An arginine specific carboxypeptidase generated in blood during coagulation or inflammation which is unrelated to carboxypeptidase N or its subunits

Campbell, William; Okada, Hidechika

doi:10.1016/0006-291x(89)90762-6

Cited by 138 publications

(95 citation statements)

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“…The activated form appeared to remove arginine residues (R) more rapidly than lysine residues (K) at the carboxyl terminus of substrates compared with CPN (5,11,13). It has also been termed plasma carboxypeptidase B (11), carboxypeptidase U (CPU) (8), and thrombin-activatable fibrinolysis inhibitor (TAFI) (12). It is known that human proCPR can be hydrolyzed by trypsin-like enzymes such as thrombin (11), thrombin/thrombomodulin complex (14), and plasmin (11), thereby acquiring enzymatic activity by which it cleaves carboxyl-terminal arginine and lysine residues from various peptides.…”

Section: Pro-carboxypeptidase R Is An Acute Phase Protein In Thementioning

confidence: 99%

“…This activity can be completely inhibited by potato carboxypeptidase inhibitor (PCI) at concentrations at which CPN is not affected (15). Because the activity of CPR is similar to that of CPN, this enzyme has been implicated in the inactivation of several natural potent peptides, including anaphylatoxins and bradykinin, as well as in the removal of arginine and lysine residues from partially plasmin-degraded fibrin (8,15,16). To elucidate the in vivo roles of proCPR and CPN, the establishment of an animal model is essential.…”

Section: Pro-carboxypeptidase R Is An Acute Phase Protein In Thementioning

confidence: 99%

“…In another experiment, BALB/c mice, 9 -12 wk of age, were injected i.p. with 0.5 or 4 mg/kg of LPS (from Escherichia coli 0111:B4, Sigma, St. Louis, MO) in 0.5 ml of saline or with 0.5 ml of saline alone and killed under anesthesia at 4,8,12, and 24 h after LPS injection. Total RNA of the livers was prepared using Trizol reagent.…”

Section: Northern Blot Analysismentioning

confidence: 99%

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Pro-Carboxypeptidase R is an Acute Phase Protein in the Mouse, Whereas Carboxypeptidase N Is Not

Sato

Miwa

Akatsu

et al. 2000

The Journal of Immunology

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Carboxypeptidase R (EC 3.4.17.20; CPR) and carboxypeptidase N (EC 3.4.17.3; CPN) cleave carboxyl-terminal arginine and lysine residues from biologically active peptides such as kinins and anaphylatoxins, resulting in regulation of their biological activity. Human proCPR, also known as thrombin-activatable fibrinolysis inhibitor, plasma pro-carboxypeptidase B, and pro-carboxypeptidase U, is a plasma zymogen activated during coagulation. CPN, however, previously termed kininase I and anaphylatoxin inactivator, is present in a stable active form in plasma. We report here the isolation of mouse proCPR and CPN cDNA clones that can induce their respective enzymatic activities in culture supernatants of transiently transfected cells. Potato carboxypeptidase inhibitor can inhibit carboxypeptidase activity in culture medium of mouse proCPR-transfected cells. The expression of proCPR mRNA in murine liver is greatly enhanced following LPS injection, whereas CPN mRNA expression remains unaffected. Furthermore, the CPR activity in plasma increased 2-fold at 24 h after LPS treatment. Therefore, proCPR can be considered a type of acute phase protein, whereas CPN is not. An increase in CPR activity may facilitate rapid inactivation of inflammatory mediators generated at the site of Gram-negative bacterial infection and may consequently prevent septic shock. In view of the ability of proCPR to also inhibit fibrinolysis, an excess of proCPR induced by LPS may contribute to hypofibrinolysis in patients suffering from disseminated intravascular coagulation caused by sepsis.

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Section: Pro-carboxypeptidase R Is An Acute Phase Protein In Thementioning

confidence: 99%

Section: Pro-carboxypeptidase R Is An Acute Phase Protein In Thementioning

confidence: 99%

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Pro-Carboxypeptidase R is an Acute Phase Protein in the Mouse, Whereas Carboxypeptidase N Is Not

Sato

Miwa

Akatsu

et al. 2000

The Journal of Immunology

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“…[7][8][9][10][11] The thrombin-TM complex also activates protein C to activated protein C (aPC), which has well-established antithrombotic and anti-inflammatory properties. [12][13][14] Activated proCPB (CPB) may function as a fibrinolysis inhibitor.…”

Section: Introductionmentioning

confidence: 99%

Thrombin-activatable procarboxypeptidase B regulates activated complement C5a in vivo

