Carboxypeptidase A3 (mast cell carboxypeptidase A), also known as CPA3, is an enzyme which in humans is encoded by the CPA3gene.[5][6] The "CPA3" gene expression has only been detected in mast cells and mast-cell-like lines, and CPA3 is located in secretory granules. CPA3 is one of 8-9 members of the A/B subfamily that includes the well-studied pancreatic enzymes carboxypeptidase A1 (CPA1), carboxypeptidase A2 (CPA2), and carboxypeptidase B. This subfamily includes 6 carboxypeptidase A-like enzymes, numbered 1-6. The enzyme now called CPA3 was originally named mast cell carboxypeptidase A, and another protein was initially called CPA3.[7] A gene nomenclature committee renamed mast cell carboxypeptidase A as CPA3, and the original CPA3 reported by Huang et al. became CPA4 to reflect the order of their discovery.
Structure
Gene
The "CPA3" gene is a 32kb-gene located at chromosome 3q24, consisting of 11 exons.
Protein
CPA3 shares significant homology with the CPA subfamily of metalloprecarboxypeptidases and all the residues essential for the coordination of the Zn2+ active site, substrate peptide anchoring, and CP activity are preserved in the putative CPA3 protein. It resembles pancreatic CPA1 in cleaving C-terminalaromatic and aliphaticamino acid residues.CPA3 contains an N-terminal sequence of 16 amino acids and a pro-peptide between the NH2-terminal signial peptide sequence and COOH-terminal CP moiety.[8][7]
Function
CPA3 has a pH optimum in the neutral to basic range. CPA3 functions together with endopeptidases secreted from mast cells such as chymases and tryptases to degrade proteins and peptides,including the apolipoprotein B component of LDL particles and angiotensin Ⅰ.[9][10] Upon mast cell activation and degranulation, CPA3, the chymases, and tryptases are released in complexes with heparin proteoglycan.The parasitic nematodeAscaris produces CPA3 inhibitors, which increase its survival during infection. This finding implies that CPA3 might be involved in host defense against certain parasites.[11] CPA3 is also reported to have an important role in the protection towards snake venom toxins and vasoconstricting peptide endothelin 1(ET1).[12][13]
Clinical significance
CPA3 provides protection from ET-1-induced damage, suggesting CPA3 could have a role in regulating sepsis. The involvement of CPA3 in autoimmune disease models makes it a potential diagnostic parameter of related diseases.[14] The significantly increased concentration of CPA3 in drug-induced anaphylaxis also implies that CPA3 could serve as a diagnostic parameter and detection of it could improve the forensic identification.[15] A new mast cell subtype reported to appear in mucosa is implicated in allergic inflammation and these mast cells have high levels of CPA3. The highly upregulated transcript of CPA3 is readily detected in luminal brushings and biopsies, making it a useful biomarker of allergic inflammation.[16][17]
^ abHuang H, Reed CP, Zhang JS, Shridhar V, Wang L, Smith DI (June 1999). "Carboxypeptidase A3 (CPA3): a novel gene highly induced by histone deacetylase inhibitors during differentiation of prostate epithelial cancer cells". Cancer Research. 59 (12): 2981–8. PMID10383164.
^von Heijne G (July 1985). "Signal sequences. The limits of variation". Journal of Molecular Biology. 184 (1): 99–105. PMID4032478.
^Kokkonen JO, Vartiainen M, Kovanen PT (December 1986). "Low density lipoprotein degradation by secretory granules of rat mast cells. Sequential degradation of apolipoprotein B by granule chymase and carboxypeptidase A". The Journal of Biological Chemistry. 261 (34): 16067–72. PMID3536921.
^Lundequist A, Tchougounova E, Abrink M, Pejler G (July 2004). "Cooperation between mast cell carboxypeptidase A and the chymase mouse mast cell protease 4 in the formation and degradation of angiotensin II". The Journal of Biological Chemistry. 279 (31): 32339–44. doi:10.1074/jbc.M405576200. PMID15173164.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^Sanglas L, Aviles FX, Huber R, Gomis-Rüth FX, Arolas JL (February 2009). "Mammalian metallopeptidase inhibition at the defense barrier of Ascaris parasite". Proceedings of the National Academy of Sciences of the United States of America. 106 (6): 1743–7. doi:10.1073/pnas.0812623106. PMID19179285.
^Metz M, Piliponsky AM, Chen CC, Lammel V, Abrink M, Pejler G, Tsai M, Galli SJ (July 2006). "Mast cells can enhance resistance to snake and honeybee venoms". Science. 313 (5786): 526–30. doi:10.1126/science.1128877. PMID16873664.
