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I fixed minor error -- the enzyme was originally called enkephalin convertase (not "convertase" alone) -- see further reading reference Fricker and Snyder 1982 (I am Prof Fricker -- I know what I'm talking about).
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{{Short description|Enzyme found in humans}}
{{Infobox_gene}}
{{Infobox_gene}}
'''Carboxypeptidase E''' (CPE), also known as '''carboxypeptidase H''' (CPH) and '''enkephalin convertase''', is an [[enzyme]] that in humans is encoded by the ''CPE'' [[gene]]<ref name="entrez">{{cite web | title = Entrez Gene: CPE carboxypeptidase E| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1363| accessdate = }}</ref> This enzyme catalyzes the release of [[C-terminal]] [[arginine]] or [[lysine]] residues from [[polypeptide]]s.
'''Carboxypeptidase E''' ('''CPE'''), also known as '''carboxypeptidase H''' ('''CPH''') and '''enkephalin convertase''', is an [[enzyme]] that in humans is encoded by the ''CPE'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: CPE carboxypeptidase E| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1363}}</ref> This enzyme catalyzes the release of [[C-terminal]] [[arginine]] or [[lysine]] residues from [[polypeptide]]s.


CPE is involved in the biosynthesis of most [[neuropeptide]]s and [[peptide hormone]]s.<ref name="pmid2897826">{{cite journal | author = Fricker LD | title = Carboxypeptidase E | journal = Annu. Rev. Physiol. | volume = 50 | issue = | pages = 309–21 | year = 1988 | pmid = 2897826 | doi = 10.1146/annurev.ph.50.030188.001521 }}</ref> The production of neuropeptides and peptide hormones typically requires two sets of enzymes that cleave the peptide precursors, which are small proteins. First, [[proprotein convertase]]s 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.<ref name="isbn1-61504-521-X">{{cite book | author = Fricker LD | title = Neuropeptides and Other Bioactive Peptides: From Discovery to Function (Color Version) | publisher = Morgan & Claypool Life Sciences | location = | year = 2012 | isbn = 1-61504-521-X | oclc = | chapter = Chapter 3.5 Carboxypeptidase E | pages = | doi = 10.4199/C00056ED1V01Y201204NPE002 }}</ref>
CPE is involved in the biosynthesis of most [[neuropeptide]]s and [[peptide hormone]]s.<ref name="pmid2897826">{{cite journal | vauthors = Fricker LD | title = Carboxypeptidase E | journal = Annual Review of Physiology | volume = 50 | pages = 309–21 | year = 1988 | pmid = 2897826 | doi = 10.1146/annurev.ph.50.030188.001521 }}</ref> The production of neuropeptides and peptide hormones typically requires two sets of enzymes that cleave the peptide precursors, which are small proteins. First, [[proprotein convertase]]s 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.<ref name="isbn1-61504-521-X">{{cite book | author = Fricker LD | title = Neuropeptides and Other Bioactive Peptides: From Discovery to Function (Color Version) | journal = Colloquium Series on Neuropeptides | volume = 1 | issue = 2 | publisher = Morgan & Claypool Life Sciences | year = 2012 | isbn = 978-1-61504-521-1 | chapter = Chapter 3.5 Carboxypeptidase E | pages = 1–92| doi = 10.4199/C00056ED1V01Y201204NPE002 }}</ref>


