Carboxypeptidase E (CPE), also known as carboxypeptidase H (CPH) and enkephalin convertase, is an enzyme that in humans is encoded by the CPEgene[1]. This enzyme catalyzes the release of C-terminalarginine or lysine residues from polypeptides.
CPE is involved in the biosynthesis of most neuropeptides and peptide hormones.[2] The production of neuropeptides and peptide hormones typically requires two sets of enzymes that cleave the peptide precursors, which are small proteins. First, proprotein convertases cut the precursor at specific sites to generate intermediates containing C-terminal basic residues (lysine and/or arginine). These intermediates are then cleaved by CPE to remove the basic residues. For some peptides, additional processing steps, such as C-terminal amidation, are subsequently required to generate the bioactive peptide, although for many peptides the action of the proprotein convertases and CPE is sufficient to produce the bioactive peptide.[3]
Carboxypeptidase E is found in brain and throughout the neuroendocrine system, including the endocrine pancreas, pituitary, and adrenal glandchromaffin cells. Within cells, carboxypeptidase E is present in the secretory granules along with its peptide substrates and products. Carboxypeptidase E is a glycoprotein that exists in both membrane-associated and soluble forms. The membrane-binding is due to an amphiphilic α-helix within the C-terminal region of the protein.
Species distribution
Carboxypeptidase E is found in all species of vertebrates that have been examined, and is also present in many other organisms that have been studied (nematode, sea slug). Carboxypeptidase E is not found in the fruit fly (Drosophila), and another enzyme (presumably carboxypeptidase D) fills in for carboxypeptidase E in this organism. In humans, CPE is encoded by the CPEgene.[1][4]
Carboxypeptidase E functions in the production of nearly all neuropeptides and peptide hormones. The enzyme acts as an exopeptidase to activate neuropeptides. It does that by cleaving off basic C-terminal amino acids, producing the active form of the peptide. Products of carboxypeptidase E include insulin, the enkephalins, vasopressin, oxytocin, and most other neuroendocrine peptide hormones and neuropeptides.
It has been proposed that membrane-associated carboxypeptidase E acts as a sorting signal for regulated secretory proteins in the trans-Golgi network of the pituitary and in secretory granules; regulated secretory proteins are mostly hormones and neuropeptides.[5] However, this role for carboxypeptidase E remains controversial, and evidence shows that this enzyme is not necessary for the sorting of regulated secretory proteins.
Clinical significance
Mice with mutant carboxypeptidase E, Cpefat, display endocrine disorders like obesity and infertility.[6] In some strains of mice, the fat mutation also causes hyperproinsulinemia in adult male mice, but this is not found in all strains of mice. The obesity and infertility in the Cpefat mice develop with age; young mice (<8 weeks of age) are fertile and have normal body weight. Peptide processing in Cpefat mice is impaired, with a large accumulation of peptides with C-terminal lysine and/or arginine extensions. Levels of the mature forms of peptides are generally reduced in these mice, but not completely eliminated. It is thought that a related enzyme (carboxypeptidase D) also contributes to neuropeptide processing and gives rise to the mature peptides in the Cpefat mice.
Mutations in the CPE gene are not common within the human population, but have been identified. One patient with extreme obesity (Body Mass Index >50) was found to have a mutation that deleted nearly the entire CPE gene.[7] This patient had intellectual disability (inability to read or write) and had abnormal glucose homeostasis, similar to mice lacking CPE activity.
In obesity, high levels of circulating free fatty acids have been reported to cause a decrease in the amount of carboxypeptidase E protein in pancreatic beta-cells, leading to beta-cell dysfunction (hyperproinsulinemia) and increased beta-cell apoptosis (via an increase in ER-stress).[8] However, because CPE is not a rate-limiting enzyme for the production of most neuropeptides and peptide hormones, it is not clear how relatively modest decreases in CPE activity can cause physiological effects.
↑Fricker LD (2012). "Chapter 3.5 Carboxypeptidase E". Neuropeptides and Other Bioactive Peptides: From Discovery to Function (Color Version). Morgan & Claypool Life Sciences. doi:10.4199/C00056ED1V01Y201204NPE002. ISBN1-61504-521-X.
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Hall C, Manser E, Spurr NK, Lim L (February 1993). "Assignment of the human carboxypeptidase E (CPE) gene to chromosome 4". Genomics. 15 (2): 461–3. doi:10.1006/geno.1993.1093. PMID8449522.
Guest PC, Arden SD, Rutherford NG, Hutton JC (August 1995). "The post-translational processing and intracellular sorting of carboxypeptidase H in the islets of Langerhans". Molecular and Cellular Endocrinology. 113 (1): 99–108. doi:10.1016/0303-7207(95)03619-I. PMID8674818.
Rovere C, Viale A, Nahon J, Kitabgi P (July 1996). "Impaired processing of brain proneurotensin and promelanin-concentrating hormone in obese fat/fat mice". Endocrinology. 137 (7): 2954–8. doi:10.1210/en.137.7.2954. PMID8770919.
Alcalde L, Tonacchera M, Costagliola S, Jaraquemada D, Pujol-Borrell R, Ludgate M (August 1996). "Cloning of candidate autoantigen carboxypeptidase H from a human islet library: sequence identity with human brain CPH". Journal of Autoimmunity. 9 (4): 525–8. doi:10.1006/jaut.1996.0070. PMID8864828.
Cool DR, Normant E, Shen F, Chen HC, Pannell L, Zhang Y, Loh YP (January 1997). "Carboxypeptidase E is a regulated secretory pathway sorting receptor: genetic obliteration leads to endocrine disorders in Cpe(fat) mice". Cell. 88 (1): 73–83. doi:10.1016/S0092-8674(00)81860-7. PMID9019408.
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Cain BM, Wang W, Beinfeld MC (September 1997). "Cholecystokinin (CCK) levels are greatly reduced in the brains but not the duodenums of Cpe(fat)/Cpe(fat) mice: a regional difference in the involvement of carboxypeptidase E (Cpe) in pro-CCK processing". Endocrinology. 138 (9): 4034–7. doi:10.1210/en.138.9.4034. PMID9275097.
Utsunomiya N, Ohagi S, Sanke T, Tatsuta H, Hanabusa T, Nanjo K (June 1998). "Organization of the human carboxypeptidase E gene and molecular scanning for mutations in Japanese subjects with NIDDM or obesity". Diabetologia. 41 (6): 701–5. doi:10.1007/s001250050971. PMID9662053.
Reznik SE, Salafia CM, Lage JM, Fricker LD (December 1998). "Immunohistochemical localization of carboxypeptidases E and D in the human placenta and umbilical cord". The Journal of Histochemistry and Cytochemistry. 46 (12): 1359–68. doi:10.1177/002215549804601204. PMID9815277.
Fan X, Olson SJ, Johnson MD (June 2001). "Immunohistochemical localization and comparison of carboxypeptidases D, E, and Z, alpha-MSH, ACTH, and MIB-1 between human anterior and corticotroph cell "basophil invasion" of the posterior pituitary". The Journal of Histochemistry and Cytochemistry. 49 (6): 783–90. doi:10.1177/002215540104900612. PMID11373325.
Friis-Hansen L, Lacourse KA, Samuelson LC, Holst JJ (June 2001). "Attenuated processing of proglucagon and glucagon-like peptide-1 in carboxypeptidase E-deficient mice". The Journal of Endocrinology. 169 (3): 595–602. doi:10.1677/joe.0.1690595. PMID11375130.
External links
The MEROPS online database for peptidases and their inhibitors: M14.005