Carboxypeptidase B2 (CPB2) also known as carboxypeptidase U (CPU), plasma carboxypeptidase B (pCPB), or thrombin-activatable fibrinolysis inhibitor (TAFI) is an enzyme that in humans is encoded by the CPB2gene.
CPB2 is synthesized by the liver and circulates in the plasma as a plasminogen-bound zymogen. When it is activated by proteolysis at residue Arg92 by the thrombin/thrombomodulin complex, CPB2 exhibits carboxypeptidase activity. Activated CPB2 reduces fibrinolysis by removing the fibrinC-terminal residues that are important for the binding and activation of plasminogen.
Carboxypeptidases are enzymes that hydrolyze C-terminal peptide bonds. The carboxypeptidase family includes metallo-, serine, and cysteine carboxypeptidases. According to their substrate specificity, these enzymes are referred to as carboxypeptidase A (cleaving aliphatic residues) or carboxypeptidase B (cleaving basic amino residues). The protein encoded by this gene is activated by thrombin and acts on carboxypeptidase B substrates. After thrombin activation, the mature protein downregulates fibrinolysis.
Fibrinolysis (simplified). Blue arrows denote stimulation, and red arrows inhibition.
^Eaton DL, Malloy BE, Tsai SP, Henzel W, Drayna D (Dec 1991). "Isolation, molecular cloning, and partial characterization of a novel carboxypeptidase B from human plasma". J Biol Chem266 (32): 21833–8. PMID1939207.
Bouma BN, Mosnier LO (2005). "Thrombin activatable fibrinolysis inhibitor (TAFI) at the interface between coagulation and fibrinolysis.". Pathophysiol. Haemost. Thromb.33 (5–6): 375–81. doi:10.1159/000083832. PMID15692247.
Marinkovic DV, Marinkovic JN, Erdös EG, Robinson CJ (1977). "Purification of carboxypeptidase B from human pancreas". Biochem. J.163 (2): 253–60. PMC1164691. PMID17398.
Valnickova Z, Thogersen IB, Christensen S, et al. (1996). "Activated human plasma carboxypeptidase B is retained in the blood by binding to alpha2-macroglobulin and pregnancy zone protein". J. Biol. Chem.271 (22): 12937–43. doi:10.1074/jbc.271.22.12937. PMID8662763.
Bajzar L, Morser J, Nesheim M (1996). "TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex". J. Biol. Chem.271 (28): 16603–8. doi:10.1074/jbc.271.28.16603. PMID8663147.
Vanhoof G, Wauters J, Schatteman K, et al. (1997). "The gene for human carboxypeptidase U (CPU)--a proposed novel regulator of plasminogen activation--maps to 13q14.11". Genomics38 (3): 454–5. doi:10.1006/geno.1996.0656. PMID8975730.
Matsumoto A, Itoh K, Matsumoto R (2000). "A novel carboxypeptidase B that processes native beta-amyloid precursor protein is present in human hippocampus". Eur. J. Neurosci.12 (1): 227–38. doi:10.1046/j.1460-9568.2000.00908.x. PMID10651877.
Marx PF, Hackeng TM, Dawson PE, et al. (2000). "Inactivation of active thrombin-activable fibrinolysis inhibitor takes place by a process that involves conformational instability rather than proteolytic cleavage". J. Biol. Chem.275 (17): 12410–5. doi:10.1074/jbc.275.17.12410. PMID10777524.
Mosnier LO, Lisman T, van den Berg HM, et al. (2002). "The defective down regulation of fibrinolysis in haemophilia A can be restored by increasing the TAFI plasma concentration". Thromb. Haemost.86 (4): 1035–9. PMID11686321.
Mosnier LO, Meijers JC, Bouma BN (2002). "The role of protein S in the activation of thrombin activatable fibrinolysis inhibitor (TAFI) and regulation of fibrinolysis". Thromb. Haemost.86 (4): 1040–6. PMID11686322.
Mosnier LO, Elisen MG, Bouma BN, Meijers JC (2002). "Protein C inhibitor regulates the thrombin-thrombomodulin complex in the up- and down regulation of TAFI activation". Thromb. Haemost.86 (4): 1057–64. PMID11686324.
Morange PE, Aillaud MF, Nicaud V, et al. (2002). "Ala147Thr and C+1542G polymorphisms in the TAFI gene are not associated with a higher risk of venous thrombosis in FV Leiden carriers". Thromb. Haemost.86 (6): 1583–4. PMID11776333.
Schneider M, Nagashima M, Knappe S, et al. (2002). "Amino acid residues in the P6-P'3 region of thrombin-activable fibrinolysis inhibitor (TAFI) do not determine the thrombomodulin dependence of TAFI activation". J. Biol. Chem.277 (12): 9944–51. doi:10.1074/jbc.M111685200. PMID11786552.
Koschinsky ML, Boffa MB, Nesheim ME, et al. (2002). "Association of a single nucleotide polymorphism in CPB2 encoding the thrombin-activable fibrinolysis inhibitor (TAF1) with blood pressure". Clin. Genet.60 (5): 345–9. doi:10.1034/j.1399-0004.2001.600504.x. PMID11903334.
Yano Y, Gabazza EC, Hori Y, et al. (2002). "Association between plasma thrombin-activatable fibrinolysis inhibitor levels and activated protein C in normotensive type 2 diabetic patients". Diabetes Care25 (7): 1245–6. doi:10.2337/diacare.25.7.1245. PMID12087030.
Antovic JP, Blombäck M (2003). "Thrombin-activatable fibrinolysis inhibitor antigen and TAFI activity in patients with APC resistance caused by factor V Leiden mutation". Thromb. Res.106 (1): 59–62. doi:10.1016/S0049-3848(02)00072-5. PMID12165290.