== Tissue distribution ==
== Tissue distribution ==


Carboxypeptidase E is found in brain and throughout the neuroendocrine system, including the endocrine pancreas, pituitary, and [[adrenal gland]] [[chromaffin cell]]s. 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.
Carboxypeptidase E is found in brain and throughout the neuroendocrine system, including the [[endocrine pancreas]], pituitary, and [[adrenal gland]] [[chromaffin cell]]s. 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 ==
== 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]].<ref name="entrez"/><ref name="pmid2334405">{{cite journal | vauthors = Manser E, Fernandez D, Loo L, Goh PY, Monfries C, Hall C, Lim L | title = Human carboxypeptidase E. Isolation and characterization of the cDNA, sequence conservation, expression and processing in vitro | journal = Biochem J | volume = 267 | issue = 2 | pages = 517–25 |date=Jun 1990 | pmid = 2334405 | pmc = 1131319 | doi = }}</ref>
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]].<ref name="entrez"/><ref name="pmid2334405">{{cite journal | vauthors = Manser E, Fernandez D, Loo L, Goh PY, Monfries C, Hall C, Lim L | title = Human carboxypeptidase E. Isolation and characterization of the cDNA, sequence conservation, expression and processing in vitro | journal = The Biochemical Journal | volume = 267 | issue = 2 | pages = 517–25 | date = April 1990 | pmid = 2334405 | pmc = 1131319 | doi = 10.1042/bj2670517}}</ref>


== Function ==
== Function ==
{{Infobox enzyme|align=left
{{Infobox enzyme
| align = left
| Name = Carboxypeptidase E
| Name = Carboxypeptidase E
| EC_number = 3.4.17.10
| EC_number = 3.4.17.10
| CAS_number = 81876-95-1
| CAS_number = 81876-95-1
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| GO_code = GO:0004183
| IUBMB_EC_number = 3/4/17/10
| image =
⚫
| GO_code = GO:0004183
| image =
| width =
| width =
| caption =
| caption =
}}
}}
Carboxypeptidase E functions in the production of nearly all neuropeptides and peptide hormones. The enzyme acts as an [[exopeptidase]] to activate [[neuropeptide]]s. 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 [[enkephalin]]s, [[vasopressin]], [[oxytocin]], and most other neuroendocrine peptide hormones and neuropeptides.
Carboxypeptidase E functions in the production of nearly all neuropeptides and peptide hormones. The enzyme acts as an [[exopeptidase]] to activate [[neuropeptide]]s. 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 [[enkephalin]]s, [[vasopressin]], [[oxytocin]], and most other neuroendocrine peptide hormones and neuropeptides.


It has been proposed that membrane-associated carboxypeptidase E acts as a [[Protein targeting#Targeting signals|sorting signal]] for regulated secretory proteins in the [[Golgi apparatus|trans-Golgi network]] of the [[pituitary]] and in secretory granules; regulated secretory proteins are mostly [[hormone]]s and [[neuropeptide]]s.<ref>{{cite journal | vauthors=Cool DR, Normant E, Shen F |title=Carboxypeptidase E is a regulated secretory pathway sorting receptor: genetic obliteration leads to endocrine disorders in Cpe(fat) mice |journal=Cell |volume=88 |issue= 1 |pages= 73–83 |year= 1997 |pmid= 9019408 |doi=10.1016/S0092-8674(00)81860-7 |display-authors=etal}}</ref> However, this role for carboxypeptidase E remains controversial, and evidence shows that this enzyme is not necessary for the sorting of regulated secretory proteins.
It has been proposed that membrane-associated carboxypeptidase E acts as a [[Protein targeting#Targeting signals|sorting signal]] for regulated secretory proteins in the [[Golgi apparatus|trans-Golgi network]] of the [[pituitary]] and in secretory granules; regulated secretory proteins are mostly [[hormone]]s and [[neuropeptide]]s.<ref>{{cite journal | vauthors = Cool DR, Normant E, Shen F, Chen HC, Pannell L, Zhang Y, Loh YP | title = Carboxypeptidase E is a regulated secretory pathway sorting receptor: genetic obliteration leads to endocrine disorders in Cpe(fat) mice | journal = Cell | volume = 88 | issue = 1 | pages = 73–83 | date = January 1997 | pmid = 9019408 | doi = 10.1016/S0092-8674(00)81860-7 | s2cid = 18629145 | doi-access = free }}</ref> 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 ==
== Clinical significance ==


