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Dipeptidyl peptidase-4 (DPP4), also known as adenosine deaminase complexing protein 2 or CD26 (cluster of differentiation 26) is a protein that, in humans, is encoded by the DPP4 gene.^[1] DPP4 is related to attractin, FAP, DPP8 and DPP9.

Function

The protein encoded by the DPP4 gene is an antigenic enzyme expressed on the surface of most cell types and is associated with immune regulation, signal transduction and apoptosis. It is an intrinsic membrane glycoprotein and a serine exopeptidase that cleaves X-proline dipeptides from the N-terminus of polypeptides.

It is a rather indiscriminate enzyme for which a diverse range of substrates are known.^[2] The substrates of CD26/DPPIV are proline(or alanine)-containing peptides and include growth factors, chemokines, neuropeptides, and vasoactive peptides. DPP4 plays a major role in glucose metabolism. It is responsible for the degradation of incretins such as GLP-1.^[3] Furthermore, it appears to work as a suppressor in the development of cancer and tumours.^[4]^[5]^[6]

DPP-4 also binds the enzyme adenosine deaminase specifically and with high affinity. The significance of this interaction has yet to be established.

Animal studies

Animal studies suggest its pathogenetic role in development of fibrosis of various organs, such as liver and kidney.^[7]^[8]

Clinical significance

CD26/DPPIV plays an important role in tumor biology, and is useful as a marker for various cancers, with its levels either on the cell surface or in the serum increased in some neoplasms and decreased in others.^[9]

A new class of oral hypoglycemics called dipeptidyl peptidase-4 inhibitors work by inhibiting the action of this enzyme, thereby prolonging incretin effect in vivo.^[10]

A new coronavirus related to SARS, named Middle East respiratory syndrome coronavirus, has been found to bind to DPP4. DPP4 is found on the surface of cells in the airways (such as the lungs) and kidneys. Scientists may be able to use this to their advantage by blocking the virus's entry into the cell.^[11]

References

^ Kameoka J, Tanaka T, Nojima Y, Schlossman SF, Morimoto C (Jul 1993). "Direct association of adenosine deaminase with a T cell activation antigen, CD26". Science 261 (5120): 466–9. doi:10.1126/science.8101391. PMID 8101391.
^ Chen X (2006). "Biochemical properties of recombinant prolyl dipeptidases DPP-IV and DPP8". Advances in Experimental Medicine and Biology. Advances in Experimental Medicine and Biology 575: 27–32. doi:10.1007/0-387-32824-6_3. ISBN 978-0-387-29058-4. PMID 16700505.
^ Barnett A (Nov 2006). "DPP-4 inhibitors and their potential role in the management of type 2 diabetes". International Journal of Clinical Practice 60 (11): 1454–70. doi:10.1111/j.1742-1241.2006.01178.x. PMID 17073841.
^ Pro B, Dang NH (Oct 2004). "CD26/dipeptidyl peptidase IV and its role in cancer". Histology and Histopathology 19 (4): 1345–51. PMID 15375776.
^ Masur K, Schwartz F, Entschladen F, Niggemann B, Zaenker KS (Dec 2006). "DPPIV inhibitors extend GLP-2 mediated tumour promoting effects on intestinal cancer cells". Regulatory Peptides 137 (3): 147–55. doi:10.1016/j.regpep.2006.07.003. PMID 16908079.
^ Wesley UV, McGroarty M, Homoyouni A (Feb 2005). "Dipeptidyl peptidase inhibits malignant phenotype of prostate cancer cells by blocking basic fibroblast growth factor signaling pathway". Cancer Research 65 (4): 1325–34. doi:10.1158/0008-5472.CAN-04-1852. PMID 15735018.
^ Kaji K, Yoshiji H, Ikenaka Y, Noguchi R, Aihara Y, Douhara A, Moriya K, Kawaratani H, Shirai Y, Yoshii J, Yanase K, Kitade M, Namisaki T, Fukui H (Mar 2014). "Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats". Journal of Gastroenterology 49 (3): 481–91. doi:10.1007/s00535-013-0783-4. PMID 23475323.
^ Min HS, Kim JE, Lee MH, Song HK, Kang YS, Lee MJ, Lee JE, Kim HW, Cha JJ, Chung YY, Hyun YY, Han JY, Cha DR (Jun 2014). "Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction". Laboratory Investigation 94 (6): 598–607. doi:10.1038/labinvest.2014.50. PMID 24687121.
^ Havre PA, Abe M, Urasaki Y, Ohnuma K, Morimoto C, Dang NH (2008). "The role of CD26/dipeptidyl peptidase IV in cancer". Frontiers in Bioscience 13 (13): 1634–45. doi:10.2741/2787. PMID 17981655.
^ Rosenstock J, Zinman B (Apr 2007). "Dipeptidyl peptidase-4 inhibitors and the management of type 2 diabetes mellitus". Current Opinion in Endocrinology, Diabetes, and Obesity 14 (2): 98–107. doi:10.1097/MED.0b013e3280a02f65. PMID 17940427.
^ Raj VS, Mou H, Smits SL, Dekkers DH, Müller MA, Dijkman R, Muth D, Demmers JA, Zaki A, Fouchier RA, Thiel V, Drosten C, Rottier PJ, Osterhaus AD, Bosch BJ, Haagmans BL (Mar 2013). "Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC". Nature (ScienceNews) 495 (7440): 251–4. doi:10.1038/nature12005. PMID 23486063. Lay summary – ScienceNews.

