DPP3

Summary

DPP3 (dipeptidyl peptidase 3, HGNC:3008) is a protein-coding gene on chromosome 11q13.2, encoding Dipeptidyl peptidase 3 (Q9NY33). Cleaves and degrades bioactive peptides, including angiotensin, Leu-enkephalin and Met-enkephalin.

This gene encodes a protein that is a member of the M49 family of metallopeptidases. This cytoplasmic protein binds a single zinc ion with its zinc-binding motif (HELLGH) and has post-proline dipeptidyl aminopeptidase activity, cleaving Xaa-Pro dipeptides from the N-termini of proteins. Increased activity of this protein is associated with endometrial and ovarian cancers. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 10072 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 173 total
• GTEx eGene: eQTL in 36 tissues, sQTL in 22 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.83 (unconstrained)
• MANE Select transcript: NM_130443
• Notable: 173 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3008
Approved symbol	DPP3
Name	dipeptidyl peptidase 3
Location	11q13.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000254986
Ensembl biotype	protein_coding
OMIM	606818
Entrez	10072

Gene structure

Transcript identifiers

Ensembl transcripts: 41 — 31 protein_coding, 5 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 2 retained_intron

MANE Select: ENST00000531863

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 3, TSL 3: 3, TSL 4: 4, TSL 5: 4

ENST00000531863, ENST00000525738, ENST00000526250, ENST00000526515, ENST00000526667, ENST00000530165, ENST00000531272, ENST00000531314, ENST00000531354, ENST00000532019, ENST00000532677, ENST00000533725, ENST00000533799, ENST00000539085, ENST00000541961, ENST00000544603, ENST00000883956, ENST00000883957, ENST00000883958, ENST00000883959, ENST00000883960, ENST00000883961, ENST00000883962, ENST00000883963, ENST00000883964, ENST00000914249, ENST00000914250, ENST00000914252, ENST00000914253, ENST00000914254, ENST00000962696, ENST00000978871, ENST00001032702, ENST00001058586, ENST00001099024, ENST00001113550, ENST00001120869, ENST00001120870, ENST00001126172, ENST00001126173, ENST00001144374

RefSeq mRNA: 3 — MANE Select: NM_130443 NM_001256670, NM_005700, NM_130443

CCDS: CCDS58147, CCDS8141

Canonical transcript exons

ENST00000531863 — 18 exons

Exon	Start	End
ENSE00001188775	66487268	66487342
ENSE00001188800	66504612	66504774
ENSE00001188803	66497298	66497477
ENSE00001188812	66495365	66495489
ENSE00001188845	66491698	66491756
ENSE00001188850	66491494	66491624
ENSE00001188856	66491253	66491383
ENSE00001188859	66487914	66488007
ENSE00001188868	66486540	66486677
ENSE00002143279	66480434	66480465
ENSE00002167171	66509079	66509657
ENSE00003475144	66495630	66495750
ENSE00003572121	66495206	66495268
ENSE00003624210	66493067	66493179
ENSE00003646495	66492716	66492910
ENSE00003664116	66493541	66493633
ENSE00003694448	66485173	66485262
ENSE00003798105	66482193	66482470

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 94.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.1665 / max 226.4664, expressed in 1807 samples.

Highest expression (Bgee): mucosa of transverse colon, oocyte, rectum, islet of Langerhans, secondary oocyte.

