• protein localization to membrane • insulin processing • cardiac left ventricle morphogenesis • Wnt signaling pathway • proteolysis • cellular protein modification process • metabolism • neuropeptide signaling pathway • peptide metabolic process • protein processing • peptide hormone secretion • protein localization to secretory granule
Sources:Amigo / QuickGO
Orthologs
Species
Human
Mouse
Entrez
1363
12876
Ensembl
ENSG00000109472
ENSMUSG00000037852
UniProt
P16870
Q00493
RefSeq (mRNA)
NM_001873
NM_013494
RefSeq (protein)
NP_001864
NP_038522
Location (UCSC)
Chr 4: 165.36 – 165.5 Mb
Chr 8: 64.59 – 64.69 Mb
PubMed search
[3]
[4]
Wikidata
View/Edit Human
View/Edit Mouse
Carboxypeptidase E (CPE), also known as carboxypeptidase H (CPH) and enkephalin convertase, is an enzyme that in humans is encoded by the CPE gene[5]. This enzyme catalyzes the release of C-terminal arginine or lysine residues from polypeptides.
CPE is involved in the biosynthesis of most neuropeptides and peptide hormones.[6] 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.[7]
Contents
1Tissue distribution
2Species distribution
3Function
4Clinical significance
5See also
6References
7Further reading
8External links
Tissue distribution
Carboxypeptidase E is found in brain and throughout the neuroendocrine system, including the endocrine pancreas, pituitary, and adrenal gland chromaffin 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 CPE gene.[5][8]
Function
Carboxypeptidase E
Identifiers
EC number
3.4.17.10
CAS number
81876-95-1
Databases
IntEnz
IntEnz view
BRENDA
BRENDA entry
ExPASy
NiceZyme view
KEGG
KEGG entry
MetaCyc
metabolic pathway
PRIAM
profile
PDB structures
RCSB PDB PDBe PDBsum
Gene Ontology
AmiGO / QuickGO
Search
PMC
articles
PubMed
articles
NCBI
proteins
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.[9] 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.[10] 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.[11] 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).[12] 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.
See also
Carboxypeptidase
Carboxypeptidase A
References
^ abcGRCh38: Ensembl release 89: ENSG00000109472 - Ensembl, May 2017
^ abcGRCm38: Ensembl release 89: ENSMUSG00000037852 - Ensembl, May 2017
^Fricker LD (2012). "Chapter 3.5 Carboxypeptidase E". Neuropeptides and Other Bioactive Peptides: From Discovery to Function (Color Version). Colloquium Series on Neuropeptides. 1. Morgan & Claypool Life Sciences. pp. 1–92. doi:10.4199/C00056ED1V01Y201204NPE002. ISBN 978-1-61504-521-1.
^Manser E, Fernandez D, Loo L, Goh PY, Monfries C, Hall C, Lim L (April 1990). "Human carboxypeptidase E. Isolation and characterization of the cDNA, sequence conservation, expression and processing in vitro". The Biochemical Journal. 267 (2): 517–25. doi:10.1042/bj2670517. PMC 1131319. PMID 2334405.
^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. PMID 9019408.
^Naggert JK, Fricker LD, Varlamov O, Nishina PM, Rouille Y, Steiner DF, Carroll RJ, Paigen BJ, Leiter EH (June 1995). "Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity". Nature Genetics. 10 (2): 135–42. doi:10.1038/ng0695-135. PMID 7663508.
^Alsters SI, Goldstone AP, Buxton JL, Zekavati A, Sosinsky A, Yiorkas AM, Holder S, Klaber RE, Bridges N, van Haelst MM, le Roux CW, Walley AJ, Walters RG, Mueller M, Blakemore AI (Jun 2015). "Truncating Homozygous Mutation of Carboxypeptidase E (CPE) in a Morbidly Obese Female with Type 2 Diabetes Mellitus, Intellectual Disability and Hypogonadotrophic Hypogonadism". PLOS ONE. 10 (6): e0131417. doi:10.1371/journal.pone.0131417. PMC 4485893. PMID 26120850.