Mice with mutant carboxypeptidase E, Cpe<sup>fat</sup>, display [[endocrine]] disorders like [[obesity]] and [[infertility]].<ref>{{cite journal | vauthors=Naggert JK, Fricker LD, Varlamov O |title=Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity |journal=Nat. Genet. |volume=10 |issue= 2 |pages= 135–42 |year= 1995 |pmid= 7663508 |doi= 10.1038/ng0695-135 |display-authors=etal}}</ref> 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 Cpe<sup>fat</sup> mice develop with age; young mice (<8 weeks of age) are fertile and have normal body weight. Peptide processing in Cpe<sup>fat</sup> 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 Cpe<sup>fat</sup> mice.
Mice with mutant carboxypeptidase E, Cpe<sup>fat</sup>, display [[endocrine]] disorders like [[obesity]] and [[infertility]].<ref>{{cite journal | vauthors = Naggert JK, Fricker LD, Varlamov O, Nishina PM, Rouille Y, Steiner DF, Carroll RJ, Paigen BJ, Leiter EH | title = Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity | journal = Nature Genetics | volume = 10 | issue = 2 | pages = 135–42 | date = June 1995 | pmid = 7663508 | doi = 10.1038/ng0695-135 | s2cid = 19798125 }}</ref> 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 Cpe<sup>fat</sup> mice develop with age; young mice (<8 weeks of age) are fertile and have normal body weight. Peptide processing in Cpe<sup>fat</sup> 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 eliminated. It is thought that a related enzyme (carboxypeptidase D) also contributes to neuropeptide processing and gives rise to the mature peptides in the Cpe<sup>fat</sup> mice.


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).<ref name="pmid18550819">{{cite journal | vauthors = Jeffrey KD, Alejandro EU, Luciani DS, Kalynyak TB, Hu X, Li H, Lin Y, Townsend RR, Polonsky KS, Johnson JD | title = Carboxypeptidase E mediates palmitate-induced beta-cell ER stress and apoptosis | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 105 | issue = 24 | pages = 8452–7 |date=June 2008 | pmid = 18550819 | pmc = 2448857 | doi = 10.1073/pnas.0711232105 }}</ref> 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.
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.<ref name="Alsters_2015">{{cite journal | vauthors = 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 | title = Truncating Homozygous Mutation of Carboxypeptidase E (CPE) in a Morbidly Obese Female with Type 2 Diabetes Mellitus, Intellectual Disability and Hypogonadotrophic Hypogonadism | journal = PLOS ONE | volume = 10 | issue = 6 | pages = e0131417 | date = Jun 2015 | pmid = 26120850 | doi = 10.1371/journal.pone.0131417 | pmc=4485893| bibcode = 2015PLoSO..1031417A | doi-access = free }}</ref> 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]]).<ref name="pmid18550819">{{cite journal | vauthors = Jeffrey KD, Alejandro EU, Luciani DS, Kalynyak TB, Hu X, Li H, Lin Y, Townsend RR, Polonsky KS, Johnson JD | title = Carboxypeptidase E mediates palmitate-induced beta-cell ER stress and apoptosis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 24 | pages = 8452–7 | date = June 2008 | pmid = 18550819 | pmc = 2448857 | doi = 10.1073/pnas.0711232105 | bibcode = 2008PNAS..105.8452J | doi-access = free }}</ref> 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.
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==See also==

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== See also ==
{{Portal|Biology}}
* [[Carboxypeptidase]]
* [[Carboxypeptidase]]
* [[Carboxypeptidase A]]
* [[Carboxypeptidase A]]