Genetic regulation across tissues (GTEx eQTL / sQTL)

DPP3 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 36 tissues and its splicing (sQTL) in 22 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 58 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Thyroid	eqtl	1.3e-40	-0.30	11:66483367:A:C
Nerve Tibial	eqtl	8.5e-28	-0.25	11:66465302:C:T
Whole Blood	eqtl	1.6e-25	+0.20	11:66480225:G:T
Pancreas	eqtl	5.5e-22	-0.37	11:66483367:A:C
Adipose Subcutaneous	eqtl	1.7e-20	-0.23	11:66474931:T:G
Artery Tibial	eqtl	5.7e-20	-0.27	11:66486614:G:T
Esophagus Mucosa	eqtl	9.3e-19	+0.17	11:66480225:G:T
Skin Sun Exposed Lower leg	sqtl	1.6e-18	-0.53	11:66449344:C:T
Adipose Visceral Omentum	eqtl	5.1e-18	-0.18	11:66474636:A:G
Thyroid	sqtl	7.6e-17	+0.55	11:66495135:T:C
Lung	eqtl	1.1e-16	-0.16	11:66476983:A:G
Skin Sun Exposed Lower leg	eqtl	1.2e-16	-0.23	11:66478465:C:T
Breast Mammary Tissue	eqtl	1.2e-16	-0.21	11:66474931:T:G
Stomach	eqtl	3.7e-16	-0.19	11:66474931:T:G
Cells Cultured fibroblasts	sqtl	6.0e-15	+0.57	11:66495135:T:C
Skin Not Sun Exposed Suprapubic	eqtl	7.6e-15	-0.24	11:66478465:C:T
Esophagus Mucosa	sqtl	4.6e-13	-0.53	11:66504671:A:G
Adipose Subcutaneous	sqtl	1.8e-12	+0.47	11:66495135:T:C
Cells EBV-transformed lymphocytes	sqtl	9.3e-12	+0.70	11:66495135:T:C
Muscle Skeletal	eqtl	1.9e-11	+0.13	11:66427707:C:T

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
115344	18.5468	1806
115343	0.6196	348