External links

The MEROPS online database for peptidases and their inhibitors: S09.003
Dipeptidyl-Peptidase IV at the US National Library of Medicine Medical Subject Headings (MeSH)
Banting and Best Diabetes Centre at UT dpp4

Molecular and Cellular Biology portal

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1. 消化管の糖尿病性自律神経ニューロパチーdiabetic autonomic neuropathy of the gastrointestinal tract [show details]
…metformin, alpha-glucosidase inhibitor, glucagon-like peptide [GLP]-1 agonist, and dipeptidyl peptidase-4 [DPP4] inhibitors) and artificial sweeteners (eg, sorbitol or polyols) can cause diarrhea in patients with…
2. Chronic pancreatitis: Managementchronic pancreatitis management [show details]
…treatment-induced hypoglycemia. Glucagon-like peptide (GLP)-1 analogues and dipeptidyl peptidase-4 (DPP4) inhibitors have not been well studied in patients with chronic pancreatitis and are generally avoided…
3. MERSコロナウイルス：臨床症状および診断middle east respiratory syndrome coronavirus clinical manifestations and diagnosis [show details]
…cases of diabetes and none of chronic kidney disease . It may be that the increased expression of DPP4 (the cellular receptor for MERS-CoV infection) found in both smokers and adults with chronic obstructive…
4. 中東呼吸器症候群（MERS）コロナウイルス：ウイルス学、発症機序、疫学middle east respiratory syndrome coronavirus virology pathogenesis and epidemiology [show details]
…peptidase 4 (DPP4; also known as CD26), which is present on the surfaces of human nonciliated bronchial epithelial cells, is a functional receptor for MERS-CoV . Expression of human and bat DPP4 in otherwise …

English Journal

Pharmacological DPP4 inhibition for the prevention of vascular diseases.

Brenner C1, Franz WM2.
International journal of cardiology.Int J Cardiol.2016 Jan 1;202:49. doi: 10.1016/j.ijcard.2015.08.175. Epub 2015 Aug 25.
PMID 26386919

An overview of novel GLP-1 receptor agonists for type II diabetes.

Tomlinson B1,2, Hu M2, Zhang Y1, Chan P3, Liu ZM4.
Expert opinion on investigational drugs.Expert Opin Investig Drugs.2015 Nov 20. [Epub ahead of print]
INTRODUCTION: The increasing prevalence of type 2 diabetes mellitus (T2DM) and the eventual need for multiple medications in most patients stimulated the development of new drug classes to reduce plasma glucose levels. The GLP-1 receptor agonists (GLP-1RAs) are established as an option for treatment
PMID 26587691

N- and C-terminally truncated forms of glucose-dependent insulinotropic polypeptide are high-affinity competitive antagonists of the human GIP receptor.

Hansen LS1,2,3, Sparre-Ulrich AH1,2, Christensen M3, Knop FK2,3, Hartmann B4,2, Holst JJ4,2, Rosenkilde MM1.
British journal of pharmacology.Br J Pharmacol.2015 Nov 17. doi: 10.1111/bph.13384. [Epub ahead of print]
BACKGROUND AND PURPOSE: Glucose-dependent insulinotropic polypeptide (GIP) impacts lipid, bone, and glucose homeostasis. The GIP receptor belongs to G protein-coupled receptor family B1 and signals through GαS. High affinity ligands for in vivo use are needed to elucidate GIP's physiological functi
PMID 26572091

Japanese Journal

Identification and Characterization of Prokaryotic Dipeptidyl-Peptidase 5 from Porphyromonas gingivalis

