A carboxypeptidase (EC number 3.4.16 – 3.4.18) is a protease enzyme that hydrolyzes (cleaves) a peptide bond at the carboxy-terminal (C-terminal) end of a protein or peptide. This is in contrast to an aminopeptidases, which cleave peptide bonds at the N-terminus of proteins. Humans, animals, bacteria and plants contain several types of carboxypeptidases that have diverse functions ranging from catabolism to protein maturation. At least two mechanisms have been discussed.

• Bertini, Ivano; Gray, Harry B.; Stiefel, Edward I.; Valentine, Joan S. (2006). Biological Inorganic Chemistry: Structure and Reactivity. Univ Science Book. pp. 180–182. ISBN 978-1891389436.

Functions

Initial studies on carboxypeptidases focused on pancreatic carboxypeptidases A1, A2, and B in the digestion of food. Most carboxypeptidases are not, however, involved in catabolism. Instead they help to mature proteins, for example Post-translational modification. They also regulate biological processes, such as the biosynthesis of neuroendocrine peptides such as insulin requires a carboxypeptidase. Carboxypeptidases also function in blood clotting, growth factor production, wound healing, reproduction, and many other processes.

Mechanism

This section needs additional citations for verification.

Carboxypeptidases hydrolyze peptides at the first amide or polypeptide bond on the C-terminal end of the chain. Carboxypeptidases act by replacing the substrate water with a carbonyl (C=O) group. The carboxypeptidase A hydrolysis reaction has two mechanistic hypotheses, via a nucleophilic water and via an anhydride.

In the first proposed mechanism, a promoted-water pathway is favoured as Glu270 deprotonates the nucleophilic water. The Zn²⁺ ion, along with positively charged residues, decreases the pKa of the bound water to approximately 7. Glu 270 has a dual role in this mechanism as it acts as a base to allow for the attack at the amide carbonyl group during nucleophilic addition. It acts as an acid during elimination when the water proton is transferred to the leaving nitrogen group. The oxygen on the amide carbonyl group does not coordinate to the Zn²⁺ until the addition of the water. The deprotonation of the Zn²⁺ coordinated water by Glu 270 provides an activated hydroxide nucleophile which attacks the amide carbonyl group in the peptide bond in a nucleophilic addition. The negatively charged intermediates that are formed during hydrolysis are stabilized by the Zn²⁺ ion. The interaction between the carbonyl group and the neighbouring arginine, Arg 217, also stabilizes the negatively charged intermediates. The zinc-bound hydroxide interacts with the amide with the electrostatic stabilization of the transition state provided by the Zn²⁺ ion and the neighbouring arginine.

The second proposed mechanism via an anhydride has similar steps but there is a direct attack of Glu270 on the carbonyl group, and then the interaction of Glu270 on the Zn²⁺-bound amide forms an anhydride instead which can subsequently be hydrolyzed by water.

Classifications

By active site mechanism

Carboxypeptidases are usually classified into one of several families based on their active site mechanism.

Enzymes that use a metal in the active site are called “metallo-carboxypeptidases” (EC number 3.4.17).

Other carboxypeptidases that use active site serine residues are called “serine carboxypeptidases” (EC number 3.4.16).

Those that use an active site cysteine are called “cysteine carboxypeptidase” (or “thiol carboxypeptidases”)(EC number 3.4.18).

These names do not refer to the selectivity of the amino acid that is cleaved.

By substrate preference

Another classification system for carboxypeptidases refers to their substrate preference.

In this classification system, carboxypeptidases that have a stronger preference for those amino acids containing aromatic or branched hydrocarbon chains are called carboxypeptidase A (A for aromatic/aliphatic).