==References==
== References ==
{{reflist}}
{{reflist}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
*{{cite journal | vauthors=Goodge KA, Hutton JC |title=Translational regulation of proinsulin biosynthesis and proinsulin conversion in the pancreatic beta-cell |journal=Semin. Cell Dev. Biol. |volume=11 |issue= 4 |pages= 235–42 |year= 2000 |pmid= 10966857 |doi= 10.1006/scdb.2000.0172 }}
* {{cite journal | vauthors = Goodge KA, Hutton JC | title = Translational regulation of proinsulin biosynthesis and proinsulin conversion in the pancreatic beta-cell | journal = Seminars in Cell & Developmental Biology | volume = 11 | issue = 4 | pages = 235–42 | date = August 2000 | pmid = 10966857 | doi = 10.1006/scdb.2000.0172 }}
*{{cite journal | author=Beinfeld MC |title=Biosynthesis and processing of pro CCK: recent progress and future challenges |journal=Life Sci. |volume=72 |issue= 7 |pages= 747–57 |year= 2003 |pmid= 12479974 |doi=10.1016/S0024-3205(02)02330-5 }}
* {{cite journal | vauthors = Beinfeld MC | title = Biosynthesis and processing of pro CCK: recent progress and future challenges | journal = Life Sciences | volume = 72 | issue = 7 | pages = 747–57 | date = January 2003 | pmid = 12479974 | doi = 10.1016/S0024-3205(02)02330-5 }}
*{{cite journal | vauthors=Fricker LD, Snyder SH |title=Enkephalin convertase: purification and characterization of a specific enkephalin-synthesizing carboxypeptidase localized to adrenal chromaffin granules |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=79 |issue= 12 |pages= 3886–90 |year= 1982 |pmid= 6808517 |doi=10.1073/pnas.79.12.3886 | pmc=346533 }}
* {{cite journal | vauthors = Fricker LD, Snyder SH | title = Enkephalin convertase: purification and characterization of a specific enkephalin-synthesizing carboxypeptidase localized to adrenal chromaffin granules | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 79 | issue = 12 | pages = 3886–90 | date = June 1982 | pmid = 6808517 | pmc = 346533 | doi = 10.1073/pnas.79.12.3886 | bibcode = 1982PNAS...79.3886F | doi-access = free }}
*{{cite journal | vauthors=O'Rahilly S, Gray H, Humphreys PJ |title=Brief report: impaired processing of prohormones associated with abnormalities of glucose homeostasis and adrenal function |journal=N. Engl. J. Med. |volume=333 |issue= 21 |pages= 1386–90 |year= 1995 |pmid= 7477119 |doi=10.1056/NEJM199511233332104 |display-authors=etal}}
* {{cite journal | vauthors = O'Rahilly S, Gray H, Humphreys PJ, Krook A, Polonsky KS, White A, Gibson S, Taylor K, Carr C | title = Brief report: impaired processing of prohormones associated with abnormalities of glucose homeostasis and adrenal function | journal = The New England Journal of Medicine | volume = 333 | issue = 21 | pages = 1386–90 | date = November 1995 | pmid = 7477119 | doi = 10.1056/NEJM199511233332104 | doi-access = free }}
*{{cite journal | vauthors=Naggert JK, Fricker LD, Varlamov O |title=Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity |journal=Nat. Genet. |volume=10 |issue= 2 |pages= 135–42 |year= 1995 |pmid= 7663508 |doi= 10.1038/ng0695-135 |display-authors=etal}}
* {{cite journal | vauthors = Naggert JK, Fricker LD, Varlamov O, Nishina PM, Rouille Y, Steiner DF, Carroll RJ, Paigen BJ, Leiter EH | title = Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity | journal = Nature Genetics | volume = 10 | issue = 2 | pages = 135–42 | date = June 1995 | pmid = 7663508 | doi = 10.1038/ng0695-135 | s2cid = 19798125 }}
*{{cite journal | vauthors=Song L, Fricker L |title=Processing of procarboxypeptidase E into carboxypeptidase E occurs in secretory vesicles |journal=J. Neurochem. |volume=65 |issue= 1 |pages= 444–53 |year= 1995 |pmid= 7790890 |doi=10.1046/j.1471-4159.1995.65010444.x }}
* {{cite journal | vauthors = Song L, Fricker L | title = Processing of procarboxypeptidase E into carboxypeptidase E occurs in secretory vesicles | journal = Journal of Neurochemistry | volume = 65 | issue = 1 | pages = 444–53 | date = July 1995 | pmid = 7790890 | doi = 10.1046/j.1471-4159.1995.65010444.x | s2cid = 6650995 }}