Ohara-Nemoto Yuko,Rouf Shakh M. A.,Naito Mariko,Yanase Amie,Tetsuo Fumi,Ono Toshio,Kobayakawa Takeshi,Shimoyama Yu,Kimura Shigenobu,Nakayama Koji,Saiki Keitarou,Konishi Kiyoshi,Nemoto Takayuki K.
Journal of Biological Chemistry 289(9), 5436-5448, 2014-02-28
… A DPP7-like activity still remained in a dpp4-7-11 disrupted P. … Examinations of dpp- and gingipain gene-disrupted mutants indicated that DPP4, DPP5, DPP7, and DPP11 together with Arg- and Lys-gingipains cooperatively liberate most dipeptides from nutrient oligopeptides. …
NAID 120005398095

日本糖尿病诊疗之现状 (特辑日中两国糖尿病诊断与治疗的现状)

戸边一之
日中医学 : (公財)日中医学協会機関誌 : bulletin of the Japan China Medical Association 28(3), 39-44, 2013-12
NAID 40019942253

日本における糖尿病診療の現状 (特集日中における糖尿病診療の現状)

渡邉一之
日中医学 : (公財)日中医学協会機関誌 : bulletin of the Japan China Medical Association 28(3), 16-22, 2013-12
NAID 40019942104

「ジペプチジルペプチダーゼ4阻害薬」

DPP4
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	1J2E, 1N1M, 1NU6, 1NU8, 1PFQ, 1R9M, 1R9N, 1RWQ, 1TK3, 1TKR, 1U8E, 1W1I, 1WCY, 1X70, 2AJL, 2BGN, 2BGR, 2BUB, 2FJP, 2G5P, 2G5T, 2G63, 2HHA, 2I03, 2I78, 2IIT, 2IIV, 2JID, 2OAG, 2OGZ, 2OLE, 2ONC, 2OPH, 2OQI, 2OQV, 2P8S, 2QJR, 2QKY, 2QOE, 2QT9, 2QTB, 2RGU, 2RIP, 3BJM, 3C43, 3C45, 3CCB, 3CCC, 3D4L, 3EIO, 3F8S, 3G0B, 3G0C, 3G0D, 3G0G, 3H0C, 3HAB, 3HAC, 3KWF, 3KWJ, 3NOX, 3O95, 3O9V, 3OC0, 3OPM, 3Q0T, 3Q8W, 3QBJ, 3SWW, 3SX4, 3VJK, 3VJL, 3VJM, 3W2T, 4A5S, 4DSA, 4DSZ, 4DTC, 4G1F, 4JH0, 4KR0, 4L72, 4LKO, 4J3J, 4N8D, 4N8E, 4PNZ, 4PV7, 4QZV, 3WQH
Identifiers
Aliases	DPP4, ADABP, ADCP2, CD26, DPPIV, TP103
External IDs	OMIM: 102720 MGI: 94919 HomoloGene: 3279 GeneCards: 1803
Genetically Related Diseases
Disease Name	References
	[1]
Gene ontology
Molecular function	• serine-type endopeptidase activity; • dipeptidyl-peptidase activity; • receptor binding; • identical protein binding; • peptidase activity; • hydrolase activity; • virus receptor activity; • protein homodimerization activity; • serine-type peptidase activity; • protease binding; • aminopeptidase activity; • protein binding;
Cellular component	• lamellipodium membrane; • extracellular region; • extracellular exosome; • lysosomal membrane; • endocytic vesicle; • integral component of membrane; • cell projection; • cell junction; • Lamellipodium; • apical plasma membrane; • membrane; • focal adhesion; • cell surface; • intercellular canaliculus; • membrane raft; • plasma membrane; • invadopodium membrane;
Biological process	• response to hypoxia; • T cell costimulation; • proteolysis; • psychomotor behavior; • behavioral fear response; • negative regulation of extracellular matrix disassembly; • regulation of cell-cell adhesion mediated by integrin; • locomotory exploration behavior; • viral entry into host cell; • endothelial cell migration; • positive regulation of cell proliferation; • T cell activation; • cell adhesion;
	Sources:Amigo / QuickGO
RNA expression pattern
	; ; ; ;
	More reference expression data
Orthologs
	1803
	13482
	ENSG00000197635
	ENSMUSG00000035000
	P27487
	P28843
	NM_001935
	NM_001159543; NM_010074
	NP_001926.2
	NP_001153015.1; NP_034204.1
	Wikidata
View/Edit Human	View/Edit Mouse

　　[★]

