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Gene Review

CPE  -  carboxypeptidase E

Homo sapiens

Synonyms: CPH, Carboxypeptidase E, Carboxypeptidase H, Enkephalin convertase, Prohormone-processing carboxypeptidase
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Disease relevance of CPE

  • The involvement of CPE and THBS1 in obesity allows us to suggest that the physiological processes controlled by these genes contribute to depot and gender-related differences in the metabolic complications of obesity [1].
  • In null-cell adenomas, CPE immunoreactivity was detected in the majority of tumors, but CPD and CPZ were identified only in a minority of cases [2].
  • Expression of 2 potential classifier gene products, carboxypeptidase E (CPE) and gamma-glutamyl hydrolase (GGH), was validated by immunohistochemistry and cross-validated on additional archival samples of pulmonary neuroendocrine tumors [3].
  • To test the model, these two residues on CPE were mutated to Ser or Ala, followed by baculovirus expression of the mutant CPEs in Sf9 cells [4].
  • Antiserum generated from a fusion protein, synthesized in Escherichia coli from constructs of the human cDNA, recognized an approx. 50 kDa membrane protein and a smaller soluble protein in rat and human brain preparations, corresponding to the two forms of native CPE [5].

Psychiatry related information on CPE

  • Adapting CPE to an Asian life style [6].
  • Claims that it is exceedingly important to train culture and gender conscious supervisors and that such training can lead to significant racial and gender learnings having implications beyond the CPE context [7].
  • The strongest predictors of the CPE total score were Conscientiousness and Extraversion; Openness and Agreeableness were specific predictors of Change and Employee, respectively [8].
  • Identifies and discusses five similarities and three differences between group psychotherapy and group supervision in a CPE setting [9].
  • With a professional staff of 24 chaplains and 11 CPE Supervisors, "The Chaplaincy," as it is called, has developed a multifaith, multi-institutional "Partnership Model" providing pastoral care leadership for a growing number of medical and health-related facilities (see the appendix for a current list) [10].

High impact information on CPE

  • A mutation of carboxypeptidase E (CPE), an enzyme active in the processing and sorting of prohormones, causes obesity in the fat/fat mouse [11].
  • Thus, obliteration of CPE, the sorting receptor, leads to multiple endocrine disorders in these genetically defective mice, including hyperproinsulinemia and infertility [12].
  • We have identified such a sorting receptor as membrane-associated carboxypeptidase E (CPE) in pituitary Golgi-enriched and secretory granule membranes [12].
  • We now demonstrate a defect in proinsulin processing associated with the virtual absence of CPE activity in extracts of fat/fat pancreatic islets and pituitaries [13].
  • The homology of CPE with CPA and CPB suggests a common evolutionary origin for the three enzymes [14].

Chemical compound and disease context of CPE

  • To address the question regarding the origin of the multiple forms of the enzyme, we have transfected a construct containing the cDNA for human CPE under the control of the murine-sarcoma-virus enhancer and metallothionein promoter into the C6 rat glioma cell line, which itself has extremely low levels of CPE expression [15].
  • Maternal leptin was higher than in cord (p < 0.001), and did not correlate with maternal age, body weight, body mass index, weight gain during pregnancy, serum glucose, cholesterol, triglycerides, CPE, cortisol or HbA1c levels, nor any biochemical values or anthropometric data of the newborns (p > 0.05) [16].
  • The influence of cimetidine on antiviral activity of leukocyte interferon (IFN-alpha (Le] was studied in plaque-reduction assays using Utrecht (U) amnion cells challenged with vesicular stomatitis virus (VSV) and in CPE inhibition assays using A549 cells challenged with encephalomyocarditis (EMC) virus and WISH cells challenged with VSV [17].
  • Does the transformation to HCC result from one or several identifiable acute events in the "healthy" carrier (or in mild CPH) or is it a gradual process of progressing chronic hepatitis B in which intercurrent exacerbations may still play a role [18]?
  • In this study, high levels of CPH activity was found in a liver metastasis of a human ileal carcinoid which expresses beta-preprotachykinin mRNA and the tachykinin neuropeptides, substance P and substance K [19].

