimposable to the one of melphalan [14].
  • The aim of this study was to examine whether anorexia and bulimia nervosa are accompanied by lower serum activity of prolyl endopeptidase (PEP;EC; post-proline cleaving enzyme), a cytosolic endopeptidase which cleaves peptide bonds on the carboxyl side of proline in proteins of relatively small molecular mass [15].
  • The growth of human transitional cell carcinoma lines was supported such that agents permissive for growth ranked as follows: Sea Plaque agarose approximately Sea Prep agarose greater than methyl cellulose greater than Bacto-agar [16].

Biological context of PREP

  • While TRH could be eliminated by alternative mechanisms, i.e. uptake or internalization, modification, hydrolysis by broad specificity peptidases such as pyroglutamyl peptidase I and prolyl endopeptidase, evidence accumulates to support a specific neuroectopeptidase as the main mechanism responsible for its extracellular inactivation [17].
  • Intrinsic variations between normal (n = 14), PE (n = 16) and IUGR pregnancies (n = 11), and their responses to oxygen (3% and 17%) and exogenous tumour necrosis alpha (TNFalpha), were recorded [5].
  • Enhanced cell death was predominantly apoptotic in PE and necrotic in IUGR [5].
  • 3% O2 promoted cell proliferation in normal placentae but this response was not reciprocated in PE and IUGR [5].
  • INTERVENTIONS: Blood pressure, 24 h non-invasive, monitoring (Spacelabs 90207) was undertaken successfully in 158 women with PE, GH or EH, whether or not they were receiving antihypertensives [18].

