Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Molting is a very important physiological behavior to arthropods. During molting, integument apolysis occurs, which is the digestion and absorption of the old endocuticle for new cuticle formation. Proteases play critical roles in this process. Molting carboxypeptidase A (Ha-CPA) is characterized from Helicoverpa armigera. The Ha-CPA transcript was mainly present in the integument from the 5th instar larvae. In the integument, the transcription level of the gene reached its peak at the 5th instar molting stage and the 6th instar prepupal stage, respectively. The examination of immunohistochemistry revealed that Ha-CPA could distribute into the molting fluid in the molting- and prepupal-stage larvae. The expression of Ha-CPA could be up-regulated by 20-hydroxyecdysone (20E). These facts indicate that Ha-CPA participates in the apolysis of the integument during larval molting and metamorphosis.
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PMID:Characterization and influences of classical insect hormones on the expression profiles of a molting carboxypeptidase A from the cotton bollworm (Helicoverpa armigera). 1952 67

When mast cells are activated they can respond by releasing their secretory granule compounds, including mast cell-specific proteases of chymase, tryptase and carboxypeptidase A (MC-CPA) type. MC-CPA is a dominant protein component of the mast cell granule and the MC-CPA gene is extremely highly expressed. Despite this, relatively little has been known of its biological function. However, the recent generation of mouse strains lacking MC-CPA has opened up new possibilities for investigations related to this protease. This recent development has revealed a role for MC-CPA in regulating innate immunity responses, including the degradation of harmful substances such as the vasoconstrictive factor endothelin 1 and snake venom toxins. Here, we summarize the current knowledge of MC-CPA.
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PMID:Novel insights into the biological function of mast cell carboxypeptidase A. 1964 69

The sulfamide moiety, similarly to the structurally related sulfonamide and sulfamate ones, is widely employed in medicinal chemistry for the design of biologically active compounds. Amongst the enzymes for which sulfamide-based inhibitors were designed are the carbonic anhydrases (CAs), and a large number of proteases belonging to the aspartic protease (HIV-1 protease, gamma-secretase), serine protease (elastase, chymase, tryptase and thrombin, among others) and metalloproteinase (carboxypeptidase A [CPA] and matrix metalloproteinase [MMP]) families. Some steroid sulfatase (STS) and protein tyrosine phosphatase inhibitors belonging to the sulfamide class of derivatives have also been reported. In all these compounds, many of which show low nanomolar affinity for the target enzymes for which they have been designed, the free or substituted sulfamide moiety plays an important role in the binding of the inhibitor to the active site cavity. This is achieved either by directly coordinating to the metal ion found in some metalloenzymes (CAs, CPA, STS), usually by means of one of the nitrogen atoms present in the sulfamide motif, or, as in the case of the cyclic sulfamides, acting as HIV protease inhibitors interacting with the catalytically critical aspartic acid residues of the active site by means of an oxygen atom belonging to the HN-SO(2)-NH motif that substitutes a catalytically essential water molecule. In other cases, the sulfamide moiety is important for inducing desired physicochemical properties to the drug-like compounds incorporating it, such as enhanced water solubility, better bioavailability etc., due to the intrinsic properties of this highly polarised moiety when attached to an organic scaffold. This interesting motif is, thus, of great value for the design of pharmacological agents with many applications.
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PMID:The sulfamide motif in the design of enzyme inhibitors. 2014 8

The first metallocarboxypeptidase (CP) was identified in pancreatic extracts more than 80 years ago and named carboxypeptidase A (CPA; now known as CPA1). Since that time, seven additional mammalian members of the CPA subfamily have been described, all of which are initially produced as proenzymes, are activated by endoproteases, and remove either C-terminal hydrophobic or basic amino acids from peptides. Here we describe the enzymatic and structural properties of carboxypeptidase O (CPO), a previously uncharacterized and unique member of the CPA subfamily. Whereas all other members of the CPA subfamily contain an N-terminal prodomain necessary for folding, bioinformatics and expression of both human and zebrafish CPO orthologs revealed that CPO does not require a prodomain. CPO was purified by affinity chromatography, and the purified enzyme was able to cleave proteins and synthetic peptides with greatest activity toward acidic C-terminal amino acids unlike other CPA-like enzymes. CPO displayed a neutral pH optimum and was inhibited by common metallocarboxypeptidase inhibitors as well as citrate. CPO was modified by attachment of a glycosylphosphatidylinositol membrane anchor to the C terminus of the protein. Immunocytochemistry of Madin-Darby canine kidney cells stably expressing CPO showed localization to vesicular membranes in subconfluent cells and to the plasma membrane in differentiated cells. CPO is highly expressed in intestinal epithelial cells in both zebrafish and human. These results suggest that CPO cleaves acidic amino acids from dietary proteins and peptides, thus complementing the actions of well known digestive carboxypeptidases CPA and CPB.
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PMID:Carboxypeptidase O is a glycosylphosphatidylinositol-anchored intestinal peptidase with acidic amino acid specificity. 2192 Oct 28