^Jeffrey KD, Alejandro EU, Luciani DS, Kalynyak TB, Hu X, Li H, Lin Y, Townsend RR, Polonsky KS, Johnson JD (June 2008). "Carboxypeptidase E mediates palmitate-induced beta-cell ER stress and apoptosis". Proceedings of the National Academy of Sciences of the United States of America. 105 (24): 8452–7. doi:10.1073/pnas.0711232105. PMC 2448857. PMID 18550819.
Goodge KA, Hutton JC (August 2000). "Translational regulation of proinsulin biosynthesis and proinsulin conversion in the pancreatic beta-cell". Seminars in Cell & Developmental Biology. 11 (4): 235–42. doi:10.1006/scdb.2000.0172. PMID 10966857.
Beinfeld MC (January 2003). "Biosynthesis and processing of pro CCK: recent progress and future challenges". Life Sciences. 72 (7): 747–57. doi:10.1016/S0024-3205(02)02330-5. PMID 12479974.
Fricker LD, Snyder SH (June 1982). "Enkephalin convertase: purification and characterization of a specific enkephalin-synthesizing carboxypeptidase localized to adrenal chromaffin granules". Proceedings of the National Academy of Sciences of the United States of America. 79 (12): 3886–90. doi:10.1073/pnas.79.12.3886. PMC 346533. PMID 6808517.
O'Rahilly S, Gray H, Humphreys PJ, Krook A, Polonsky KS, White A, Gibson S, Taylor K, Carr C (November 1995). "Brief report: impaired processing of prohormones associated with abnormalities of glucose homeostasis and adrenal function". The New England Journal of Medicine. 333 (21): 1386–90. doi:10.1056/NEJM199511233332104. PMID 7477119.
Naggert JK, Fricker LD, Varlamov O, Nishina PM, Rouille Y, Steiner DF, Carroll RJ, Paigen BJ, Leiter EH (June 1995). "Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity". Nature Genetics. 10 (2): 135–42. doi:10.1038/ng0695-135. PMID 7663508.
Song L, Fricker L (July 1995). "Processing of procarboxypeptidase E into carboxypeptidase E occurs in secretory vesicles". Journal of Neurochemistry. 65 (1): 444–53. doi:10.1046/j.1471-4159.1995.65010444.x. PMID 7790890.
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. PMID 8449522.
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. PMID 8674818.
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. PMID 8770919.
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. PMID 8864828.
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. PMID 9019408.
Maeda K, Okubo K, Shimomura I, Mizuno K, Matsuzawa Y, Matsubara K (May 1997). "Analysis of an expression profile of genes in the human adipose tissue". Gene. 190 (2): 227–35. doi:10.1016/S0378-1119(96)00730-5. PMID 9197538.
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. PMID 9275097.
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. PMID 9662053.
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. PMID 9815277.
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. PMID 11373325.
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. CiteSeerX 10.1.1.521.1042. doi:10.1677/joe.0.1690595. PMID 11375130.
External links
The MEROPS online database for peptidases and their inhibitors: M14.005
Carboxypeptidase+E at the US National Library of Medicine Medical Subject Headings (MeSH)
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I'm trying to debug some problems with my Java code, which establishes a http/https connection. I'm wondering why the connection gets ridiculously slow (more than one minute for downloading a small web page) when debugging, even when stepping-over the method which does the network work. And if there is some remedy. Below I post an example (you can change https: to http: , and try debugging this from Eclipse pressing F11 - for stepping, place a breakpoint in the first main() statement, and press F6 when it pauses there. My results (time in milliseconds) : conn time total time http (not stepping) 60 350 http (stepping over) 1100 1500 https (not stepping) 570 1300 https (stepping over) 21000 83000