• Carboxypeptidase A usually refers to the pancreatic exopeptidase that hydrolyzes peptide bonds of C-terminal residues with aromatic or aliphatic side-chains. Most scientists in the field now refer to this enzyme as CPA1, and to a related pancreatic carboxypeptidase as CPA2.
• In addition, there are 4 other mammalian enzymes named CPA-3 through CPA-6, and none of these are expressed in the pancreas. Instead, these other CPA-like enzymes have diverse functions.
  • CPA3 (also known as mast-cell CPA) is involved in the digestion of proteins by mast cells.
  • CPA4 (previously known as CPA-3, but renumbered when mast-cell CPA was designated CPA-3) may be involved in tumor progression, but this enzyme has not been well studied.
  • CPA5 has not been well studied.
  • CPA6 is expressed in many tissues during mouse development, and in adult shows a more limited distribution in brain and several other tissues. CPA6 is present in the extracellular matrix where it is enzymatically active. A human mutation of CPA-6 has been linked to Duane’s syndrome (abnormal eye movement). Recently, mutations in CPA6 were found to be linked to epilepsy. CPA6 is also one of several enzymes which degrade enkephalins.
• CPA-1 and CPA-2 (and, it is presumed, all other CPAs) employ a zinc ion within the protein for hydrolysis of the peptide bond at the C-terminal end of an amino acid residue. Loss of the zinc leads to loss of activity, which can be replaced easily by zinc, and also by some other divalent metals (cobalt, nickel). Carboxypeptidase A is produced in the pancreas and is crucial to many processes in the human body to include digestion, post-translational modification of proteins, blood clotting, and reproduction.
• This vast scope of functionality for a single protein makes it the ideal model for research regarding other zinc proteases of unknown structure. Recent biomedical research on collagenase, enkephalinase, and angiotensin-converting enzyme used carboxypeptidase A for inhibitor synthesis and kinetic testing. For example, a drug that treats high blood pressure, Captopril, was designed based on a carboxypeptidase A inhibitor. Carboxypeptidase A and the target enzyme of Captopril, angiotensin-converting enzyme, have very similar structures, as they both contain a zinc ion within the active site. This allowed for a potent carboxypeptidase A inhibitor to be used to inhibit the enzyme and, thus, lower blood pressure through the renin-angiotensin-aldosterone system.^{[Christianson DW, Lipscomb WN (February 1989). “Carboxypeptidase A”. Accounts of Chemical Research. 22 (2): 62–9. doi:10.1021/ar00158a003.]}
• Carboxypeptidase A (CPA) contains a zinc (Zn²⁺) metal center in a tetrahedral geometry with amino acid residues in close proximity around zinc to facilitate catalysis and binding. Out of the 307 amino acids bonded in a peptide chain, the following amino acid residues are important for catalysis and binding; Glu-270, Arg-71, Arg-127, Asn-144, Arg-145, and Tyr-248. Figure 1 illustrates the tetrahedral zinc complex active site with the important amino acid residues that surround the complex.^{[Christianson, D., W., and Lipscomb, W., N. (1989) Carboxypeptidase A. American Chemical Society, Vol (22): 62-69.]}
• The zinc metal is a strong electrophilic Lewis acid catalyst which stabilizes a coordinated water molecule as well as stabilizes the negative intermediates that occur throughout the hydrolytic reaction. Stabilization of both the coordinated water molecule and negative intermediates are assisted by polar residues in the active site which are in close proximity to facilitate hydrogen bonding.^{[Christianson, D., W., and Lipscomb, W., N. (1989) Carboxypeptidase A. American Chemical Society, Vol (22): 62-69.]}
• The active site can be characterized into two sub-sites denoted as S₁’ and S₁. The S₁’ sub-site is the hydrophobic pocket of the enzyme, and Tyr-248 acts to ‘cap’ the hydrophobic pocket after substrate or inhibitor is bound (SITE).^{[Christianson, D., W., and Lipscomb, W., N. (1989) Carboxypeptidase A. American Chemical Society, Vol (22): 62-69.]} The hydrogen bonding from the hydroxyl group in Tyr-248 facilitates this conformation due to interaction with the terminal carboxylates of substrates that bind. Substantial movement is required for this enzyme and induced fit model explains how this interaction occurs.
• A triad of residues interact to the C-terminal carboxylate through hydrogen bonding:
  • Salt linkage with positively charged Arg-145
  • Hydrogen bond from Tyr-248
  • Hydrogen bond from the nitrogen of the Asn-144 amide
• Classified as a metalloexopeptidase, carboxypeptidase A consists of a single polypeptide chain bound to a zinc ion. This characteristic metal ion is located within the active site of the enzyme, along with five amino acid residues that are involved in substrate binding: Arg-71, Arg-127, Asn-144, Arg-145, Tyr-248, and Glu-270. X-ray crystallographic studies have revealed five subsites on the protein. These allosteric sites are involved in creating the ligand-enzyme specificity seen in most bioactive enzymes. One of these subsites induces a conformational change at Tyr-248 upon binding of a substrate molecule at the primary active site. The phenolic hydroxyl of tyrosine forms a hydrogen bond with the terminal carboxylate of the ligand. In addition, a second hydrogen bond is formed between the tyrosine and a peptide linkage of longer peptide substrates. These changes make the bond between the enzyme and ligand, whether it is substrate or inhibitor, much stronger. This property of carboxypeptidase A led to the first clause of Daniel E. Koshland, Jr.’s “induced fit” hypothesis.