Top tissues by expression

showing 100 of 283 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	94.70	gold quality
oocyte	CL:0000023	93.65	gold quality
rectum	UBERON:0001052	92.18	gold quality
islet of Langerhans	UBERON:0000006	91.79	gold quality
secondary oocyte	CL:0000655	91.27	gold quality
granulocyte	CL:0000094	90.34	gold quality
adrenal tissue	UBERON:0018303	90.09	gold quality
transverse colon	UBERON:0001157	89.83	gold quality
pharyngeal mucosa	UBERON:0000355	89.55	gold quality
esophagus mucosa	UBERON:0002469	89.39	gold quality
esophagus squamous epithelium	UBERON:0006920	89.37	gold quality
stromal cell of endometrium	CL:0002255	89.08	gold quality
right adrenal gland	UBERON:0001233	88.84	gold quality
gall bladder	UBERON:0002110	88.78	gold quality
colonic mucosa	UBERON:0000317	88.76	gold quality
epithelium of esophagus	UBERON:0001976	88.75	gold quality
right adrenal gland cortex	UBERON:0035827	88.72	gold quality
monocyte	CL:0000576	88.57	gold quality
body of stomach	UBERON:0001161	88.50	gold quality
gastrocnemius	UBERON:0001388	88.49	gold quality
vermiform appendix	UBERON:0001154	88.38	gold quality
left adrenal gland	UBERON:0001234	88.26	gold quality
ganglionic eminence	UBERON:0004023	88.19	gold quality
minor salivary gland	UBERON:0001830	88.16	gold quality
palpebral conjunctiva	UBERON:0001812	88.13	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.04	gold quality
mononuclear cell	CL:0000842	87.98	gold quality
left adrenal gland cortex	UBERON:0035825	87.98	gold quality
leukocyte	CL:0000738	87.97	gold quality
mouth mucosa	UBERON:0003729	87.94	gold quality
duodenum	UBERON:0002114	87.88	gold quality
caecum	UBERON:0001153	87.82	gold quality
adrenal gland	UBERON:0002369	87.66	gold quality
epithelium of nasopharynx	UBERON:0001951	87.65	silver quality
mucosa of sigmoid colon	UBERON:0004993	87.64	gold quality
metanephros cortex	UBERON:0010533	87.62	gold quality
small intestine	UBERON:0002108	87.57	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.52	gold quality
adrenal cortex	UBERON:0001235	87.46	gold quality
muscle of leg	UBERON:0001383	87.42	gold quality
pancreas	UBERON:0001264	87.33	gold quality
large intestine	UBERON:0000059	87.24	gold quality
colon	UBERON:0001155	87.18	gold quality
esophagus	UBERON:0001043	87.17	gold quality
tonsil	UBERON:0002372	87.13	gold quality
intestine	UBERON:0000160	87.11	gold quality
lymph node	UBERON:0000029	87.06	gold quality
stomach	UBERON:0000945	87.00	gold quality
saliva-secreting gland	UBERON:0001044	86.88	gold quality
upper lobe of left lung	UBERON:0008952	86.82	gold quality
cortical plate	UBERON:0005343	86.78	gold quality
squamous epithelium	UBERON:0006914	86.74	gold quality
lower esophagus mucosa	UBERON:0035834	86.48	gold quality
upper lobe of lung	UBERON:0008948	86.31	gold quality
right lobe of liver	UBERON:0001114	85.98	gold quality
body of pancreas	UBERON:0001150	85.94	gold quality
ileal mucosa	UBERON:0000331	85.88	gold quality
bone marrow cell	CL:0002092	85.76	gold quality
superior surface of tongue	UBERON:0007371	85.75	gold quality
gingiva	UBERON:0001828	85.73	gold quality
gingival epithelium	UBERON:0001949	85.42	silver quality
smooth muscle tissue	UBERON:0001135	85.41	gold quality
spleen	UBERON:0002106	85.34	gold quality
ventricular zone	UBERON:0003053	85.29	gold quality
right lobe of thyroid gland	UBERON:0001119	85.19	gold quality
left coronary artery	UBERON:0001626	85.10	gold quality
thoracic aorta	UBERON:0001515	85.04	gold quality