^Maurer M, Wedemeyer J, Metz M, Piliponsky AM, Weller K, Chatterjea D, Clouthier DE, Yanagisawa MM, Tsai M, Galli SJ (November 2004). "Mast cells promote homeostasis by limiting endothelin-1-induced toxicity". Nature. 432 (7016): 512–6. doi:10.1038/nature03085. PMID15543132.
^Benoist C, Mathis D (19 December 2002). "Mast cells in autoimmune disease". Nature. 420 (6917): 875–8. doi:10.1038/nature01324. PMID12490961.
^Guo XJ, Wang YY, Zhang HY, Jin QQ, Gao CR (December 2015). "Mast cell tryptase and carboxypeptidase A expression in body fluid and gastrointestinal tract associated with drug-related fatal anaphylaxis". World Journal of Gastroenterology. 21 (47): 13288–93. doi:10.3748/wjg.v21.i47.13288. PMID26715811.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^Dougherty RH, Sidhu SS, Raman K, Solon M, Solberg OD, Caughey GH, Woodruff PG, Fahy JV (May 2010). "Accumulation of intraepithelial mast cells with a unique protease phenotype in T(H)2-high asthma". The Journal of Allergy and Clinical Immunology. 125 (5): 1046–1053.e8. doi:10.1016/j.jaci.2010.03.003. PMID20451039.
^Takabayashi T, Kato A, Peters AT, Suh LA, Carter R, Norton J, Grammer LC, Tan BK, Chandra RK, Conley DB, Kern RC, Fujieda S, Schleimer RP (August 2012). "Glandular mast cells with distinct phenotype are highly elevated in chronic rhinosinusitis with nasal polyps". The Journal of Allergy and Clinical Immunology. 130 (2): 410–20.e5. doi:10.1016/j.jaci.2012.02.046. PMID22534535.
^Schwartz LB, Riedel C, Schratz JJ, Austen KF (March 1982). "Localization of carboxypeptidase A to the macromolecular heparin proteoglycan-protein complex in secretory granules of rat serosal mast cells". Journal of Immunology. 128 (3): 1128–33. PMID6799569.
^Ryan CA (September 1971). "Inhibition of carboxypeptidase A by a naturally occurring polypeptide from potatoes". Biochemical and Biophysical Research Communications. 44 (5): 1265–70. PMID5160409.
^Miller LA, Cochrane DE, Feldberg RS, Carraway RE (June 1998). "Inhibition of neurotensin-stimulated mast cell secretion and carboxypeptidase A activity by the peptide inhibitor of carboxypeptidase A and neurotensin-receptor antagonist SR 48692". International Archives of Allergy and Immunology. 116 (2): 147–53. PMID9652308.
^Normant E, Martres MP, Schwartz JC, Gros C (December 1995). "Purification, cDNA cloning, functional expression, and characterization of a 26-kDa endogenous mammalian carboxypeptidase inhibitor". Proceedings of the National Academy of Sciences of the United States of America. 92 (26): 12225–9. PMID8618874.
^Piliponsky AM, Chen CC, Nishimura T, Metz M, Rios EJ, Dobner PR, Wada E, Wada K, Zacharias S, Mohanasundaram UM, Faix JD, Abrink M, Pejler G, Pearl RG, Tsai M, Galli SJ (April 2008). "Neurotensin increases mortality and mast cells reduce neurotensin levels in a mouse model of sepsis". Nature Medicine. 14 (4): 392–8. doi:10.1038/nm1738. PMID18376408.
Further reading
Natsuaki M, Stewart CB, Vanderslice P, Schwartz LB, Natsuaki M, Wintroub BU, Rutter WJ, Goldstein SM (August 1992). "Human skin mast cell carboxypeptidase: functional characterization, cDNA cloning, and genealogy". The Journal of Investigative Dermatology. 99 (2): 138–45. doi:10.1111/1523-1747.ep12616776. PMID1629626.
Goldstein SM, Kaempfer CE, Proud D, Schwartz LB, Irani AM, Wintroub BU (October 1987). "Detection and partial characterization of a human mast cell carboxypeptidase". Journal of Immunology. 139 (8): 2724–9. PMID2443571.
Pascual R, Burgos FJ, Salva M, Soriano F, Mendez E, Aviles FX (February 1989). "Purification and properties of five different forms of human procarboxypeptidases". European Journal of Biochemistry / FEBS. 179 (3): 609–16. doi:10.1111/j.1432-1033.1989.tb14590.x. PMID2920728.
Dikov MM, Springman EB, Yeola S, Serafin WE (October 1994). "Processing of procarboxypeptidase A and other zymogens in murine mast cells". The Journal of Biological Chemistry. 269 (41): 25897–904. PMID7929294.
Chen ZQ, He SH (February 2004). "Cloning and expression of human colon mast cell carboxypeptidase". World Journal of Gastroenterology. 10 (3): 342–7. PMID14760754.