• The S₁ sub-site is where catalysis occurs in CPA, and the zinc ion is coordinated by Glu-72, His-69, and His-196 enzyme residues. A plane exists that bisects the active-site groove where residues Glu-270 and Arg-127 are on opposite sides of the zinc-water coupled complex. The zinc is electron rich due to glutamine ligands coordinating the zinc because before substrate binds, Glu-72 coordinates bidentate but shifts to monodentate after substrate binds. As a result, the zinc metal is not able to deprotonate the coordinated water molecule to make a hydroxyl nucleophile.^{[Christianson, D., W., and Lipscomb, W., N. (1989) Carboxypeptidase A. American Chemical Society, Vol (22): 62-69.]}
• Glu-270 and Arg-127 play an important role in catalysis. Arg-127 acts to stabilize the carbonyl of the substrate that is bound to amino group of phenylalanine. Simultaneously, the water molecule coordinated to zinc is deprotonated by Glu-270 and interacts with the carbonyl stabilized by Arg-127. This creates an intermediate where the negatively charged oxygen is coordinated to zinc, and through unfavorable electrostatic interactions between Glu-270 and the ionized product facilitates the release of the product at the end of catalysis.^{[Christianson, D., W., and Lipscomb, W., N. (1989) Carboxypeptidase A. American Chemical Society, Vol (22): 62-69.]}
• In recent computational studies, the mechanism of catalysis is similar but the difference in mechanism is that deprotonated water molecule binds to the carbon of the carbonyl, whereas Figure 2 shows the hydroxyl group stays coordinated to zinc. Then proteolysis occurs and the water molecule is then introduced back into the active site to coordinate to zinc.^{[Valdez CE, Morgenstern A, Eberhart ME, Alexandrova AN (November 2016). “Predictive methods for computational metalloenzyme redesign – a test case with carboxypeptidase A”. Physical Chemistry Chemical Physics. 18 (46): 31744–31756. Bibcode:2016PCCP…1831744V. doi:10.1039/c6cp02247b. PMID 27841396. S2CID 3545851.]}
• Several studies have been conducted exploring the details of the bond between carboxypeptidase A and substrate and how this affects the rate of hydrolysis. In 1934, it was first discovered through kinetic experiments that, in order for substrate to bind, the peptide that is to be hydrolyzed must be adjacent to a terminal free hydroxyl group. Also, the rate of hydrolysis can be enhanced if the C-terminal residue is branched aliphatic or aromatic. However, if the substrate is a dipeptide with a free amino group, it undergoes hydrolysis slowly; this, however, can be avoided if the amino group is blocked by N-acylation.^{[Lipscomb WN (March 1970). “Structure and mechanism in the enzymic activity of carboxypeptidase A and relations to chemical sequence”. Accounts of Chemical Research. 3 (3): 81–9. doi:10.1021/ar50027a001.]}
• It is quite clear that the structure of the enzyme, to be specific the active site, is very important in understanding the mechanism of reaction. For this reason, Rees and colleagues studied the enzyme-ligand complex to get a clear answer for the role of the zinc ion. These studies found that, in free enzyme, the zinc coordination number is five; the metal center is coordinated with two imidazole Nδ1 nitrogens, the two carboxylate oxygens of glutamate-72, and a water molecule to form a distorted tetrahedral. However, once ligand binds at the active site of carboxypeptidase A, this coordination number can vary from five to six. When bound to dipeptide glycyl-L-tyrosine, the amino nitrogen of the dipeptide and the carbonyl oxygen replaced the water ligand. This would yield a coordination number of six for the zinc in the carboxypeptidase A- dipeptide glycyl-L-tyrosine complex. Electron density maps gave evidence that the amino nitrogen occupies a second position near glutamate-270. The closeness of these two residues would result in a steric hindrance preventing the water ligand from coordinating with zinc. This would result in a coordination number of five. Data for both are substantial, indicating that both situations occur naturally.^{[Rees DC, Lewis M, Honzatko RB, Lipscomb WN, Hardman KD (June 1981). “Zinc environment and cis peptide bonds in carboxypeptidase A at 1.75-A resolution”. Proceedings of the National Academy of Sciences of the United States of America. 78 (6): 3408–12. Bibcode:1981PNAS…78.3408R. doi:10.1073/pnas.78.6.3408. PMC 319577. PMID 6943549.]}
• There are two proposed mechanisms for the catalytic function of carboxypeptidase A. The first is a nucleophilic pathway involving a covalent acyl enzyme intermediate containing active site base Glu-270. Evidence for this anhydride intermediate is mixed; Suh and colleagues isolated what is assumed to by the acyl intermediate. However, confirmation of the acyl enzyme was done without trapping experiments, making the conclusions weak.^{[Christianson DW, Lipscomb WN (February 1989). “Carboxypeptidase A”. Accounts of Chemical Research. 22 (2): 62–9. doi:10.1021/ar00158a003.]}
• The second proposed mechanism is a promoted water pathway. This mechanism involves attack of a water molecule at the scissile peptide linkage of the substrate. This process is promoted by the zinc ion and assisted by residue Glu-270.^{[Christianson DW, Lipscomb WN (February 1989). “Carboxypeptidase A”. Accounts of Chemical Research. 22 (2): 62–9. doi:10.1021/ar00158a003.]}
• See also
  • Carboxypeptidase A inhibitor
  • Carboxypeptidase B
  • Carboxypeptidase
  • Carboxypeptidase E
• The MEROPS online database for peptidases and their inhibitors: M14.001
• Carboxypeptidases+A at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

