Human mast cell carboxypeptidase. Purification and characterization.

Goldstein, Sanford M.; Kaempfer, C E; Kealey, J T; Wintroub, Bruce U.

doi:10.1172/jci114061

Cited by 78 publications

(54 citation statements)

References 25 publications

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“…Among the various MC proteases it is clear that the chymase mMCP-4 plays a major role in Ang II formation. However, we also provide evidence that MC CPA, an enzyme to which few biological functions have been ascribed previously, can convert Ang I to Ang II, a finding that is also supported by a previous study performed in a purified system (13). Importantly, neither of these enzymes is itself essential for Ang II formation, but when both of them are inactivated, negligible amounts of Ang II are generated.…”

Section: Discussionsupporting

confidence: 90%

Cooperation between Mast Cell Carboxypeptidase A and the Chymase Mouse Mast Cell Protease 4 in the Formation and Degradation of Angiotensin II

Lundequist

Tchougounova

Åbrink

et al. 2004

Journal of Biological Chemistry

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The octapeptide angiotensin II (Ang II) exerts a wide range of effects on the cardiovascular system but has also been implicated in the regulation of cell proliferation, fibrosis, and apoptosis. Ang II is formed by cleavage of Ang I by angiotensin-converting enzyme, but there is also evidence for non-angiotensin-converting enzyme-dependent conversion of Ang I to Ang II. Here we address the role of mast cell proteases in Ang II production by using two different mouse strains lacking mast cell heparin or mouse mast cell protease 4 (mMCP-4), the chymase that may be the functional homologue to human chymase. Ang I was added to ex vivo cultures of peritoneal cells, and the generation of Ang II and other metabolites was analyzed. Activation of mast cells resulted in marked increases in both the formation and subsequent degradation of Ang II, and both of these processes were strongly reduced in heparin-deficient peritoneal cells. In the mMCP-4 ؊/؊ cell cultures no reduction in the rate of Ang II generation was seen, but the formation of Ang-(5-10) was completely abrogated. Addition of a carboxypeptidase A (CPA) inhibitor to wild type cells caused complete inhibition of the formation of Ang-(1-9) and Ang-(1-7) but did not inhibit Ang II formation. However, when the CPA inhibitor was added to the mMCP-4 ؊/؊ cultures, essentially complete inhibition of Ang II formation was obtained. Taken together, the results of this study indicate that mast cell chymase and CPA have key roles in both the generation and degradation of Ang II.

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Section: Discussionsupporting

confidence: 90%

Cooperation between Mast Cell Carboxypeptidase A and the Chymase Mouse Mast Cell Protease 4 in the Formation and Degradation of Angiotensin II

Lundequist

Tchougounova

Åbrink

et al. 2004

Journal of Biological Chemistry

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“…13,14 Inhibitors of ACE or both ACE and neprilysin 11,44 (eg, omapatrilat) may enhance the release of Ang 1-9 by raising Ang I concentration. Heart tissue is rich in CATA but also contains other enzymes that cleave Ang I at His 9 -Leu, 10 including a carboxypeptidase A-type enzyme, 45 mast cell carboxypeptidase, 16,45,46 and ACE II. 17,18 The pH optimum for CATA peptidase is at pH 5.5 with short synthetic substrates, but with longer active peptides, the pH curve is not sharp.…”

Section: Discussionmentioning

confidence: 99%

“…Carboxypeptidase A of mast cells, 16 an ACE variant (ACE II) that cleaves single C-terminal amino acid of Ang I, 17,18 and a serine peptidase from platelets 19 -21 named deamidase, can all release Ang 1-9. Deamidase is very likely identical with cathepsin A 19,20 (CATA), also called lysosomal protective protein 22 or lysosomal carboxypeptidase A.…”

