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Gene Review

CPB1  -  carboxypeptidase B1 (tissue)

Homo sapiens

Synonyms: CPB, Carboxypeptidase B, PASP, PCPB, Pancreas-specific protein
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Disease relevance of CPB1

  • Isolation of a cDNA encoding a human serum marker for acute pancreatitis. Identification of pancreas-specific protein as pancreatic procarboxypeptidase B [1].
  • To target thrombosis in a new way, we have identified and optimized a phosphinic acid-containing inhibitor of CPB, EF6265 [(S)-7-amino-2-[[[(R)-2-methyl-1-(3-phenylpropanoylamino) propyl]hydroxyphosphinoyl]methyl]heptanoic acid] and determined both the pharmacological profile and pathophysiological role of CPB in rat thrombolysis [2].
  • The cysteine proteinases CPA and CPB from Leishmania major induced Th1 responses in patients with leishmaniasis due to Leishmania guyanensis [3].
  • 5. The levels of PASP in peripheral serum were less than 0.1 mg/L in normal subjects, 0.7-3 mg/L in cases of acute pancreatitis, and less than 0.1 mg/L in cases of pancreatic carcinoma, prostatic diseases, and other abdominal diseases investigated [4].
  • The strength of this mouse strain is that it develops spontaneous autoimmune diabetes, which shares many similarities to autoimmune or type 1a diabetes (T1D) in human subjects, including the presence of pancreas-specific autoantibodies, autoreactive CD4+ and CD8+ T cells, and genetic linkage to disease syntenic to that found in humans [5].

Psychiatry related information on CPB1

  • When, as usual in prior CS-CPB studies, impairment was defined by neuropsychological test score declines (increases ignored), results were spurious [6].
  • A comparison of compliance to the FMCEA CPB indicators was made between the benchmark FMCEA hospitals and the FMCEA peer group hospitals [7].

High impact information on CPB1

  • To identify the DNA elements required for pancreas-specific expression of the rat elastase I gene, we joined the 5'-flanking region of this gene to the human growth hormone (hGH) structural gene and introduced the fusion gene into mice [8].
  • Pancreas-specific Tgfbr2 knockout mice have been generated, alone or in the context of active Kras (Kras(G12D)) expression, using the Cre-loxP system driven by the endogenous Ptf1a (pancreatic transcription factor-1a) locus [9].
  • This pathway appears to be independent of CREB, with CPB being the likely target of phosphorylation by PKA [10].
  • In contrast, the intron/exon organization of the MC-CPA gene was conserved, most closely resembling the CPB gene [11].
  • MC-CPA is unique among carboxypeptidases in having a CPA-like substrate-binding pocket and enzymatic activity despite overall protein and gene structures more similar to CPB [11].

Chemical compound and disease context of CPB1


Biological context of CPB1

  • The deduced amino acid sequence of PASP/PCPB cDNA predicts the translation of a 416-amino acid preproenzyme with a 15-amino acid signal/leader peptide and a 95-amino acid activation peptide [1].
  • The proenzyme portion of this protein has 76% identity with rat PCPB and 84% identity with bovine carboxypeptidase B. DNA and RNA blot analyses indicate that human PCPB mRNA (1,400 nucleotides) is transcribed from a single locus in the human genome in a tissue-specific fashion [1].
  • During 12 episodes of pancreatic graft rejection, PASP in serum was also increased but no changes of isoforms in serum were detected [17].
  • To investigate the effect of basic carboxypeptidases on fibrinolysis under conditions of constant carboxypeptidase activity, we employed pancreatic carboxypeptidase B (CPB), a homologous, stable basic carboxypeptidase, as a surrogate for TAFIa [18].
  • EF6265 specifically inhibited plasma CPB activity with an IC(50) (50% inhibitory concentration) of 8.3 nM and enhanced tPA-mediated clot lysis in a concentration-dependent manner [2].