Anatomical context of PREP


Associations of PREP with chemical compounds


Regulatory relationships of PREP


Other interactions of PREP


Analytical, diagnostic and therapeutic context of PREP


  1. Molecular cloning and characterization of prolyl endopeptidase from human T cells. Shirasawa, Y., Osawa, T., Hirashima, A. J. Biochem. (1994) [Pubmed]
  2. Preclinical development of a recombinant toxin containing circularly permuted interleukin 4 and truncated Pseudomonas exotoxin for therapy of malignant astrocytoma. Puri, R.K., Hoon, D.S., Leland, P., Snoy, P., Rand, R.W., Pastan, I., Kreitman, R.J. Cancer Res. (1996) [Pubmed]
  3. Neutral proteases in human osteoarthritic synovium. Martel-Pelletier, J., Cloutier, J.M., Pelletier, J.P. Arthritis Rheum. (1986) [Pubmed]
  4. Rv1818c-encoded PE_PGRS protein of Mycobacterium tuberculosis is surface exposed and influences bacterial cell structure. Delogu, G., Pusceddu, C., Bua, A., Fadda, G., Brennan, M.J., Zanetti, S. Mol. Microbiol. (2004) [Pubmed]
  5. Altered cell kinetics in cultured placental villous explants in pregnancies complicated by pre-eclampsia and intrauterine growth restriction. Crocker, I.P., Tansinda, D.M., Baker, P.N. J. Pathol. (2004) [Pubmed]
  6. Effects of psychological stress on serum prolyl endopeptidase and dipeptidyl peptidase IV activity in humans: higher serum prolyl endopeptidase activity is related to stress-induced anxiety. Maes, M., Goossens, F., Lin, A., De Meester, I., Van Gastel, A., Scharpé, S. Psychoneuroendocrinology (1998) [Pubmed]
  7. Novel proline endopeptidase inhibitors do not modify Abeta40/42 formation and degradation by human cells expressing wild-type and swedish mutated beta-amyloid precursor protein. Petit, A., Barelli, H., Morain, P., Checler, F. Br. J. Pharmacol. (2000) [Pubmed]
  8. Lower serum activity of prolyl endopeptidase in fibromyalgia is related to severity of depressive symptoms and pressure hyperalgesia. Maes, M., Libbrecht, I., Van Hunsel, F., Lin, A.H., Bonaccorso, S., Goossens, F., De Meester, I., De Clerck, L., Biondi, M., Scharpe, S., Janca, A. Psychological medicine. (1998) [Pubmed]
  9. Left ventricular function during dynamic exercise in untrained and moderately trained subjects. Brandao, M.U., Wajngarten, M., Rondon, E., Giorgi, M.C., Hironaka, F., Negrao, C.E. J. Appl. Physiol. (1993) [Pubmed]
  10. Bovine fibroblast growth factor: comparison of brain and pituitary preparations. Lemmon, S.K., Riley, M.C., Thomas, K.A., Hoover, G.A., Maciag, T., Bradshaw, R.A. J. Cell Biol. (1982) [Pubmed]
  11. Deletion of PREPL, a gene encoding a putative serine oligopeptidase, in patients with hypotonia-cystinuria syndrome. Jaeken, J., Martens, K., Francois, I., Eyskens, F., Lecointre, C., Derua, R., Meulemans, S., Slootstra, J.W., Waelkens, E., de Zegher, F., Creemers, J.W., Matthijs, G. Am. J. Hum. Genet. (2006) [Pubmed]
  12. A human serine endopeptidase, purified with respect to activity against a peptide with phosphoserine in the P1' position, is apparently identical with prolyl endopeptidase. Rosén, J., Tomkinson, B., Pettersson, G., Zetterqvist, O. J. Biol. Chem. (1991) [Pubmed]
  13. Vitamin E status of Chinese population in Taiwan. Chen, L.H., Hsu, S.J., Huang, C., Chen, J.S. Am. J. Clin. Nutr. (1977) [Pubmed]
  14. Engineering a thermostable human prolyl endopeptidase for antibody-directed enzyme prodrug therapy. Heinis, C., Alessi, P., Neri, D. Biochemistry (2004) [Pubmed]
  15. Lower serum activity of prolyl endopeptidase in anorexia and bulimia nervosa. Maes, M., Monteleone, P., Bencivenga, R., Goossens, F., Maj, M., van West, D., Bosmans, E., Scharpe, S. Psychoneuroendocrinology (2001) [Pubmed]
  16. Growth of urinary transitional cell carcinoma cell lines in agar, agarose and methyl cellulose. Flanigan, R.C., Pavlik, E.J., van Nagell, J.R., Keaton, K., Ragland, A., Kenady, D.E. J. Urol. (1985) [Pubmed]
  17. TRH inactivation in the extracellular compartment: role of pyroglutamyl peptidase II. Charli, J.L., Vargas, M.A., Cisneros, M., de Gortari, P., Baeza, M.A., Jasso, P., Bourdais, J., Peréz, L., Uribe, R.M., Joseph-Bravo, P. Neurobiology (Budapest, Hungary) (1998) [Pubmed]
  18. The prevalence and clinical significance of nocturnal hypertension in pregnancy. Brown, M.A., Davis, G.K., McHugh, L. J. Hypertens. (2001) [Pubmed]
  19. Pyroglutamyl peptidase I and prolyl endopeptidase in human semen: increased activity in necrozoospermia. Valdivia, A., Irazusta, J., Fernández, D., Múgica, J., Ochoa, C., Casis, L. Regul. Pept. (2004) [Pubmed]
  20. Subcellular localization suggests novel functions for prolyl endopeptidase in protein secretion. Schulz, I., Zeitschel, U., Rudolph, T., Ruiz-Carrillo, D., Rahfeld, J.U., Gerhartz, B., Bigl, V., Demuth, H.U., Rossner, S. J. Neurochem. (2005) [Pubmed]
  21. Distribution of prolyl endopeptidase activities in rat and human brain. Irazusta, J., Larrinaga, G., González-Maeso, J., Gil, J., Meana, J.J., Casis, L. Neurochem. Int. (2002) [Pubmed]
  22. Effect of S 17092, a novel prolyl endopeptidase inhibitor, on substance P and alpha-melanocyte-stimulating hormone breakdown in the rat brain. Bellemère, G., Morain, P., Vaudry, H., Jégou, S. J. Neurochem. (2003) [Pubmed]
  23. Cloning and sequence analysis of the gene encoding human lymphocyte prolyl endopeptidase. Vanhoof, G., Goossens, F., Hendriks, L., De Meester, I., Hendriks, D., Vriend, G., Van Broeckhoven, C., Scharpé, S. Gene (1994) [Pubmed]
  24. Characterization of a prolyl endopeptidase (kininase) from human urine using fluorogenic quenched substrates. Quinto, B.M., Juliano, M.A., Hirata, I., Carmona, A.K., Juliano, L., Casarini, D.E. Int. J. Biochem. Cell Biol. (2000) [Pubmed]
  25. Prolyl endopeptidase. Wilk, S. Life Sci. (1983) [Pubmed]
  26. A prolyl endopeptidase-inhibiting antioxidant from Phyllanthus ussurensis. Chung, S.K., Nam, J.A., Jeon, S.Y., Kim, S.I., Lee, H.J., Chung, T.H., Song, K.S. Arch. Pharm. Res. (2003) [Pubmed]
  27. Proteases in human lenses and their possible significance. Swanson, A.A., Davis, R.M., Meinhardt, N.C. Curr. Eye Res. (1985) [Pubmed]
  28. Activity of dipeptidyl peptidase II and dipeptidyl peptidase IV in human gingiva with chronic marginal periodontitis. Mizutani, T., Mizutani, H., Kaneda, T., Hagihara, M., Nagatsu, T. Arch. Oral Biol. (1990) [Pubmed]
  29. No genetic association of the human prolyl endopeptidase gene in the Dutch celiac disease population. Diosdado, B., Stepniak, D.T., Monsuur, A.J., Franke, L., Wapenaar, M.C., Mearin, M.L., Koning, F., Wijmenga, C. Am. J. Physiol. Gastrointest. Liver Physiol. (2005) [Pubmed]
  30. A Kazal prolyl endopeptidase inhibitor isolated from the skin of Phyllomedusa sauvagii. Gebhard, L.G., Carrizo, F.U., Stern, A.L., Burgardt, N.I., Faivovich, J., Lavilla, E., Ermácora, M.R. Eur. J. Biochem. (2004) [Pubmed]
  31. Post-proline cleaving enzyme. Purification of this endopeptidase by affinity chromatography. Koida, M., Walter, R. J. Biol. Chem. (1976) [Pubmed]
  32. Limited efficiency of prolyl-endopeptidase in the detoxification of gliadin peptides in celiac disease. Matysiak-Budnik, T., Candalh, C., Cellier, C., Dugave, C., Namane, A., Vidal-Martinez, T., Cerf-Bensussan, N., Heyman, M. Gastroenterology (2005) [Pubmed]
  33. Factor V Q506 mutation (activated protein C resistance) associated with reduced intrapartum blood loss--a possible evolutionary selection mechanism. Lindqvist, P.G., Svensson, P.J., Dahlbäck, B., Marsál, K. Thromb. Haemost. (1998) [Pubmed]
  34. Prothrombotic genotypes are not associated with pre-eclampsia and gestational hypertension: results from a large population-based study and systematic review. Morrison, E.R., Miedzybrodzka, Z.H., Campbell, D.M., Haites, N.E., Wilson, B.J., Watson, M.S., Greaves, M., Vickers, M.A. Thromb. Haemost. (2002) [Pubmed]
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