Biological context of CPE

  • The recent finding that Cpe(fat)/Cpe(fat) mice, which lack carboxypeptidase E (CPE) activity because of a point mutation, are still capable of a reduced amount of neuroendocrine peptide processing suggested that additional carboxypeptidases (CPs) participate in this processing reaction [20].
  • The human CPE gene consists of 9 exons spanning more than 60 kb [21].
  • Thus, genetic variation in the CPE gene does not appear to play a major role in the pathogenesis of NIDDM or obesity in Japanese subjects [21].
  • Human CPE mRNA transcripts directed the synthesis in reticulocyte lysate of a 54 kDa translation product, which in the presence of dog pancreas microsomal membranes was co-translationally processed with cleavage, insertion into membranes and glycosylation [5].
  • To summarize, we uncovered a rare non-conservative missense mutation in CPE and demonstrated that the mutant protein has altered enzymatic properties [22].

Anatomical context of CPE


Associations of CPE with chemical compounds

  • In contrast with full-length CPE, neither CPE-Delta4 nor CPE-Delta15 floated in sucrose density gradients [25].
  • Identification of gp17 glycoprotein and characterization of prostatic acid phosphatase (PAP) and carboxypeptidase E (CPE) fragments in a human seminal plasma fraction interacting with concanavalin A [26].
  • Both NPE and CPE gave similar cAMP responses (8-13 fold) to the beta-adrenergic agonist, isoproterenol [27].
  • Enkephalin convertase is markedly stimulated by CoCl2 and inhibited by EDTA or 1,10-phenanthroline, unlike the lysosomal carboxypeptidase [28].
  • Processing of the CPH precursor occurred rapidly (t(1/2) = 30) after an initial delay of 15-30 min and the enzyme was secreted in parallel with the insulin-related peptides in response to glucose-stimulation within 1 h after radiolabelling [29].

Physical interactions of CPE

  • Mutation of residues S472 or E473 to A in the cytoplasmic tail of CPE obliterated its binding to ARF6, and internalization from the plasma membrane of Tac-CPE25 mutated at S472 or E473 was significantly reduced [30].
  • CPE:occludin interactions result in formation of an approximately 200kDa CPE complex and internalization of occludin into the cytoplasm [31].

Regulatory relationships of CPE

  • The confirmation of the existence of a single isoform of CPH expressed in brain and endocrine tissues simplifies future experiments to elucidate the role of CPH as autoantigen [32].
  • In conclusion, the CR, CP, and CPE could effectively inhibit growth by down-regulated expression of PCNA, and induce apoptosis in Hela cells [33].
  • G protein alpha-stimulating activity polypeptide (Gsalpha) and carboxypeptidase E (CPE) were the most highly expressed genes in human insulinoma, as derived by EST sequencing and cDNA array respectively [34].

Other interactions of CPE

  • Carboxypeptidase E and thrombospondin-1 are differently expressed in subcutaneous and visceral fat of obese subjects [1].
  • Treatment of cultured ciliary epithelial cells with veratridine and phorbol ester up-regulates CPE and PAM [35].
  • Kaplan-Meier survival analysis revealed that immunostaining for CPE was a statistically significant predictor of good prognosis, whereas GGH expression correlated with poor prognosis [3].
  • A fusion protein containing the extracellular domain of the human interleukin-2 receptor Tac (N-Tac) and the C-terminal 25 amino acids of CPE was transfected into Neuro2A cells [25].
  • Thus, CPE recycles back to the TGN by a novel mechanism requiring ARF6 interaction and activity [30].