Anatomical context of CPB1

  • Integrin expression on neutrophils passing the CPB at CPB1 was decreased (P < 0.05) [19].
  • In pancreatic cytosol and pancreatic juice, the major band corresponded to PASP (45 K) but weak bands were also seen at MW of 40, 30 and 16 K. In serum from 15 patients with acute pancreatitis, PASP was highly increased [17].
  • These results confirm that circulating procarboxypeptidase B functions as a fibrinolysis inhibitor's zymogen and validates the use of CPB inhibitors as both an enhancer of physiological fibrinolysis in microcirculation and as a novel adjunctive agent to tPA for thromboembolic diseases while maintaining a small effect on primary hemostasis [2].
  • Transfection of cpb1 into a cpb null mutant resulted in expression of an active enzyme that was shown by immunogold labeling with anti-CPB antibodies to be targeted to large lysosomes [20].
  • The following concentrations of PASP (mg/kg wet weight) were found in human tissues: normal pancreas 100-1,000; pancreatic carcinoma 0.1-20; prostate 0.5-5; and 13 other tissues less than 0 [4].

Associations of CPB1 with chemical compounds

  • The tandemly arranged CPB genes of Leishmania mexicana are polycistronically transcribed and encode cysteine proteases that are differentially stage-specific; CPB1 and CPB2 are expressed predominantly in metacyclics, whereas CPB3-CPB18 are expressed mainly in amastigotes [21].
  • The complex between human alpha2M and plasma CPB dissociated during SDS-polyacrylamide gel electrophoresis and transverse urea gel electrophoresis suggesting that the interaction was noncovalent and depended on the tertiary structure of the native alpha2M molecule [22].
  • Native polyacrylamide gel electrophoresis of blood samples removed from the mice revealed that plasma CPB migrated as a high molecular weight band [22].
  • A 66-kDa glycosylated carboxypeptidase, plasma pro-carboxypeptidase B (pro-plasma CPB), has recently been identified in human blood (Eaton, D. L., Malloy, B. E., Tsai, S. P., Henzel, W., and Drayna, D. (1991) J. Biol. Chem. 266, 21833-21838) [22].
  • Abolition of the glycosylation site in the mature domain of CPB did not affect enzyme processing, targeting or in vitro activity towards gelatin [23].

Physical interactions of CPB1

  • Since activated plasma CPB no longer binds plasminogen, the active enzyme may not be retained in the circulation [22].

Regulatory relationships of CPB1

  • Together, these results suggest a model in which PAX4 expression is activated during pancreatic development by a combination of pancreas-specific factors but is then switched off once PAX4 protein reaches sufficient levels [24].

Other interactions of CPB1

  • Because TAFIa- or CPB-exposed (DD)E produces little stimulation of Glu-Pg activation by t-PA, (DD)E is not degraded into fragment E and d-dimer, the latter of which has been reported to impair fibrin polymerization [25].
  • This gene is a member of a carboxypeptidase gene family that includes CPA and CPB [26].
  • The homology of CPE with CPA and CPB suggests a common evolutionary origin for the three enzymes [26].
  • In both cell lines and transgenic animals, a 4.9-kilobase pair region directly upstream of the human PAX4 gene transcriptional start site acts as a potent pancreas-specific promoter [24].
  • HNF1 is a liver enriched atypical homeoprotein isolated from vertebrates which is involved in the transcriptional activation of liver, kidney, intestine and pancreas specific genes [27].