Nishimura

Myles

Piliposky

et al. 2006

Blood

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Plasma procarboxypeptidase B (proCPB)is activated by the endothelial thrombinprothrombomodulin complex. Activated (CPB) functions as a fibrinolysis inhibitor, but it may play a broader role by inactivating inflammatory mediators. To test this hypothesis, C5a-induced alveolitis was studied in wild-type (WT) and proCPBdeficient mice (proCPB ؊/؊ ). C5a-induced alveolitis, as measured by cell counts and total protein contents in bronchoalveolar lavage fluids, was markedly enhanced in the proCPB ؊/؊ mice. E229K thrombin, a thrombin mutant with minimal clotting activity but retaining its ability to activate protein C and proCPB, attenuated C5a-induced alveolitis in WT but not in proCPB ؊/؊ mice, indicating that its beneficial effect is mediated primarily by its activation of proCPB. Lung tissue histology confirmed these cellular inflammatory responses. Delayed administration of E229K thrombin after the C5a instillation was ineffective in reducing alveolitis in WT mice, suggesting that the beneficial effect of E229K thrombin is due to the direct inhibition of C5a by CPB. Our studies show that thrombin-activatable proCPB, in addition to its role in fibrinolysis, has intrinsic anti-inflammatory functions. Its activation, along with protein C, by the endothelial thrombin-TM complex represents a homeostatic response to counteract the inflammatory mediators generated at the site of vascular injury. IntroductionThe complement system is part of the innate immune system and plays a major role in the host defense against pyrogenic bacterial infection. 1,2 It is also involved in a wide variety of acute and chronic inflammatory disorders, including sepsis, acute respiratory distress syndrome, rheumatoid arthritis, and glomerulonephritis. The complement system consists of multiple proteins in plasma and on cell surfaces and can be activated by 3 distinct pathways, all converging on the cleavage of C3 into C3a and C3b. C3b in turn becomes an essential component of the C5 convertase enzyme complex, leading to cleavage of C5 into C5a and C5b. Both C3a and C5a are strong chemoattractants. 1,2 They cause oxidative burst and enhance phagocytosis and granule enzyme release in neutrophils. They are vasodilators at sites of inflammation. C3a and C5a exert their effects through binding to cellular C3a receptors (C3aR) and C5a receptors (C5aR), respectively. C5aR are found on circulating myeloid cells, including neutrophils, monocytes, eosinophils, and basophils, as well as nonmyeloid cells in many organs, especially in the lung and the liver. 2-4 Widespread up-regulation of the C5aR occurs during sepsis, and mice deficient in C5aR succumbed to bacterial pneumonias in animal models, indicating that C5a/ C5aR signaling is essential in host defenses in the lung and other organs. 5,6 Both C3a and C5a are inhibited by carboxypeptidase N (CPN), a constitutively active plasma carboxypeptidase.Thrombin-activatable procarboxypeptidase B (proCPB), also known as procarboxypeptidase U, procarboxypeptidase R, and thrombin-activatable fibrinolysis inhib...

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“…However, a novel plasma carboxypeptidase B was originally identified independently in two laboratories in 1989 (4,6). It has been assigned different names: carboxypeptidase R (CPR), carboxypeptidase U (CPU), plasma carboxypeptidase B, and more recently activated thrombin-activatable fibrinolysis inhibitor (activated TAFI).…”

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confidence: 99%

Inactivation of C3a and C5a Octapeptides by Carboxypeptidase R and Carboxypeptidase N

Campbell

Lazoura

Okada

et al. 2002

Microbiology and Immunology

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Pro-carboxypeptidase R (proCPR), also known as thrombin-activatable fibrinolysis inhibitor (TAFI), precursor of carboxypeptidase U and plasma carboxypeptidase B is present in plasma and following activation by thrombin/thrombomodulin and/or plasmin can remove arginine from the carboxyterminal of C3a and C5a. We have shown that this enzyme can remove terminal arginine from the C5a octapeptide much more efficiently than the classical anaphylatoxin inactivator, carboxypeptidase N (CPN). Since we have previously demonstrated that proCPR is significantly upregulated in the inflammatory state, this enzyme would appear to significantly contribute to the inactivation of C5a, the most potent of the complement derived anaphylatoxins.

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An arginine specific carboxypeptidase generated in blood during coagulation or inflammation which is unrelated to carboxypeptidase N or its subunits

Cited by 138 publications

References 11 publications

Pro-Carboxypeptidase R is an Acute Phase Protein in the Mouse, Whereas Carboxypeptidase N Is Not

Pro-Carboxypeptidase R is an Acute Phase Protein in the Mouse, Whereas Carboxypeptidase N Is Not

Thrombin-activatable procarboxypeptidase B regulates activated complement C5a in vivo

Inactivation of C3a and C5a Octapeptides by Carboxypeptidase R and Carboxypeptidase N

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