ascending aorta	UBERON:0001496	85.03	gold quality
cerebellar hemisphere	UBERON:0002245	84.95	gold quality
lower esophagus	UBERON:0013473	84.89	gold quality
right hemisphere of cerebellum	UBERON:0014890	84.88	gold quality
lower esophagus muscularis layer	UBERON:0035833	84.87	gold quality
fundus of stomach	UBERON:0001160	84.77	gold quality
coronary artery	UBERON:0001621	84.76	gold quality
apex of heart	UBERON:0002098	84.75	gold quality
cerebellar cortex	UBERON:0002129	84.70	gold quality
skin of leg	UBERON:0001511	84.68	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	84.68	gold quality
penis	UBERON:0000989	84.65	gold quality
right coronary artery	UBERON:0001625	84.65	gold quality
nasal cavity epithelium	UBERON:0005384	84.65	gold quality
ectocervix	UBERON:0012249	84.64	gold quality
prostate gland	UBERON:0002367	84.44	gold quality
aorta	UBERON:0000947	84.35	gold quality
jejunal mucosa	UBERON:0000399	84.31	gold quality
embryo	UBERON:0000922	84.30	gold quality
left lobe of thyroid gland	UBERON:0001120	84.28	gold quality
muscle layer of sigmoid colon	UBERON:0035805	84.27	gold quality
skin of abdomen	UBERON:0001416	84.19	gold quality
adult mammalian kidney	UBERON:0000082	84.10	gold quality
blood	UBERON:0000178	83.98	gold quality
tibial artery	UBERON:0007610	83.88	gold quality
popliteal artery	UBERON:0002250	83.87	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	83.69	gold quality
oral cavity	UBERON:0000167	83.63	gold quality
lateral nuclear group of thalamus	UBERON:0002736	83.61	silver quality
thyroid gland	UBERON:0002046	83.55	gold quality
nasal cavity mucosa	UBERON:0001826	83.51	gold quality
zone of skin	UBERON:0000014	83.47	gold quality
urinary bladder	UBERON:0001255	83.44	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Frontal cortex	tissue	32.2
Caudate putamen	tissue	28.4
Colon	tissue	27.3	medium
Rectum	tissue	24.4	medium
Duodenum	tissue	23.1	medium
Tonsil	tissue	21.7	medium
Locus coeruleus	tissue	20.5
Esophagus	tissue	20.4	medium
Lymph node	tissue	19.9	medium
Bone marrow	tissue	19.5	low
Appendix	tissue	19.2	medium
Small intestine	tissue	19.1	medium
Stomach 1	tissue	17.7	medium
Thalamus	tissue	16.7
Midbrain	tissue	16.3
Thymus	tissue	16.2
Pons	tissue	16.1
Superior colliculi	tissue	16.0
Spinal cord	tissue	15.6
Medulla oblongata	tissue	15.1
Hippocampal formation	tissue	15.1
Postcentral gyrus	tissue	15.1
Retina	tissue	14.9
Urinary bladder	tissue	14.8	low
Substantia nigra	tissue	14.8
Corpus callosum	tissue	14.6
Smooth muscle	tissue	14.4	medium
Putamen	tissue	13.9
Hippocampus	tissue	13.9	not detected
Salivary gland	tissue	13.7	low
Cerebral cortex	tissue	13.6	medium
Somatosensory cortex	tissue	13.6
Placenta	tissue	13.3	medium
Lung	tissue	13.3	medium
Kidney	tissue	13.2	medium
Liver	tissue	13.1	medium
Skin 1	tissue	13.0	medium
Motor cortex	tissue	13.0
Gallbladder	tissue	13.0	medium
Nucleus accumbens	tissue	12.8
Vagina	tissue	12.6	medium
Occipital cortex	tissue	12.5
Basal ganglia	tissue	12.3	not detected
Ventral forebrain	tissue	12.3
Prefrontal cortex	tissue	12.0
Seminal vesicle	tissue	12.0	medium
Hypothalamus	tissue	12.0
Septum	tissue	11.9
Periaqueductal gray	tissue	11.8
Temporal cortex	tissue	11.8
Retrosplenial and cingulate cortex	tissue	11.7
Entorhinal cortex	tissue	11.6
Pancreas	tissue	11.4	low
Prostate	tissue	11.3	medium
Retrosplenial cortex	tissue	11.1
Skeletal muscle	tissue	11.0	medium
Parathyroid gland	tissue	10.6	not detected
Insular cortex	tissue	10.6
Adipose tissue	tissue	10.5	medium
Adrenal gland	tissue	10.5	medium