Analytical, diagnostic and therapeutic context of CPB1


  1. Isolation of a cDNA encoding a human serum marker for acute pancreatitis. Identification of pancreas-specific protein as pancreatic procarboxypeptidase B. Yamamoto, K.K., Pousette, A., Chow, P., Wilson, H., el Shami, S., French, C.K. J. Biol. Chem. (1992) [Pubmed]
  2. Enhancement of fibrinolysis by EF6265 [(S)-7-amino-2-[[[(R)-2-methyl-1-(3-phenylpropanoylamino)propyl]hydroxyphosphinoyl] methyl]heptanoic acid], a specific inhibitor of plasma carboxypeptidase B. Suzuki, K., Muto, Y., Fushihara, K., Kanemoto, K., Iida, H., Sato, E., Kikuchi, C., Matsushima, T., Kato, E., Nomoto, M., Yoshioka, S., Ishii, H. J. Pharmacol. Exp. Ther. (2004) [Pubmed]
  3. Th1 cell development induced by cysteine proteinases A and B in localized cutaneous leishmaniasis due to Leishmania guyanensis. Pascalis, H., Lavergne, A., Bourreau, E., Prévot-Linguet, G., Kariminia, A., Pradinaud, R., Rafati, S., Launois, P. Infect. Immun. (2003) [Pubmed]
  4. A novel serum assay for pancreatic cellular damage. II. High tissue specificity of a pancreatic protein. Pousette, A., Fernstad, R., Sköldefors, H., Carlström, K. Pancreas (1988) [Pubmed]
  5. The NOD mouse: a model of immune dysregulation. Anderson, M.S., Bluestone, J.A. Annu. Rev. Immunol. (2005) [Pubmed]
  6. Evaluating neuroprotective agents for clinical anti-ischemic benefit using neurological and neuropsychological changes after cardiac surgery under cardiopulmonary bypass. Methodological strategies and results of a double-blind, placebo-controlled trial of GM1 ganglioside. Grieco, G., d'Hollosy, M., Culliford, A.T., Jonas, S. Stroke (1996) [Pubmed]
  7. External validation of compliance to perfusion quality indicators. Dickinson, T., Riley, J., Zabetakis, P.M. Perfusion (2004) [Pubmed]
  8. Specific expression of an elastase-human growth hormone fusion gene in pancreatic acinar cells of transgenic mice. Ornitz, D.M., Palmiter, R.D., Hammer, R.E., Brinster, R.L., Swift, G.H., MacDonald, R.J. Nature (1985) [Pubmed]
  9. Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-beta signaling in cooperation with active Kras expression. Ijichi, H., Chytil, A., Gorska, A.E., Aakre, M.E., Fujitani, Y., Fujitani, S., Wright, C.V., Moses, H.L. Genes Dev. (2006) [Pubmed]
  10. CREB-independent regulation by CBP is a novel mechanism of human growth hormone gene expression. Cohen, L.E., Hashimoto, Y., Zanger, K., Wondisford, F., Radovick, S. J. Clin. Invest. (1999) [Pubmed]
  11. Cloning and characterization of the novel gene for mast cell carboxypeptidase A. Reynolds, D.S., Gurley, D.S., Austen, K.F. J. Clin. Invest. (1992) [Pubmed]
  12. Secondary myelodysplasia and acute leukemia in breast cancer patients after autologous bone marrow transplant. Laughlin, M.J., McGaughey, D.S., Crews, J.R., Chao, N.J., Rizzieri, D., Ross, M., Gockerman, J., Cirrincione, C., Berry, D., Mills, L., Defusco, P., LeGrand, S., Peters, W.P., Vredenburgh, J.J. J. Clin. Oncol. (1998) [Pubmed]
  13. Sulfonylurea treatment of type 2 diabetic patients does not reduce the vasodilator response to ischemia. Spallarossa, P., Schiavo, M., Rossettin, P., Cordone, S., Olivotti, L., Cordera, R., Brunelli, C. Diabetes Care (2001) [Pubmed]
  14. alpha 1-Adrenergic responsiveness during coronary artery bypass surgery: effect of preoperative ejection fraction. Schwinn, D.A., McIntyre, R.W., Hawkins, E.D., Kates, R.A., Reves, J.G. Anesthesiology (1988) [Pubmed]
