Dipeptidyl peptidase-4

Dipeptidyl-peptidase 4

Ribbon diagram of human DPP-4.
From PDB: 1PFQ.

Available structures

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, 4J3J, 4JH0, 4KR0, 4L72, 4LKO, 4N8D, 4N8E, 4PNZ, 4PV7, 4QZV

Identifiers

Symbols

DPP4 ; ADABP; ADCP2; CD26; DPPIV; TP103

External IDs

OMIM: 102720 MGI: 94919 HomoloGene: 3279 ChEMBL: 284 GeneCards: DPP4 Gene

EC number

3.4.14.5

Gene ontology
Molecular function	• virus receptor activity • protease binding • serine-type endopeptidase activity • receptor binding • protein binding • serine-type peptidase activity • dipeptidyl-peptidase activity • identical protein binding • protein homodimerization activity
Cellular component	• lysosomal membrane • plasma membrane • focal adhesion • cell surface • membrane • integral component of membrane • apical plasma membrane • lamellipodium • endocytic vesicle • lamellipodium membrane • membrane raft • intercellular canaliculus • extracellular exosome • invadopodium membrane
Biological process	• behavioral fear response • response to hypoxia • proteolysis • positive regulation of cell proliferation • negative regulation of extracellular matrix disassembly • T cell costimulation • regulation of cell-cell adhesion mediated by integrin • locomotory exploration behavior • psychomotor behavior • T cell activation • endothelial cell migration • viral entry into host cell
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 2:
161.99 – 162.07 Mb

Chr 2:
62.33 – 62.41 Mb

PubMed search

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

PDB gallery

1j2e: Crystal structure of Human Dipeptidyl peptidase IV

1n1m: Human Dipeptidyl Peptidase IV/CD26 in complex with an inhibitor

1nu6: Crystal structure of human Dipeptidyl Peptidase IV (DPP-IV)

1nu8: Crystal structure of human dipeptidyl peptidase IV (DPP-IV) in complex with Diprotin A (ILI)

1pfq: crystal structure of human apo dipeptidyl peptidase IV / CD26

1r9m: Crystal Structure of Human Dipeptidyl Peptidase IV at 2.1 Ang. Resolution.

1r9n: Crystal Structure of human dipeptidyl peptidase IV in complex with a decapeptide (tNPY) at 2.3 Ang. Resolution

1rwq: Human Dipeptidyl peptidase IV in complex with 5-aminomethyl-6-(2,4-dichloro-phenyl)-2-(3,5-dimethoxy-phenyl)-pyrimidin-4-ylamine

1tk3: Crystal Structure Of Human Apo Dipeptidyl Peptidase IV/CD26

1tkr: Human Dipeptidyl Peptidase IV/CD26 inhibited with Diisopropyl FluoroPhosphate

1u8e: HUMAN DIPEPTIDYL PEPTIDASE IV/CD26 MUTANT Y547F

1w1i: CRYSTAL STRUCTURE OF DIPEPTIDYL PEPTIDASE IV (DPPIV OR CD26) IN COMPLEX WITH ADENOSINE DEAMINASE

1wcy: Crystal Structure Of Human Dipeptidyl Peptidase IV (DPPIV) Complex With Diprotin A

1x70: HUMAN DIPEPTIDYL PEPTIDASE IV IN COMPLEX WITH A BETA AMINO ACID INHIBITOR

2ajl: X-ray Structure of Novel Biaryl-Based Dipeptidyl peptidase IV inhibitor

2bgn: HIV-1 TAT PROTEIN DERIVED N-TERMINAL NONAPEPTIDE TRP2-TAT (1-9) BOUND TO THE ACTIVE SITE OF DIPEPTIDYL PEPTIDASE IV (CD26)

2bgr: CRYSTAL STRUCTURE OF HIV-1 TAT DERIVED NONAPEPTIDES TAT(1-9) BOUND TO THE ACTIVE SITE OF DIPEPTIDYL PEPTIDASE IV (CD26)

2bub: CRYSTAL STRUCTURE OF HUMAN DIPEPTIDYL PEPTIDASE IV (CD26) IN COMPLEX WITH A REVERSED AMIDE INHIBITOR

2fjp: Human dipeptidyl peptidase IV/CD26 in complex with an inhibitor

2g5p: Crystal structure of human dipeptidyl peptidase IV (DPPIV) complexed with cyanopyrrolidine (C5-pro-pro) inhibitor 21ac

2g5t: Crystal structure of human dipeptidyl peptidase IV (DPPIV) complexed with cyanopyrrolidine (C5-pro-pro) inhibitor 21ag

2g63: Crystal structure of human dipeptidyl peptidase IV (DPPIV) complexed with cyanopyrrolidine (C5-pro-pro) inhibitor 24b

2hha: The structure of DPP4 in complex with an oxadiazole inhibitor

2i03: Crystal structure of human dipeptidyl peptidase 4 (DPP IV) with potent alkynyl cyanopyrrolidine (ABT-279)

2iit: Human dipeptidyl peptidase 4 in complex with a diazepan-2-one inhibitor

2iiv: Human dipeptidyl peptidase 4 in complex with a diazepan-2-one inhibitor

2ogz: Crystal structure of DPP-IV complexed with Lilly aryl ketone inhibitor

2oph: Human dipeptidyl peptidase IV in complex with an alpha amino acid inhibitor

2oqi: Human Dipeptidyl Peptidase IV (DPP4) with Piperidinone-constrained phenethylamine