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Piriform cortex (19.7), Nucleus ambiguus (18.9), Centromedial thalamic nucleus (18.7), Flocculonodular lobe (18.4), Cerebellar cortex (18.3).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB, ELK1, ETS1, NFE2L2

miRNA regulators (miRDB)

Targeting DPP3 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 51 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4282	99.99	75.36	6408
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-512-3P	99.97	67.35	1049
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-6828-5P	99.31	69.21	1433
HSA-MIR-593-3P	99.22	67.28	1327

Functional genomics

gnomAD constraint: pLI 2.97e-13, LOEUF 0.827, missense Z 1.89 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000531863 — one region, missense o/e 0.86.

Literature-anchored findings (GeneRIF, showing 30)

• In malignant neoplasms of the ovary DPP III activity increased with growing histologic grade. (PMID:14529681)
• the conserved tyrosine could be involved in transition state stabilization during the catalytic action of M49 peptidases. (PMID:18163885)
• Ets-1/Elk-1 is a critical mediator of DPP3 transcription in human glioblastoma cells. (PMID:20236318)
• results provide the basis for the design of specific inhibitors that enable the elucidation of the exact role of DPP III and the exploration of its potential as a target of pain intervention strategies (PMID:22493238)
• The activity of the yeast and human dipeptidyl peptidase III were examined. (PMID:23362197)
• Amplification and mRNA overexpression of the DPP3 gene is associated with squamous cell lung carcinomas. (PMID:23382044)
• Combined results of mutational analysis and mass spectrometry suggest that glutathionylation (formation of mixed disulfide) of Cys176 and Cys654 contributes to human DPP III inactivation by oxidized glutathione. (PMID:23667907)
• Deletion/mutagenesis of C/EBP-beta binding motif of DPP III promoter significantly increased its activity and abolished its responsiveness to IL-6 in glioblastoma cells. (PMID:24472318)
• The study used three different conformations of human dipeptidyl-peptidase III (DPP III) to investigate the influence of the protein environment on ligand binding and the Zn(2+) coordination. (PMID:25192149)
• Kinetic studies revealed that the single mutant D496G lost selectivity due to the increase of the Km value. The D496G, but not S504G, showed significantly decreased binding of peptides with N-terminal arginine, and of tynorphin. (PMID:25581752)
• the DPP III conformational landscape and the influence of ligand binding on the protein structure and dynamics, was investigated. (PMID:26334575)
• biological function of human dipeptidyl peptidase III (PMID:26887037)
• several crystal structures of complexes of human dipeptidyl peptidase III with different peptides. (PMID:27025154)
• Evidence for concurrent expression of hDPP III mRNA V-I and V-II in multiple human tumor derived cell lines. (PMID:27153830)
• We conclude that DPP 3 may influence the cellular expression of Ang-(1-7) and potentially reflect a therapeutic target to augment the actions of the peptide (PMID:27315786)
• Enzyme-inhibitor complex is stabilized by intermolecular hydrogen bonding network, electrostatic and hydrophobic interactions which mostly involve constituent amino acid residues of the hDPP III substrate binding subsites S1, S1’, S2, S2’ and S3’. (PMID:30198396)
• Circulating dipeptidyl peptidase-3 at admission is associated with circulatory failure, acute kidney injury and death in severely ill burn patients. (PMID:32321571)
• Circulatory dipeptidyl peptidase 3 (cDPP3) is a potential biomarker for early detection of secondary brain injury after aneurysmal subarachnoid hemorrhage. (PMID:33549902)
• Dipeptidyl peptidase 3, a marker of the antagonist pathway of the renin-angiotensin-aldosterone system in patients with heart failure. (PMID:33742751)
• Plasma proenkephalin A 119-159 and dipeptidyl peptidase 3 on admission after cardiac arrest help predict long-term neurological outcome. (PMID:33930500)
• DPP3/CDK1 contributes to the progression of colorectal cancer through regulating cell proliferation, cell apoptosis, and cell migration. (PMID:34023852)
• The emerging role of dipeptidyl peptidase 3 in pathophysiology. (PMID:35278345)
• Dipeptidyl Peptidase 3 Activity as a Promising Biomarker of Bone Fragility in Postmenopausal Women. (PMID:35745051)
• DPP3 expression promotes cell proliferation and migration in vitro and tumour growth in vivo, which is associated with poor prognosis of oesophageal carcinoma. (PMID:36382663)
• A Novel Indicator of Myocardial Injury after Acute Myocardial Infarction: ‘DPP-3’. (PMID:36514254)
• Involvement of DPP3 in modulating oncological features and oxidative stress response in esophageal squamous cell carcinoma. (PMID:37531267)
• Identification of an Additional Metal-Binding Site in Human Dipeptidyl Peptidase III. (PMID:37628928)
• Dipeptidyl-peptidase 3 and IL-6: potential biomarkers for diagnostics in COVID-19 and association with pulmonary infiltrates. (PMID:37733154)
• DPP3 promotes breast cancer tumorigenesis by stabilizing FASN and promoting lipid synthesis. (PMID:38655619)
• [Dipeptidyl peptidase 3 (DPP3) inhibits immune escape of gastric cancer cells through down-regulation of major histocompatibility complex class I chain-related gene B (MICB) expression]. (PMID:39442988)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	dpp3	ENSDARG00000020676
mus_musculus	Dpp3	ENSMUSG00000063904
rattus_norvegicus	Dpp3	ENSRNOG00000031485
rattus_norvegicus	Dpp3l1	ENSRNOG00000067192
drosophila_melanogaster	DppIII	FBGN0037580
caenorhabditis_elegans	dpt-1	WBGENE00008532