  15. Glucose homeostasis. Comparison between hypothermic and normothermic cardiopulmonary bypass. Lehot, J.J., Piriz, H., Villard, J., Cohen, R., Guidollet, J. Chest (1992) [Pubmed]
  16. Laboratory modalities for assessing hemostasis during cardiopulmonary bypass. Fekete, L.F., Bick, R.L. Semin. Thromb. Hemost. (1976) [Pubmed]
  17. Isoforms of procarboxypeptidase B, (pancreas-specific protein, PASP) in human serum, pancreatic tissue and juice. Fernstad, R., Kylander, C., Tsai, L., Tydén, G., Pousette, A. Scand. J. Clin. Lab. Invest. Suppl. (1993) [Pubmed]
  18. The intrinsic threshold of the fibrinolytic system is modulated by basic carboxypeptidases, but the magnitude of the antifibrinolytic effect of activated thrombin-activable fibrinolysis inhibitor is masked by its instability. Walker, J.B., Bajzar, L. J. Biol. Chem. (2004) [Pubmed]
  19. Low degree of activation of circulating neutrophils determined by flow cytometry during cardiac surgery with cardiopulmonary bypass. Tárnok, A., Bocsi, J., Rössler, H., Schlykow, V., Schneider, P., Hambsch, J. Cytometry. (2001) [Pubmed]
  20. The multiple cpb cysteine proteinase genes of Leishmania mexicana encode isoenzymes that differ in their stage regulation and substrate preferences. Mottram, J.C., Frame, M.J., Brooks, D.R., Tetley, L., Hutchison, J.E., Souza, A.E., Coombs, G.H. J. Biol. Chem. (1997) [Pubmed]
  21. The stage-regulated expression of Leishmania mexicana CPB cysteine proteases is mediated by an intercistronic sequence element. Brooks, D.R., Denise, H., Westrop, G.D., Coombs, G.H., Mottram, J.C. J. Biol. Chem. (2001) [Pubmed]
  22. Activated human plasma carboxypeptidase B is retained in the blood by binding to alpha2-macroglobulin and pregnancy zone protein. Valnickova, Z., Thogersen, I.B., Christensen, S., Chu, C.T., Pizzo, S.V., Enghild, J.J. J. Biol. Chem. (1996) [Pubmed]
  23. Processing and trafficking of cysteine proteases in Leishmania mexicana. Brooks, D.R., Tetley, L., Coombs, G.H., Mottram, J.C. J. Cell. Sci. (2000) [Pubmed]
  24. Autoregulation and maturity onset diabetes of the young transcription factors control the human PAX4 promoter. Smith, S.B., Watada, H., Scheel, D.W., Mrejen, C., German, M.S. J. Biol. Chem. (2000) [Pubmed]
  25. Thrombin-activable fibrinolysis inhibitor attenuates (DD)E-mediated stimulation of plasminogen activation by reducing the affinity of (DD)E for tissue plasminogen activator. A potential mechanism for enhancing the fibrin specificity of tissue plasminogen activator. Stewart, R.J., Fredenburgh, J.C., Rischke, J.A., Bajzar, L., Weitz, J.I. J. Biol. Chem. (2000) [Pubmed]
  26. Carboxypeptidase E. Fricker, L.D. Annu. Rev. Physiol. (1988) [Pubmed]
  27. The bifunctional DCOH protein binds to HNF1 independently of its 4-alpha-carbinolamine dehydratase activity. Sourdive, D.J., Transy, C., Garbay, S., Yaniv, M. Nucleic Acids Res. (1997) [Pubmed]
  28. Purification and characterization of TAFI, a thrombin-activable fibrinolysis inhibitor. Bajzar, L., Manuel, R., Nesheim, M.E. J. Biol. Chem. (1995) [Pubmed]
  29. The clinical value of human pancreas-specific protein procarboxypeptidase B as an indicator of necrosis in acute pancreatitis: comparison to CRP and LDH. Rau, B., Cebulla, M., Uhl, W., Schoenberg, M.H., Beger, H.G. Pancreas (1998) [Pubmed]
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