*{{cite journal | vauthors=Hall C, Manser E, Spurr NK, Lim L |title=Assignment of the human carboxypeptidase E (CPE) gene to chromosome 4 |journal=Genomics |volume=15 |issue= 2 |pages= 461–3 |year= 1993 |pmid= 8449522 |doi= 10.1006/geno.1993.1093 }}
* {{cite journal | vauthors = Hall C, Manser E, Spurr NK, Lim L | title = Assignment of the human carboxypeptidase E (CPE) gene to chromosome 4 | journal = Genomics | volume = 15 | issue = 2 | pages = 461–3 | date = February 1993 | pmid = 8449522 | doi = 10.1006/geno.1993.1093 }}
*{{cite journal | vauthors=Guest PC, Arden SD, Rutherford NG, Hutton JC |title=The post-translational processing and intracellular sorting of carboxypeptidase H in the islets of Langerhans |journal=Mol. Cell. Endocrinol. |volume=113 |issue= 1 |pages= 99–108 |year= 1996 |pmid= 8674818 |doi=10.1016/0303-7207(95)03619-I }}
* {{cite journal | vauthors = Guest PC, Arden SD, Rutherford NG, Hutton JC | title = The post-translational processing and intracellular sorting of carboxypeptidase H in the islets of Langerhans | journal = Molecular and Cellular Endocrinology | volume = 113 | issue = 1 | pages = 99–108 | date = August 1995 | pmid = 8674818 | doi = 10.1016/0303-7207(95)03619-I | s2cid = 25659964 }}
*{{cite journal | vauthors=Rovere C, Viale A, Nahon J, Kitabgi P |title=Impaired processing of brain proneurotensin and promelanin-concentrating hormone in obese fat/fat mice |journal=Endocrinology |volume=137 |issue= 7 |pages= 2954–8 |year= 1996 |pmid= 8770919 |doi=10.1210/en.137.7.2954 }}
* {{cite journal | vauthors = Rovere C, Viale A, Nahon J, Kitabgi P | title = Impaired processing of brain proneurotensin and promelanin-concentrating hormone in obese fat/fat mice | journal = Endocrinology | volume = 137 | issue = 7 | pages = 2954–8 | date = July 1996 | pmid = 8770919 | doi = 10.1210/endo.137.7.8770919 | doi-access = free }}
*{{cite journal | vauthors=Alcalde L, Tonacchera M, Costagliola S |title=Cloning of candidate autoantigen carboxypeptidase H from a human islet library: sequence identity with human brain CPH |journal=J. Autoimmun. |volume=9 |issue= 4 |pages= 525–8 |year= 1996 |pmid= 8864828 |doi= 10.1006/jaut.1996.0070 |display-authors=etal}}
* {{cite journal | vauthors = Alcalde L, Tonacchera M, Costagliola S, Jaraquemada D, Pujol-Borrell R, Ludgate M | title = Cloning of candidate autoantigen carboxypeptidase H from a human islet library: sequence identity with human brain CPH | journal = Journal of Autoimmunity | volume = 9 | issue = 4 | pages = 525–8 | date = August 1996 | pmid = 8864828 | doi = 10.1006/jaut.1996.0070 }}
*{{cite journal | vauthors=Cool DR, Normant E, Shen F |title=Carboxypeptidase E is a regulated secretory pathway sorting receptor: genetic obliteration leads to endocrine disorders in Cpe(fat) mice |journal=Cell |volume=88 |issue= 1 |pages= 73–83 |year= 1997 |pmid= 9019408 |doi=10.1016/S0092-8674(00)81860-7 |display-authors=etal}}
* {{cite journal | vauthors = Cool DR, Normant E, Shen F, Chen HC, Pannell L, Zhang Y, Loh YP | title = Carboxypeptidase E is a regulated secretory pathway sorting receptor: genetic obliteration leads to endocrine disorders in Cpe(fat) mice | journal = Cell | volume = 88 | issue = 1 | pages = 73–83 | date = January 1997 | pmid = 9019408 | doi = 10.1016/S0092-8674(00)81860-7 | s2cid = 18629145 | doi-access = free }}
*{{cite journal | vauthors=Maeda K, Okubo K, Shimomura I |title=Analysis of an expression profile of genes in the human adipose tissue |journal=Gene |volume=190 |issue= 2 |pages= 227–35 |year= 1997 |pmid= 9197538 |doi=10.1016/S0378-1119(96)00730-5 |display-authors=etal}}
* {{cite journal | vauthors = Maeda K, Okubo K, Shimomura I, Mizuno K, Matsuzawa Y, Matsubara K | title = Analysis of an expression profile of genes in the human adipose tissue | journal = Gene | volume = 190 | issue = 2 | pages = 227–35 | date = May 1997 | pmid = 9197538 | doi = 10.1016/S0378-1119(96)00730-5 }}