Analytical, diagnostic and therapeutic context of CPE


  1. Carboxypeptidase E and thrombospondin-1 are differently expressed in subcutaneous and visceral fat of obese subjects. Ramis, J.M., Franssen-van Hal, N.L., Kramer, E., Llado, I., Bouillaud, F., Palou, A., Keijer, J. Cell. Mol. Life Sci. (2002) [Pubmed]
  2. Immunohistochemical localization of carboxypeptidases D, E, and Z in pituitary adenomas and normal human pituitary. Fan, X., Olson, S.J., Blevins, L.S., Allen, G.S., Johnson, M.D. J. Histochem. Cytochem. (2002) [Pubmed]
  3. Identification of carboxypeptidase E and gamma-glutamyl hydrolase as biomarkers for pulmonary neuroendocrine tumors by cDNA microarray. He, P., Varticovski, L., Bowman, E.D., Fukuoka, J., Welsh, J.A., Miura, K., Jen, J., Gabrielson, E., Brambilla, E., Travis, W.D., Harris, C.C. Hum. Pathol. (2004) [Pubmed]
  4. Identification of a novel prohormone sorting signal-binding site on carboxypeptidase E, a regulated secretory pathway-sorting receptor. Zhang, C.F., Snell, C.R., Loh, Y.P. Mol. Endocrinol. (1999) [Pubmed]
  5. Human carboxypeptidase E. Isolation and characterization of the cDNA, sequence conservation, expression and processing in vitro. Manser, E., Fernandez, D., Loo, L., Goh, P.Y., Monfries, C., Hall, C., Lim, L. Biochem. J. (1990) [Pubmed]
  6. Adapting CPE to an Asian life style. Keidel, K.W. Journal of pastoral care. (1975) [Pubmed]
  7. Racial and gender myths as key factors in pastoral supervision. Robinson, E., Needham, M.A. Journal of pastoral care. (1991) [Pubmed]
  8. Personality traits in leadership behavior. Kornør, H., Nordvik, H. Scandinavian journal of psychology. (2004) [Pubmed]
  9. Group supervision versus group psychotherapy: similarities and differences for clinical pastoral education. Bogia, B.P. Journal of pastoral care. (1987) [Pubmed]
  10. The HealthCare Chaplaincy, Inc., New York, New York. Handzo, G.F., Smith, W.J., Twiname, J., Twiname, C., Weiss, W.M. Journal of health care chaplaincy. (1999) [Pubmed]
  11. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Jackson, R.S., Creemers, J.W., Ohagi, S., Raffin-Sanson, M.L., Sanders, L., Montague, C.T., Hutton, J.C., O'Rahilly, S. Nat. Genet. (1997) [Pubmed]
  12. Carboxypeptidase E is a regulated secretory pathway sorting receptor: genetic obliteration leads to endocrine disorders in Cpe(fat) mice. Cool, D.R., Normant, E., Shen, F., Chen, H.C., Pannell, L., Zhang, Y., Loh, Y.P. Cell (1997) [Pubmed]
  13. Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Naggert, J.K., Fricker, L.D., Varlamov, O., Nishina, P.M., Rouille, Y., Steiner, D.F., Carroll, R.J., Paigen, B.J., Leiter, E.H. Nat. Genet. (1995) [Pubmed]
  14. Carboxypeptidase E. Fricker, L.D. Annu. Rev. Physiol. (1988) [Pubmed]
  15. Processing and secretion of human carboxypeptidase E by C6 glioma cells. Manser, E., Fernandez, D., Lim, L. Biochem. J. (1991) [Pubmed]
  16. Cord blood leptin levels: relationship to body weight, body mass index, sex and insulin and cortisol levels of maternal-newborn pairs at delivery. Kirel, B., Tekin, N., Tekin, B., Kiliç, F.S., Doğruel, N., Aydoğdu, S.D. Journal of pediatric endocrinology & metabolism : JPEM. (2000) [Pubmed]
  17. Antiviral and antiproliferative activities of human leukocyte interferon potentiated by cimetidine in vitro. Hirai, N., Hill, N.O., Motoo, Y., Osther, K. J. Interferon Res. (1985) [Pubmed]
  18. Relation of the hepatitis B virus carrier state to hepatocellular carcinoma. Popper, H., Shafritz, D.A., Hoofnagle, J.H. Hepatology (1987) [Pubmed]
  19. Identification of zymogen and mature forms of human carboxypeptidase H. A processing enzyme for the synthesis of peptide hormones. Hook, V.Y., Affolter, H.U. FEBS Lett. (1988) [Pubmed]
  20. Identification of mouse CPX-1, a novel member of the metallocarboxypeptidase gene family with highest similarity to CPX-2. Lei, Y., Xin, X., Morgan, D., Pintar, J.E., Fricker, L.D. DNA Cell Biol. (1999) [Pubmed]
  21. Organization of the human carboxypeptidase E gene and molecular scanning for mutations in Japanese subjects with NIDDM or obesity. Utsunomiya, N., Ohagi, S., Sanke, T., Tatsuta, H., Hanabusa, T., Nanjo, K. Diabetologia (1998) [Pubmed]