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1922471) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 22 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased bone marrow cell number	1
decreased body length	1
decreased body weight	1
decreased length of long bones	1
increased osteoclast cell number	1
decreased osteoblast cell number	1
increased bone resorption	1
decreased circulating serum albumin level	1
decreased circulating total protein level	1
decreased apoptosis	1
abnormal optic disk morphology	1
abnormal interferon-gamma secretion	1
increased tumor necrosis factor secretion	1
increased interleukin-1 beta secretion	1
increased interleukin-10 secretion	1
increased interleukin-6 secretion	1
decreased trabecular bone thickness	1
decreased bone volume	1
increased osteoid volume	1
increased osteoid thickness	1
increased bone trabecular spacing	1
decreased bone ossification	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Nematostella vectensis	A7RZW4	57.9%	Diamond
Dictyostelium discoideum	Q557H1	47.6%	Diamond
Saccharomyces cerevisiae S288C	Q08225	39.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
DPP3-DT	ncRNA	101928069
PELI3	protein-coding	246330
MRPL11	protein-coding	65003
ZDHHC24	protein-coding	254359
BBS1	protein-coding	582
ACTN3	protein-coding	89
CCDC87	protein-coding	55231
CTSF	protein-coding	8722

Protein

Protein identifiers

Dipeptidyl peptidase 3 — Q9NY33 (reviewed: Q9NY33)

Alternative names: Dipeptidyl aminopeptidase III, Dipeptidyl arylamidase III, Dipeptidyl peptidase III, Enkephalinase B

All UniProt accessions (8): E9PKK8, E9PNX5, E9PPK9, E9PQ14, E9PQF2, G3V180, G3V1D3, Q9NY33

UniProt curated annotations — full annotation on UniProt →

Function. Cleaves and degrades bioactive peptides, including angiotensin, Leu-enkephalin and Met-enkephalin. Also cleaves Arg-Arg-beta-naphthylamide (in vitro).

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Detected in placenta (at protein level). Detected in erythrocytes (at protein level).

Activity regulation. Activated by Co(2+). Inhibited by EDTA and o-phenanthroline (in vitro).

Cofactor. Binds 1 zinc ion per subunit.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the peptidase M49 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9NY33-1	1	yes
Q9NY33-2	2
Q8NFJ9-2	3, DPP3-BBS1
Q9NY33-4	4

RefSeq proteins (3): NP_001243599, NP_005691, NP_569710* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005317	DPP3_euk	Family
IPR039461	Peptidase_M49	Family

Pfam: PF03571

Enzyme classification (BRENDA)

• EC 3.4.14.4 — dipeptidyl-peptidase III (BRENDA: 25 organisms, 122 substrates, 378 inhibitors, 72 Km, 59 kcat entries)

Substrate kinetics (BRENDA)

26 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ARG-ARG-2-NAPHTHYLAMIDE	0.001–0.3	27
L-ARG-L-ARG 2-NAPHTHYLAMIDE	0.0026–0.0251	7
L-ARG-L-ARG-2-NAPHTHYLAMIDE	0.0028–0.5789	5
ALA-ALA-2-NAPHTHYLAMIDE	0.24–0.441	4
L-ALA-L-ALA 2-NAPHTHYLAMIDE	0.0945–0.2316	3
L-LYS-L-ALA-2-NAPHTHYLAMIDE	0.07–0.2	3
LEU-ENKEPHALIN	0.0057–0.22	3
ALA-ARG-2-NAPHTHYLAMIDE	0.005–0.0172	2
ARG-ARG-2-NAPHTYLAMIDE	0.031–0.035	2
ARG-ARG-4-METHYLCOUMARIN 7-AMIDE	0.0026–0.055	2
PROCTOLIN	0.0038–0.0045	2
ARG-ARG-4-METHOXY-2-NAPHTHYLAMIDE	0.022	1
ARG-ARG-4-METHOXY-BETA-NAPHTHYLAMIDE	0.039	1
ARG-ARG-BETA-NAPHTHYLAMIDE	0.009	1
ARG-TYR-LEU-PRO-THR	0.004	1