*{{cite journal | vauthors=Cain BM, Wang W, Beinfeld MC |title=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 |journal=Endocrinology |volume=138 |issue= 9 |pages= 4034–7 |year= 1997 |pmid= 9275097 |doi=10.1210/en.138.9.4034 }}
* {{cite journal | vauthors = Cain BM, Wang W, Beinfeld MC | title = 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 | journal = Endocrinology | volume = 138 | issue = 9 | pages = 4034–7 | date = September 1997 | pmid = 9275097 | doi = 10.1210/endo.138.9.5490 | doi-access = free }}
*{{cite journal | vauthors=Lacourse KA, Friis-Hansen L, Rehfeld JF, Samuelson LC |title=Disturbed progastrin processing in carboxypeptidase E-deficient fat mice |journal=FEBS Lett. |volume=416 |issue= 1 |pages= 45–50 |year= 1997 |pmid= 9369230 |doi=10.1016/S0014-5793(97)01164-2 }}
* {{cite journal | vauthors = Lacourse KA, Friis-Hansen L, Rehfeld JF, Samuelson LC | title = Disturbed progastrin processing in carboxypeptidase E-deficient fat mice | journal = FEBS Letters | volume = 416 | issue = 1 | pages = 45–50 | date = October 1997 | pmid = 9369230 | doi = 10.1016/S0014-5793(97)01164-2 | hdl = 2027.42/116303 | s2cid = 9680236 | url = https://deepblue.lib.umich.edu/bitstream/2027.42/116303/1/feb2s0014579397011642.pdf | doi-access = free }}
*{{cite journal | vauthors=Utsunomiya N, Ohagi S, Sanke T |title=Organization of the human carboxypeptidase E gene and molecular scanning for mutations in Japanese subjects with NIDDM or obesity |journal=Diabetologia |volume=41 |issue= 6 |pages= 701–5 |year= 1998 |pmid= 9662053 |doi=10.1007/s001250050971 |display-authors=etal}}
* {{cite journal | vauthors = Utsunomiya N, Ohagi S, Sanke T, Tatsuta H, Hanabusa T, Nanjo K | title = Organization of the human carboxypeptidase E gene and molecular scanning for mutations in Japanese subjects with NIDDM or obesity | journal = Diabetologia | volume = 41 | issue = 6 | pages = 701–5 | date = June 1998 | pmid = 9662053 | doi = 10.1007/s001250050971 | doi-access = free }}
*{{cite journal | vauthors=Reznik SE, Salafia CM, Lage JM, Fricker LD |title=Immunohistochemical localization of carboxypeptidases E and D in the human placenta and umbilical cord |journal=J. Histochem. Cytochem. |volume=46 |issue= 12 |pages= 1359–68 |year= 1999 |pmid= 9815277 |doi= 10.1177/002215549804601204}}
* {{cite journal | vauthors = Reznik SE, Salafia CM, Lage JM, Fricker LD | title = Immunohistochemical localization of carboxypeptidases E and D in the human placenta and umbilical cord | journal = The Journal of Histochemistry and Cytochemistry | volume = 46 | issue = 12 | pages = 1359–68 | date = December 1998 | pmid = 9815277 | doi = 10.1177/002215549804601204 | doi-access = free }}
*{{cite journal | vauthors=Fan X, Olson SJ, Johnson MD |title=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 |journal=J. Histochem. Cytochem. |volume=49 |issue= 6 |pages= 783–90 |year= 2001 |pmid= 11373325 |doi= 10.1177/002215540104900612}}
* {{cite journal | vauthors = Fan X, Olson SJ, Johnson MD | title = 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 | journal = The Journal of Histochemistry and Cytochemistry | volume = 49 | issue = 6 | pages = 783–90 | date = June 2001 | pmid = 11373325 | doi = 10.1177/002215540104900612 | doi-access = free }}
*{{cite journal | vauthors=Friis-Hansen L, Lacourse KA, Samuelson LC, Holst JJ |title=Attenuated processing of proglucagon and glucagon-like peptide-1 in carboxypeptidase E-deficient mice |journal=J. Endocrinol. |volume=169 |issue= 3 |pages= 595–602 |year= 2001 |pmid= 11375130 |doi=10.1677/joe.0.1690595 }}
* {{cite journal | vauthors = Friis-Hansen L, Lacourse KA, Samuelson LC, Holst JJ | title = Attenuated processing of proglucagon and glucagon-like peptide-1 in carboxypeptidase E-deficient mice | journal = The Journal of Endocrinology | volume = 169 | issue = 3 | pages = 595–602 | date = June 2001 | pmid = 11375130 | doi = 10.1677/joe.0.1690595 | citeseerx = 10.1.1.521.1042 }}
{{refend}}
{{refend}}