  22. Missense polymorphism in the human carboxypeptidase E gene alters enzymatic activity. Chen, H., Jawahar, S., Qian, Y., Duong, Q., Chan, G., Parker, A., Meyer, J.M., Moore, K.J., Chayen, S., Gross, D.J., Glaser, B., Permutt, M.A., Fricker, L.D. Hum. Mutat. (2001) [Pubmed]
  23. Immunohistochemical localization of carboxypeptidases E and D in the human placenta and umbilical cord. Reznik, S.E., Salafia, C.M., Lage, J.M., Fricker, L.D. J. Histochem. Cytochem. (1998) [Pubmed]
  24. Immunohistochemical localization and comparison of carboxypeptidases D, E, and Z, alpha-MSH, ACTH, and MIB-1 between human anterior and corticotroph cell "basophil invasion" of the posterior pituitary. Fan, X., Olson, S.J., Johnson, M.D. J. Histochem. Cytochem. (2001) [Pubmed]
  25. Sorting of carboxypeptidase E to the regulated secretory pathway requires interaction of its transmembrane domain with lipid rafts. Zhang, C.F., Dhanvantari, S., Lou, H., Loh, Y.P. Biochem. J. (2003) [Pubmed]
  26. Identification of gp17 glycoprotein and characterization of prostatic acid phosphatase (PAP) and carboxypeptidase E (CPE) fragments in a human seminal plasma fraction interacting with concanavalin A. Marquínez, A.C., Andreetta, A.M., González, N., Wolfenstein-Todel, C., Scacciati de Cerezo, J.M. J. Protein Chem. (2003) [Pubmed]
  27. High affinity vasoactive intestinal peptide receptors on fetal human nonpigmented ciliary epithelial cells. Crook, R.B., Lui, G.M., Alvarado, J.A., Fauss, D.J., Polansky, J.R. Curr. Eye Res. (1994) [Pubmed]
  28. Enkephalin convertase: purification and characterization of a specific enkephalin-synthesizing carboxypeptidase localized to adrenal chromaffin granules. Fricker, L.D., Snyder, S.H. Proc. Natl. Acad. Sci. U.S.A. (1982) [Pubmed]
  29. The post-translational processing and intracellular sorting of carboxypeptidase H in the islets of Langerhans. Guest, P.C., Arden, S.D., Rutherford, N.G., Hutton, J.C. Mol. Cell. Endocrinol. (1995) [Pubmed]
  30. Recycling of Raft-associated prohormone sorting receptor carboxypeptidase E requires interaction with ARF6. Arnaoutova, I., Jackson, C.L., Al-Awar, O.S., Donaldson, J.G., Loh, Y.P. Mol. Biol. Cell (2003) [Pubmed]
  31. New insights into the cytotoxic mechanisms of Clostridium perfringens enterotoxin. McClane, B.A., Chakrabarti, G. Anaerobe (2004) [Pubmed]
  32. Cloning of candidate autoantigen carboxypeptidase H from a human islet library: sequence identity with human brain CPH. Alcalde, L., Tonacchera, M., Costagliola, S., Jaraquemada, D., Pujol-Borrell, R., Ludgate, M. J. Autoimmun. (1996) [Pubmed]
  33. Chrysin and its phosphate ester inhibit cell proliferation and induce apoptosis in Hela cells. Zhang, T., Chen, X., Qu, L., Wu, J., Cui, R., Zhao, Y. Bioorg. Med. Chem. (2004) [Pubmed]
  34. Gene expression profiling in human insulinoma tissue: genes involved in the insulin secretion pathway and cloning of novel full-length cDNAs. Wang, X.C., Xu, S.Y., Wu, X.Y., Song, H.D., Mao, Y.F., Fan, H.Y., Yu, F., Mou, B., Gu, Y.Y., Xu, L.Q., Zhou, X.O., Chen, Z., Chen, J.L., Hu, R.M. Endocr. Relat. Cancer (2004) [Pubmed]
  35. Identification of a neuropeptide and neuropeptide-processing enzymes in aqueous humor confers neuroendocrine features to the human ocular ciliary epithelium. Ortego, J., Escribano, J., Crabb, J., Coca-Prados, M. J. Neurochem. (1996) [Pubmed]
  36. Molecular cloning of Aplysia neuronal cDNAs that encode carboxypeptidases related to mammalian prohormone processing enzymes. Fan, X., Nagle, G.T. DNA Cell Biol. (1996) [Pubmed]
  37. Depletion of carboxypeptidase E, a regulated secretory pathway sorting receptor, causes misrouting and constitutive secretion of proinsulin and proenkephalin, but not chromogranin A. Normant, E., Loh, Y.P. Endocrinology (1998) [Pubmed]
  38. Early detection of human cytomegalovirus infection after kidney transplantation by nucleic acid sequence-based amplification. Blok, M.J., Christiaans, M.H., Goossens, V.J., van Hooff, J.P., Sillekens, P., Middeldorp, J.M., Bruggeman, C.A. Transplantation (1999) [Pubmed]
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