UniProt features (89 total): helix 42, strand 26, turn 5, sequence variant 4, sequence conflict 3, binding site 3, splice variant 2, initiator methionine 1, chain 1, active site 1, modified residue 1

Structure

Experimental structures (PDB)

10 structures by resolution:

PDB	Title	Method	Resolution (Å)
5E33	Structure of human DPP3 in complex with met-enkephalin	X-RAY DIFFRACTION	1.84
3FVY	Crystal structure of human Dipeptidyl Peptidase III	X-RAY DIFFRACTION	1.9
5E3A	Structure of human DPP3 in complex with opioid peptide leu-enkephalin	X-RAY DIFFRACTION	2.05
5EHH	Structure of human DPP3 in complex with endomorphin-2.	X-RAY DIFFRACTION	2.38
3T6B	Structure of human DPPIII in complex with the opioid peptide Tynorphin, at 2.4 Angstroms	X-RAY DIFFRACTION	2.4
5E2Q	Structure of human DPP3 in complex with angiotensin-II	X-RAY DIFFRACTION	2.4
7OUP	Structure of human DPP3 in complex with a hydroxyethylene transition state peptidomimetic	X-RAY DIFFRACTION	2.65
5EGY	Structure of ligand free human DPP3 in closed form.	X-RAY DIFFRACTION	2.74
5E3C	Structure of human DPP3 in complex with hemorphin like opioid peptide IVYPW	X-RAY DIFFRACTION	2.77
3T6J	Structure of human DPPIII in complex with the opioid peptide Tynorphin, at 3.0 Angstroms	X-RAY DIFFRACTION	2.98

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NY33-F1	95.56	0.92

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Peptidases, Metallopeptidases, Predicted intracellular proteins, Plasma proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol

Antibody reliability (HPA): IH approved · IF supported

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1)

Position	Role
451

Ligand- & substrate-binding residues (3)

Position	Role
450	Zn(2+)
455	Zn(2+)
508	Zn(2+)

Post-translational modifications (1)

Type	Positions
N-acetylalanine	2

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 7; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

7 pathways:

ID	Pathway	Evidence
R-HSA-9755511	KEAP1-NFE2L2 pathway	curated
R-HSA-8951664	Neddylation	curated
R-HSA-9711123	Cellular response to chemical stress	—
R-HSA-8953897	Cellular responses to stimuli	—
R-HSA-2262752	Cellular responses to stress	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-597592	Post-translational protein modification	—

MSigDB gene sets: 176 (showing top): GOMF_METALLOPEPTIDASE_ACTIVITY, chr11q13, CAGCTG_AP4_Q5, LIAO_METASTASIS, TIEN_INTESTINE_PROBIOTICS_24HR_UP, RYTTCCTG_ETS2_B, ELK1_01, P300_01, NIKOLSKY_BREAST_CANCER_11Q12_Q14_AMPLICON, ROSTY_CERVICAL_CANCER_PROLIFERATION_CLUSTER, NERF_Q2, GOBP_PROTEOLYSIS, SCGGAAGY_ELK1_02, MGGAAGTG_GABP_B, GOMF_METALLOEXOPEPTIDASE_ACTIVITY

GO Biological Process (1): proteolysis (GO:0006508)

GO Molecular Function (9): aminopeptidase activity (GO:0004177), metalloexopeptidase activity (GO:0008235), dipeptidyl-peptidase activity (GO:0008239), zinc ion binding (GO:0008270), protein binding (GO:0005515), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