==External links==
== External links ==
* The [[MEROPS]] online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=M14.005 M14.005]
* The [[MEROPS]] online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=M14.005 M14.005]
* {{MeshName|Carboxypeptidase+E}}
* {{MeshName|Carboxypeptidase+E}}
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{{Proteases}}
{{Proteases}}
{{Enzymes}}
{{Enzymes}}
{{Portal bar|Molecular and Cellular Biology|border=no}}


[[Category:Proteins]]
[[Category:Proteins]]

Latest revision as of 17:57, 13 January 2024

CPE
Identifiers
AliasesCPE, CPH, carboxypeptidase E, IDDHH, BDVS
External IDsOMIM: 114855; MGI: 101932; HomoloGene: 48052; GeneCards: CPE; OMA:CPE - orthologs
Orthologs
SpeciesHumanMouse
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 MbChr 8: 65.05 – 65.15 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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]

Tissue distribution

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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

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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

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Carboxypeptidase E
Identifiers
EC no.3.4.17.10
CAS no.81876-95-1
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins

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

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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 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

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000109472 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000037852 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b "Entrez Gene: CPE carboxypeptidase E".
  6. ^ Fricker LD (1988). "Carboxypeptidase E". Annual Review of Physiology. 50: 309–21. doi:10.1146/annurev.ph.50.030188.001521. PMID 2897826.
  7. ^ Fricker LD (2012). "Chapter 3.5 Carboxypeptidase E". Neuropeptides and Other Bioactive Peptides: From Discovery to Function (Color Version). Vol. 1. Morgan & Claypool Life Sciences. pp. 1–92. doi:10.4199/C00056ED1V01Y201204NPE002. ISBN 978-1-61504-521-1. {{cite book}}: |journal= ignored (help)
  8. ^ 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.
  9. ^ 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. S2CID 18629145.
  10. ^ 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. S2CID 19798125.
  11. ^ 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. Bibcode:2015PLoSO..1031417A. doi:10.1371/journal.pone.0131417. PMC 4485893. PMID 26120850.
  12. ^ 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. Bibcode:2008PNAS..105.8452J. doi:10.1073/pnas.0711232105. PMC 2448857. PMID 18550819.

Further reading

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