Carboxypeptidases that cleave positively charged amino acids (arginine, lysine) are called carboxypeptidase B (B for basic).

• Carboxypeptidase B (EC3.4.17.2, protaminase, pancreatic carboxypeptidase B, tissue carboxypeptidase B, peptidyl-L-lysine [L-arginine]hydrolase) is a carboxypeptidase that preferentially acts upon basic amino acids, such as arginine and lysine.^{[Folk JE (1970). “Carboxypeptidase B (porcine pancreas)”. Methods Enzymol. 19: 504–508. doi:10.1016/0076-6879(70)19036-7.][Brodrick JW, Geokas MC, Largman C (December 1976). “Human carboxypeptidase B. II. Purification of the enzyme from pancreatic tissue and comparison with the enzymes present in pancreatic secretion”. Biochimica et Biophysica Acta (BBA) – Enzymology. 452 (2): 468–81. doi:10.1016/0005-2744(76)90197-2. PMID 1009123.][Butterworth J, Duncan JJ (September 1979). “Carboxypeptidase B activity of cultured skin fibroblasts and relationship to cystic fibrosis”. Clinica Chimica Acta; International Journal of Clinical Chemistry. 97 (1): 39–43. doi:10.1016/0009-8981(79)90023-8. PMID 40714.][Wallace EF, Evans CJ, Jurik SM, Mefford IN, Barchas JD (1982). “Carboxypeptidase B activity from adrenal medulla–is it involved in the processing of proenkephalin?”. Life Sciences. 31 (16–17): 1793–6. doi:10.1016/0024-3205(82)90212-0. PMID 6130442.]} 
• This serum enzyme is also responsible for rapidly metabolizing the C5aprotein into C5a des-Arg, with one less amino acid.
  • C5a is an anaphylatoxin, causing increased expression of adhesion molecules on endothelium, contraction of smooth muscle, and increased vascular permeability. C5a des-Arg is a much less potent anaphylatoxin. Both C5a and C5a des-Arg can trigger mast cell degranulation, releasing proinflammatory molecules histamine and TNF-α. C5a is also an effective chemoattractant,^{[Seow V, Lim J, Cotterell AJ, Yau MK, Xu W, Lohman RJ, et al. (April 2016). “Receptor residence time trumps drug-likeness and oral bioavailability in determining efficacy of complement C5a antagonists”. Scientific Reports. 6 (1): 24575. doi:10.1038/srep24575. PMC 4837355. PMID 27094554.]} initiating accumulation of complement and phagocytic cells at sites of infection or recruitment of antigen-presenting cells to lymph nodes.^{[Gerard NP, Gerard C (February 1991). “The chemotactic receptor for human C5a anaphylatoxin”. Nature. 349 (6310): 614–617. doi:10.1038/349614a0. PMID 1847994. S2CID 4338594.]} C5a plays a key role in increasing migration and adherence of neutrophils and monocytes to vessel walls. White blood cells are activated by upregulation of integrinavidity, the lipoxygenase pathway and arachidonic acid metabolism. C5a also modulates the balance between activating versus inhibitory IgGFc receptors on leukocytes, thereby enhancing the autoimmune response.^{[Manthey HD, Woodruff TM, Taylor SM, Monk PN (November 2009). “Complement component 5a (C5a)”. The International Journal of Biochemistry & Cell Biology. 41 (11): 2114–2117. doi:10.1016/j.biocel.2009.04.005. PMID 19464229.]}
    • Anaphylatoxins are able to trigger degranulation (release of substances) of endothelial cells, mast cells or phagocytes, which produce a local inflammatory response. If the degranulation is widespread, it can cause a shock-like syndrome similar to that of an allergic reaction.
    • Anaphylatoxins indirectly mediate:
      • smooth muscle cells contraction, for example bronchospasms
      • increase in the permeability of blood capillaries
      • C5a indirectly mediates chemotaxis—receptor-mediated movement of leukocytes in the direction of the increasing concentration of anaphylatoxins
    • Important anaphylatoxins:
      • C5a has the highest specific biological activity and is able to act directly on neutrophils and monocytes to speed up the phagocytosis of pathogens.
      • C3a works with C5a to activate mast cells, recruit antibody, complement and phagocytic cells and increase fluid in the tissue, all of which contribute to the initiation of the adaptive immune response.
      • C4a is the least active anaphylatoxin.
    • Although some drugs (morphine, codeine, synthetic ACTH) and some neurotransmitters (norepinephrine, substance P) are important mediators of degranulation of mast cells or basophils, they are generally not called anaphylatoxins. This term is reserved only for fragments of the complement system.
    • See also
      • Allergy
      • Anaphylatoxin receptors
      • Anaphylaxis
      • Complement system
      • Inflammation
      • Immune system
      • Nervous system
    • Further reading
      • Gerard C, Gerard NP (1994). “C5A anaphylatoxin and its seven transmembrane-segment receptor”. Annual Review of Immunology. 12: 775–808. doi:10.1146/annurev.iy.12.040194.004015. PMID 8011297.