mentioning

confidence: 99%

Angiotensin 1-9 and 1-7 Release in Human Heart

et al. 2002

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Abstract-Human heart tissue enzymes cleave angiotensin (Ang) I to release Ang 1-9, Ang II, or Ang 1-7. In atrial homogenate preparations, cathepsin A (deamidase) is responsible for 65% of the liberated Ang 1-9. Ang 1-7 was released (88% to 100%) by a metallopeptidase, as established with peptidase inhibitors. Ang II was liberated to about equal degrees by ACE and chymase-type enzymes. Cathepsin A's presence in heart tissue was also proven because it deamidated enkephalinamide substrate by immunoprecipitation of cathepsin A with antiserum to human recombinant enzyme and by immunohistochemistry. In immunohistochemistry, cathepsin A was detected in myocytes of atrial tissue. The products of Ang I cleavage, Ang 1-9 and Ang 1-7, potentiated the effect of an ACE-resistant bradykinin analog and enhanced kinin effect on the B 2 receptor in Chinese hamster ovary cells transfected to express human ACE and B 2 (CHO/AB), and in human pulmonary arterial endothelial cells. Ang 1-9 and 1-7 augmented arachidonic acid and nitric oxide (NO) release by kinin. Direct assay of NO liberation by bradykinin from endothelial cells was potentiated at 10 nmol/L concentration, 2.4-fold (Ang 1-9) and 2.1-fold (Ang 1-7); in higher concentrations, Ang 1-9 was significantly more active than Ang 1-7. Both peptides had traces of activity in the absence of bradykinin. Ang 1-9 and Ang 1-7 potentiated bradykinin action on the B 2 receptor by raising arachidonic acid and NO release at much lower concentrations than their 50% inhibition concentrations (IC 50 s) with ACE.

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“…Cathepsin G is serine protease expressed by MC TC cells [17] as well as by neutrophils and monocytes. Mast cell carboxypeptidase A3 is zinc-dependent exopeptidase [18][19][20][21][22] with a similar catalytic profile as pancreatic carboxypeptidase A. β-Hexosaminidase, like β-tryptase, is stored in the secretory granules of both MC TC type and MC T type, and can be used as a maker of degranulation for mast cells of at least 20% purity [3].…”

Section: Introductionmentioning

confidence: 99%

Active monomers of human β-tryptase have expanded substrate specificities

Fukuoka

Schwartz

2007

International Immunopharmacology

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Abstractβ-Tryptase, a product of the TPSAB1 and TPSB2 genes, is a trypsin-like serine protease that is a major and selective component of the secretory granules of all human mast cells, accounting for as much as 25% of cell protein. Once mast cells are activated, β-tryptase is released along with histamine and heparin proteoglycan. β-Tryptase is a unique enzyme with a homotetrameric structure in which active sites face into the central cavity of the four monomers, stabilized by heparin-proteoglycan. This structure makes β-tryptase resistant to most biological inhibitors of serine proteases. Without stabilization, at neutral pH β-tryptase converts to inactive monomers. Tryptase levels are elevated in bronchoalveolar lavage (BAL) fluid obtained from atopic asthmatics and in serum during systemic anaphylactic shock. Several synthetic small molecular weight β-tryptase inhibitors reduced Aginduced airway hypersensitivity in animals, suggesting β-tryptase is involved in the pathogenesis of airway inflammation. Although the major biologic substrate(s) of β-tryptase remain ambiguous, the protease can digest several proteins of potential biologic importance, including fibrinogen, fibronectin, pro-urokinase, pro-matrix metalloprotease-3 (proMMP-3), protease activated receptor-2 (PAR2) and complement component C3. Recently, monomers of β-tryptase with enzymatic activity have been detected in vitro. Here we discuss how β-tryptase monomers with enzymatic activity were identified as well as their potential role in vivo.

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Human mast cell carboxypeptidase. Purification and characterization.

Cited by 78 publications

References 25 publications

Cooperation between Mast Cell Carboxypeptidase A and the Chymase Mouse Mast Cell Protease 4 in the Formation and Degradation of Angiotensin II

Cooperation between Mast Cell Carboxypeptidase A and the Chymase Mouse Mast Cell Protease 4 in the Formation and Degradation of Angiotensin II

Angiotensin 1-9 and 1-7 Release in Human Heart

Active monomers of human β-tryptase have expanded substrate specificities

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