2oqv: Human Dipeptidyl Peptidase IV (DPP4) with piperidine-constrained phenethylamine

2p8s: Human dipeptidyl peptidase IV/CD26 in complex with a cyclohexalamine inhibitor

Proteins: clusters of differentiation (see also list of human clusters of differentiation)

1-50	CD1 a-c 1A 1D 1E CD2 CD3 γ δ ε CD4 CD5 CD6 CD7 CD8 a CD9 CD10 CD11 a b c d CD13 CD14 CD15 CD16 A B CD18 CD19 CD20 CD21 CD22 CD23 CD24 CD25 CD26 CD27 CD28 CD29 CD30 CD31 CD32 A B CD33 CD34 CD35 CD36 CD37 CD38 CD39 CD40 CD41 CD42 a b c d CD43 CD44 CD45 CD46 CD47 CD48 CD49 a b c d e f CD50

51-100	CD51 CD52 CD53 CD54 CD55 CD56 CD57 CD58 CD59 CD61 CD62 E L P CD63 CD64 A B C CD66 a b c d e f CD68 CD69 CD70 CD71 CD72 CD73 CD74 CD78 CD79 a b CD80 CD81 CD82 CD83 CD84 CD85 a d e h j k CD86 CD87 CD88 CD89 CD90 CD91 - CD92 CD93 CD94 CD95 CD96 CD97 CD98 CD99 CD100

101-150	CD101 CD102 CD103 CD104 CD105 CD106 CD107 a b CD108 CD109 CD110 CD111 CD112 CD113 CD114 CD115 CD116 CD117 CD118 CD119 CD120 a b CD121 a b CD122 CD123 CD124 CD125 CD126 CD127 CD129 CD130 CD131 CD132 CD133 CD134 CD135 CD136 CD137 CD138 CD140b CD141 CD142 CD143 CD144 CD146 CD147 CD148 CD150

151-200	CD151 CD152 CD153 CD154 CD155 CD156 a b c CD157 CD158 (a d e i k) CD159 a c CD160 CD161 CD162 CD163 CD164 CD166 CD167 a b CD168 CD169 CD170 CD171 CD172 a b g CD174 CD177 CD178 CD179 a b CD180 CD181 CD182 CD183 CD184 CD185 CD186 CD191 CD192 CD193 CD194 CD195 CD196 CD197 CDw198 CDw199 CD200

201-250	CD201 CD202b CD204 CD205 CD206 CD207 CD208 CD209 CDw210 a b CD212 CD213a 1 2 CD217 CD218 (a b) CD220 CD221 CD222 CD223 CD224 CD225 CD226 CD227 CD228 CD229 CD230 CD233 CD234 CD235 a b CD236 CD238 CD239 CD240CE CD240D CD241 CD243 CD244 CD246 CD247 - CD248 CD249

251-300	CD252 CD253 CD254 CD256 CD257 CD258 CD261 CD262 CD263 CD264 CD265 CD266 CD267 CD268 CD269 CD271 CD272 CD273 CD274 CD275 CD276 CD278 CD279 CD280 CD281 CD282 CD283 CD284 CD286 CD288 CD289 CD290 CD292 CDw293 CD294 CD295 CD297 CD298 CD299

301-350	CD300A CD301 CD302 CD303 CD304 CD305 CD306 CD307 CD309 CD312 CD314 CD315 CD316 CD317 CD318 CD320 CD321 CD322 CD324 CD325 CD326 CD328 CD329 CD331 CD332 CD333 CD334 CD335 CD336 CD337 CD338 CD339 CD340 CD344 CD349 CD350

Cluster of differentiation by lineage

Lymphoid

B cell

plasma cell: CD38
CD138

T/NK

T cell	Pan-T antigens: CD3 CD7 CD1 CD4 CD8 CD13 CD18 CD26 CD27 CD28

NK cell	CD16 CD56/NCAM CD57

All	CD2

All

Myeloid

CFU-GM/
Myelomonocyte

MEP

CFU-Meg	CD34/CD36 CD42 CD41/CD61

CFU-E	CD36 CD71

All (pan-myeloid)

CD13
CD33

Stem cell

CD34

Hydrolase: proteases (EC 3.4)

3.4.11-19: Exopeptidase

3.4.11	Aminopeptidase Alanine Arginyl Aspartyl Cystinyl Leucyl Glutamyl Methionyl 1 2 O

3.4.13	Dipeptidase 1 2 3

3.4.14	Dipeptidyl peptidase Cathepsin C Dipeptidyl peptidase-4 Tripeptidyl peptidase Tripeptidyl peptidase I Tripeptidyl peptidase II

3.4.15	Angiotensin-converting enzyme

3.4.16	Serine type carboxypeptidases: Cathepsin A DD-transpeptidase

3.4.17	Metalloexopeptidases Carboxypeptidase A A2 B C E Glutamate II

Other/ungrouped	Metalloexopeptidase

3.4.21-25: Endopeptidase

Other/ungrouped: Amyloid precursor protein secretase

3.4.99: Unknown

Staphylokinase

Proteins: enzymes

Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis Enzyme kinetics Lineweaver–Burk plot Michaelis–Menten kinetics

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Types	EC1 Oxidoreductases(list) EC2 Transferases(list) EC3 Hydrolases(list) EC4 Lyases(list) EC5 Isomerases(list) EC6 Ligases(list)

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