      • Pan ZK (November 1998). “Anaphylatoxins C5a and C3a induce nuclear factor kappaB activation in human peripheral blood monocytes”. Biochimica et Biophysica Acta (BBA) – Gene Structure and Expression. 1443 (1–2): 90–8. doi:10.1016/S0167-4781(98)00198-5. PMID 9838061.
      • Anaphylatoxin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  • C5a is a powerful inflammatory mediator, and seems to be a key factor in the development of pathology of many inflammatory diseases involving the complement system such as sepsis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythemotosis, psoriasis. The inhibitor of C5a that can block its effects would be helpful in medical applications. Another candidate is PMX53 or PMX205 that is highly specific for CD88 and effectively reduces inflammatory response.^{[Woodruff TM, Crane JW, Proctor LM, Buller KM, Shek AB, de Vos K, et al. (July 2006). “Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration”. FASEB Journal. 20 (9): 1407–1417. doi:10.1096/fj.05-5814com. PMID 16816116. S2CID 9206660.][Jain U, Woodruff TM, Stadnyk AW (January 2013). “The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10”. British Journal of Pharmacology. 168 (2): 488–501. doi:10.1111/j.1476-5381.2012.02183.x. PMC 3572573. PMID 22924972.]} C5a has been identified as a key mediator of neutrophil dysfunction in sepsis, with antibody blockade of C5a improving outcomes in experimental models.^{[Huber-Lang MS, Younkin EM, Sarma JV, McGuire SR, Lu KT, Guo RF, et al. (September 2002). “Complement-induced impairment of innate immunity during sepsis”. Journal of Immunology. 169 (6): 3223–3231. doi:10.4049/jimmunol.169.6.3223. PMID 12218141.]} This has also been shown in humans,^{[Conway Morris A, Kefala K, Wilkinson TS, Dhaliwal K, Farrell L, Walsh T, et al. (July 2009). “C5a mediates peripheral blood neutrophil dysfunction in critically ill patients”. American Journal of Respiratory and Critical Care Medicine. 180 (1): 19–28. doi:10.1164/rccm.200812-1928OC. PMC 2948533. PMID 19324972.]} with C5a-mediated neutrophil dysfunction predicting subsequent nosocomial infection^{[Morris AC, Brittan M, Wilkinson TS, McAuley DF, Antonelli J, McCulloch C, et al. (May 2011). “C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients”. Blood. 117 (19): 5178–5188. doi:10.1182/blood-2010-08-304667. PMID 21292772.][Conway Morris A, Datta D, Shankar-Hari M, Stephen J, Weir CJ, Rennie J, et al. (May 2018). “Cell-surface signatures of immune dysfunction risk-stratify critically ill patients: INFECT study”. Intensive Care Medicine. 44 (5): 627–635. doi:10.1007/s00134-018-5247-0. PMC 6006236. PMID 29915941.]} and death from sepsis.^{[Conway Morris A, Anderson N, Brittan M, Wilkinson TS, McAuley DF, Antonelli J, et al. (November 2013). “Combined dysfunctions of immune cells predict nosocomial infection in critically ill patients”. British Journal of Anaesthesia. 111 (5): 778–787. doi:10.1093/bja/aet205. PMID 23756248][Unnewehr H, Rittirsch D, Sarma JV, Zetoune F, Flierl MA, Perl M, et al. (April 2013). “Changes and regulation of the C5a receptor on neutrophils during septic shock in humans”. Journal of Immunology. 190 (8): 4215–4225. doi:10.4049/jimmunol.1200534. PMID 23479227.]} 
  • Recent data demonstrates that C5a not only impairs phagocytosis by neutrophils but also impairs phagosomal maturation,^{[Wood AJ, Vassallo AM, Ruchaud-Sparagano MH, Scott J, Zinnato C, Gonzalez-Tejedo C, et al. (August 2020). “C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodeling”. JCI Insight. 5 (15). doi:10.1172/jci.insight.137029. PMC 7455072. PMID 32634128.]} inducing a marked alteration in the neutrophil phosphoproteomic response to bacterial targets. C5a binding to C5aR1 and C5aR2 (C5L2) mediates the formation of neutrophil extracellular traps and release of cytotoxic histones to the extracellular space, which is believed to act as a pathogenetic process of acute respiratory distress syndrome (ARDS)^{[Bosmann M, Grailer JJ, Ruemmler R, Russkamp NF, Zetoune FS, Sarma JV, et al. (December 2013). “Extracellular histones are essential effectors of C5aR- and C5L2-mediated tissue damage and inflammation in acute lung injury”. FASEB Journal. 27 (12): 5010–5021. doi:10.1096/fj.13-236380. PMC 3834784. PMID 23982144.]} and promote tumor growth and metastasis.^{[Ortiz-Espinosa S, Morales X, Senent Y, Alignani D, Tavira B, Macaya I, et al. (March 2022). “Complement C5a induces the formation of neutrophil extracellular traps by myeloid-derived suppressor cells to promote metastasis”. Cancer Letters. 529: 70–84. doi:10.1016/j.canlet.2021.12.027. PMID 34971753.]}
• The MEROPS online database for peptidases and their inhibitors: M14.003
• Carboxypeptidase+B at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