Tumor cells are surrounded by infiltrating inflammatory cells, such as lymphocytes, neutrophils, macrophages, and mast cells. A body of evidence indicates that mast cells are associated with various types of tumors. Although role of mast cells can be directly related to their granule content, their function in angiogenesis and tumor progression remains obscure. This study aims to understand the role of mast cells in these processes. Tumors were chemically induced in BALB/c mice and tumor progression was divided into Phases I, II and III. Phase I tumors exhibited a large number of mast cells, which increased in phase II and remained unchanged in phase III. The expression of mouse mast cell protease (mMCP)-4, mMCP-5, mMCP-6, mMCP-7, and carboxypeptidase A were analyzed at the 3 stages. Our results show that with the exception of mMCP-4 expression of these mast cell chymase (mMCP-5), tryptases (mMCP-6 and 7), and carboxypeptidase A (mMC-CPA) increased during tumor progression. Chymase and tryptase activity increased at all stages of tumor progression whereas the number of mast cells remained constant from phase II to III. The number of new blood vessels increased significantly in phase I, while in phases II and III an enlargement of existing blood vessels occurred. In vitro, mMCP-6 and 7 are able to induce vessel formation. The present study suggests that mast cells are involved in induction of angiogenesis in the early stages of tumor development and in modulating blood vessel growth in the later stages of tumor progression.
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PMID:Expression of mast cell proteases correlates with mast cell maturation and angiogenesis during tumor progression. 2281 22

MCs (mast cells) adversely affect atherosclerosis by promoting the progression of lesions and plaque destabilization. MC chymase cleaves apoA-I (apolipoprotein A-I), the main protein component of HDL (high-density lipoprotein). We previously showed that C-terminally truncated apoA-I (cleaved at the carboxyl side of Phe(225)) is present in normal human serum using a newly developed specific mAb (monoclonal antibody). In the present study, we aimed to identify chymase-induced cleavage sites in both lipid-free and lipid-bound (HDL(3)) forms of apoA-I. Lipid-free apoA-I was preferentially digested by chymase, at the C-terminus rather than the N-terminus. Phe(229) and Tyr(192) residues were the main cleavage sites. Interestingly, the Phe(225) residue was a minor cleavage site. In contrast, the same concentration of chymase failed to digest apoA-I in HDL(3); however, a 100-fold higher concentration of chymase modestly digested apoA-I in HDL(3) at only the N-terminus, especially at Phe(33). CPA (carboxypeptidase A) is another MC protease, co-localized with chymase in severe atherosclerotic lesions. CPA, in vitro, further cleaved C-terminal Phe(225) and Phe(229) residues newly exposed by chymase, but did not cleave Tyr(192). These results indicate that several forms of C-terminally and N-terminally truncated apoA-I could exist in the circulation. They may be useful as new biomarkers to assess the risk of CVD (cardiovascular disease).
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PMID:Identification of sites in apolipoprotein A-I susceptible to chymase and carboxypeptidase A digestion. 2307 35

Carboxypeptidases (CPs) are proteases that hydrolyze C-terminal peptide bonds. They are involved in regulating the complement system of the immune system. Here, we report the molecular characterization and immune response of two carboxypeptidases, named carboxypeptidase A (Rb-CPA) and carboxypeptidase N1 (Rb-CPN1), from rock bream. The genomic sequence of Rb-CPA contains 12 exons interrupted by 11 introns, while the genomic sequence of Rb-CPN1 has 9 exons and 8 introns. The cDNA sequence of Rb-CPA encodes a 421-amino-acid (AA) polypeptide (48kDa), and the cDNA of Rb-CPN1 encodes a 448-AA polypeptide (51kDa). The amino acid sequences of Rb-CPA and Rb-CPN1 were found to harbor two characteristic Zn-binding signature domains and a peptidase-M14 Zn carboxypeptidase site. Pairwise analysis revealed that Rb-CPA and Rb-CPN1 had the highest identity with the corresponding proteins from Anoplopoma fimbria (87.6%) and Dicentrarchus labrax (96.9%), respectively. qPCR results indicated that Rb-CPA and Rb-CPN1 were constitutively expressed mainly in the kidney, heart, liver, and head kidney. Both genes were transcriptionally regulated in the liver upon challenge with pathogenic bacteria (Streptococcus iniae, Edwardsiella tarda), rock bream iridovirus (RBIV), and the immune modulators polyinosinic:polycytidylic acid and lipopolysaccharide. Taken together, our findings suggest that Rb-CPA and Rb-CPN1 have immune-related functions in rock bream.
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PMID:Two carboxypeptidase counterparts from rock bream (Oplegnathus fasciatus): molecular characterization, genomic arrangement and immune responses upon pathogenic stresses. 2545 48

The constitutive heparin+ (HP) mast cells (MCs) in mice express mouse MC protease (mMCP)-5 and carboxypeptidase A (mMC-CPA). The amino acid sequence of mMCP-5 is most similar to that of human chymase-1, as are the nucleotide sequences of their genes and transcripts. Using a homologous recombination approach, a C57BL/6 mouse line was created that possessed a disrupted mMCP-5 gene. The resulting mice were fertile and had no obvious developmental abnormality. Lack of mMCP-5 protein did not alter the granulation of the IL-3/IL-9-dependent mMCP-2+ MCs in the jejunal mucosa of Trichinella spiralis-infected mice. In contrast, the constitutive HP+ MCs in the tongues of mMCP-5-null mice were poorly granulated and lacked mMC-CPA protein. Bone marrow-derived MCs were readily developed from the transgenic mice using IL-3. Although these MCs contained high levels of mMC-CPA mRNA, they also lacked the latter exopeptidase. mMCP-5 protein is therefore needed to target translated mMC-CPA to the secretory granule along with HP-containing serglycin proteoglycans. Alternately, mMCP-5 is needed to protect mMC-CPA from autolysis in the cell's granules. Fibronectin was identified as a target of mMCP-5, and the exocytosis of mMCP-5 from the MCs in the mouse's peritoneal cavity resulted in the expression of metalloproteinase protease-9, which has been implicated in arthritis. In support of the latter finding, experimental arthritis was markedly reduced in mMCP-5-null mice relative to wild-type mice in two disease models.
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PMID:Experimental Arthritis Is Dependent on Mouse Mast Cell Protease-5. 2819 42


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