英: dipeptidyl-peptidase IV inhibitor
同: DPP4阻害薬、ジペプチジルペプチダーゼIV阻害薬、ジペプチジルペプチダーゼIV阻害剤、ジペプチジルペプチダーゼ4阻害剤
関: ジペプチジルペプチダーゼ4 DPP4、糖尿病治療薬、シタグリプチン

「ジペプチジルペプチダーゼ4」

　　[★]

英: dipeptidyl peptidase 4 DPP4
関: DPP4阻害薬

「dipeptidyl peptidase-4」

　　[★] ジペプチジルペプチダーゼ4 DPP4

「DPP4阻害薬」

　　[★] ジペプチジルペプチダーゼ4阻害薬

「DPP」

　　[★]

「DP」

　　[★]

[pmid8101391-1] Kameoka J, Tanaka T, Nojima Y, Schlossman SF, Morimoto C (Jul 1993). "Direct association of adenosine deaminase with a T cell activation antigen, CD26". Science 261 (5120): 466–9. doi:10.1126/science.8101391. PMID 8101391.

[pmid16700505-2] Chen X (2006). "Biochemical properties of recombinant prolyl dipeptidases DPP-IV and DPP8". Advances in Experimental Medicine and Biology. Advances in Experimental Medicine and Biology 575: 27–32. doi:10.1007/0-387-32824-6_3. ISBN 978-0-387-29058-4. PMID 16700505.

[pmid17073841-3] Barnett A (Nov 2006). "DPP-4 inhibitors and their potential role in the management of type 2 diabetes". International Journal of Clinical Practice 60 (11): 1454–70. doi:10.1111/j.1742-1241.2006.01178.x. PMID 17073841.

[4] Pro B, Dang NH (Oct 2004). "CD26/dipeptidyl peptidase IV and its role in cancer". Histology and Histopathology 19 (4): 1345–51. PMID 15375776.

[5] Masur K, Schwartz F, Entschladen F, Niggemann B, Zaenker KS (Dec 2006). "DPPIV inhibitors extend GLP-2 mediated tumour promoting effects on intestinal cancer cells". Regulatory Peptides 137 (3): 147–55. doi:10.1016/j.regpep.2006.07.003. PMID 16908079.

[6] Wesley UV, McGroarty M, Homoyouni A (Feb 2005). "Dipeptidyl peptidase inhibits malignant phenotype of prostate cancer cells by blocking basic fibroblast growth factor signaling pathway". Cancer Research 65 (4): 1325–34. doi:10.1158/0008-5472.CAN-04-1852. PMID 15735018.

[pmid23475323-7] Kaji K, Yoshiji H, Ikenaka Y, Noguchi R, Aihara Y, Douhara A, Moriya K, Kawaratani H, Shirai Y, Yoshii J, Yanase K, Kitade M, Namisaki T, Fukui H (Mar 2014). "Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats". Journal of Gastroenterology 49 (3): 481–91. doi:10.1007/s00535-013-0783-4. PMID 23475323.

[pmid24687121-8] Min HS, Kim JE, Lee MH, Song HK, Kang YS, Lee MJ, Lee JE, Kim HW, Cha JJ, Chung YY, Hyun YY, Han JY, Cha DR (Jun 2014). "Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction". Laboratory Investigation 94 (6): 598–607. doi:10.1038/labinvest.2014.50. PMID 24687121.

[pmid17981655-9] Havre PA, Abe M, Urasaki Y, Ohnuma K, Morimoto C, Dang NH (2008). "The role of CD26/dipeptidyl peptidase IV in cancer". Frontiers in Bioscience 13 (13): 1634–45. doi:10.2741/2787. PMID 17981655.

[pmid17940427-10] Rosenstock J, Zinman B (Apr 2007). "Dipeptidyl peptidase-4 inhibitors and the management of type 2 diabetes mellitus". Current Opinion in Endocrinology, Diabetes, and Obesity 14 (2): 98–107. doi:10.1097/MED.0b013e3280a02f65. PMID 17940427.

[pmid23486063-11] Raj VS, Mou H, Smits SL, Dekkers DH, Müller MA, Dijkman R, Muth D, Demmers JA, Zaki A, Fouchier RA, Thiel V, Drosten C, Rottier PJ, Osterhaus AD, Bosch BJ, Haagmans BL (Mar 2013). "Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC". Nature (ScienceNews) 495 (7440): 251–4. doi:10.1038/nature12005. PMID 23486063. Lay summary – ScienceNews.

リンク元	「ジペプチジルペプチダーゼ4阻害薬」「ジペプチジルペプチダーゼ4」「dipeptidyl peptidase-4」
拡張検索	「DPP4阻害薬」
関連記事	「DPP」「DP」

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案内

案内

DPP4