A metallo-carboxypeptidase that cleaves a C-terminal glutamate from the peptide N-acetyl-L-aspartyl-L-glutamate is called “glutamate carboxypeptidase“.

• Glutamate carboxypeptidase (EC 3.4.17.11, carboxypeptidase G, carboxypeptidase G1, carboxypeptidase G2, glutamyl carboxypeptidase, N-pteroyl-L-glutamate hydrolase) is an enzyme.^{[Goldman P, Levy CC (October 1967). “Carboxypeptidase G: purification and properties”. Proceedings of the National Academy of Sciences of the United States of America. 58 (4): 1299–306. Bibcode:1967PNAS…58.1299G. doi:10.1073/pnas.58.4.1299. PMC 223923. PMID 5237864][McCullough JL, Chabner BA, Bertino JR (December 1971). “Purification and properties of carboxypeptidase G 1”. The Journal of Biological Chemistry. 246 (23): 7207–13. doi:10.1016/S0021-9258(19)45873-0. PMID 5129727.][Albrecht AM, Boldizsar E, Hutchison DJ (May 1978). “Carboxypeptidase displaying differential velocity in hydrolysis of methotrexate, 5-methyltetrahydrofolic acid, and leucovorin”. Journal of Bacteriology. 134 (2): 506–13. doi:10.1128/jb.134.2.506-513.1978. PMC 222280. PMID 26657.][Sherwood RF, Melton RG, Alwan SM, Hughes P (May 1985). “Purification and properties of carboxypeptidase G2 from Pseudomonas sp. strain RS-16. Use of a novel triazine dye affinity method”. European Journal of Biochemistry. 148 (3): 447–53. doi:10.1111/j.1432-1033.1985.tb08860.x. PMID 3838935.]} 
• This enzyme catalyses the following chemical reaction
  • Release of C-terminalglutamate residues from a wide range of N-acylating moieties, including peptidyl, aminoacyl, benzoyl, benzyloxycarbonyl, folyl and pteroyl groups
• This zinc enzyme is produced by pseudomonads, Flavobacterium sp. and Acinetobacter sp.
• Glutamate+carboxypeptidase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• See also Glutamate carboxypeptidase II

A serine carboxypeptidase that cleaves the C-terminal residue from peptides containing the sequence -Pro-Xaa (Pro is proline, Xaa is any amino acid on the C-terminus of a peptide) is called “prolyl carboxypeptidase“.

• Lysosomal Pro-Xaa carboxypeptidase (EC 3.4.16.2, angiotensinase C, lysosomal carboxypeptidase C, peptidylprolylamino acid carboxypeptidase, aminoacylproline carboxypeptidase, prolyl carboxypeptidase, carboxypeptidase P, proline-specific carboxypeptidase P, PCP) is an enzyme.^{[Odya CE, Erdös EG (1981). “Human prolylcarboxypeptidase”. Methods in Enzymology. 80 Pt C: 460–6. doi:10.1016/s0076-6879(81)80040-7. PMID 7341916.][ Walter R, Simmons WH, Yoshimoto T (April 1980). “Proline specific endo- and exopeptidases”. Molecular and Cellular Biochemistry. 30 (2): 111–27. doi:10.1007/bf00227927. PMID 6991912.]} 
• This enzyme catalyses the following chemical reaction
  • Cleavage of a -Pro-Xaa bond to release a C-terminal amino acid
• A lysosomal peptidase active at acidic pH that inactivates angiotensin II. This enzyme is inhibited by diisopropyl fluorophosphate.
• Lysosomal+Pro-Xaa+carboxypeptidase at the U.S. National Library of Medicine Medical Subject Headings (MeSH) human prolylcarboxypeptidase entry at OMIM: http://omim.org/entry/176785

Activation

Some, but not all, carboxypeptidases are initially produced in an inactive form; this precursor form is referred to as a procarboxypeptidase. In the case of pancreatic carboxypeptidase A, the inactive zymogen form – pro-carboxypeptidase A – is converted to its active form – carboxypeptidase A – by the enzyme trypsin. This mechanism ensures that the cells wherein pro-carboxypeptidase A is produced are not themselves digested.

See also

• Carboxypeptidase E
• Carboxypeptidase A
• Enzyme category EC number 3.4
• Thrombin-activatable fibrinolysis inhibitor aka plasma carboxypeptidase B2
• bacterial transpeptidase, an alanine carboxypeptidase
• bradykinin is broken down among other enzymes by carboxypeptidase N
• D-Ala carboxypeptidase is a penicillin-binding protein
• Phenylalanine might inhibit carboxypeptidase A
• Martha L. Ludwig

Further reading

• Klusák V, Barinka C, Plechanovová A, Mlcochová P, Konvalinka J, Rulísek L, Lubkowski J (May 2009). “Reaction mechanism of glutamate carboxypeptidase II revealed by mutagenesis, X-ray crystallography, and computational methods”. Biochemistry. 48 (19): 4126–4138. doi:10.1021/bi900220s. PMC 7289149. PMID 19301871.

External links

• Carboxypeptidases at the US National Library of Medicine Medical Subject Headings (MeSH)

Hydrolase: proteases (EC 3.4)

Categories: 

• Proteins
• Enzymes
• Metabolism