5 top-level categories:

Category	Pathways
Post-translational protein modification	1
Cellular response to chemical stress	1
Cellular responses to stimuli	1
Metabolism of proteins	1
Cellular responses to stress	1

GO top-level categories

14 GO namespaces:

Category	Terms
exopeptidase activity	3
cellular anatomical structure	2
protein metabolic process	1
metallopeptidase activity	1
transition metal ion binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
cytoplasm	1
extracellular vesicle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 5 of 13 annotations. The rest are phylogenetic / computational / electronic (IEA).

5 experimentally-supported GO terms:

GO term	NS	Evidence
proteolysis	BP	direct assay
cytosol	CC	direct assay
extracellular exosome	CC	high-throughput assay
dipeptidyl-peptidase activity	MF	direct assay
zinc ion binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 890 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DPP3	RNPEP	Q9H4A4	697
DPP3	AMER1	Q5JTC6	685
DPP3	DPP7	Q9UHL4	677
DPP3	PALB2	Q86YC2	651
DPP3	PREP	P48147	619
DPP3	MME	P08473	567
DPP3	PGAM5	Q96HS1	560
DPP3	DPP9	Q86TI2	555
DPP3	ANPEP	P15144	542
DPP3	CHD6	Q8TD26	539
DPP3	THOP1	P52888	538
DPP3	KEAP1	Q14145	529
DPP3	DPP4	P27487	513
DPP3	ACE	P12821	507
DPP3	MMEL1	Q495T6	505

IntAct

Human interaction partners of DPP3 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

7 partners by confidence:

Partner	Interaction type	MIscore	Records
KEAP1	physical association	0.910	10
POT1	physical association	0.370	1
TERF1	physical association	0.370	1
TERF2IP	physical association	0.370	1
TINF2	physical association	0.370	1
ATP5F1C	physical association	0.000	1
HSPA8	physical association	0.000	1

BioGRID (60 interactions; top human partners by supporting records): KEAP1 (Two-hybrid; 10 records), BBS1 (Affinity Capture-MS; 2 records), PARK2 (Affinity Capture-MS; 2 records), AASS (Co-fractionation), AGR2 (Proximity Label-MS), ALDH8A1 (Co-fractionation), APEH (Affinity Capture-MS), APEX1 (Affinity Capture-RNA), APP (Reconstituted Complex), ASS1 (Co-fractionation), ATP5C1 (Two-hybrid), CEBPA (Protein-peptide), CLIC1 (Affinity Capture-MS), DLD (Co-fractionation), DSTN (Co-fractionation)

SIGNOR signaling

2 signaling interactions:

A	Effect	B	Mechanism
DPP3	“down-regulates quantity by destabilization”	KEAP1	cleavage
DPP3	“down-regulates quantity by destabilization”	Angiotensin-2	cleavage

Disease & clinical

Genetic variants

Variant evidence for DPP3: 173 ClinVar records (0 pathogenic / likely pathogenic); 1 GWAS association.

ClinVar

173 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	135
Likely benign	1
Benign	10

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 53 predictions of 1,437):

Position(s)	Effect	Δscore	Sites
11:66482471–66482472	donor_loss	1.0000	5
11:66485171–66485172	acceptor_loss	1.0000	5
11:66485263–66485264	donor_loss	1.0000	5
11:66486538–66486539	acceptor_loss	1.0000	6
11:66486678–66486679	donor_loss	1.0000	5
11:66487266–66487267	acceptor_loss	1.0000	6
11:66487912–66487913	acceptor_loss	1.0000	6
11:66488008–66488009	donor_loss	1.0000	5
11:66491251–66491252	acceptor_loss	1.0000	5
11:66491384–66491385	donor_loss	1.0000	5

AlphaMissense

1,878 missense substitutions predicted likely pathogenic (of 4,908 scored), across 472 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M546	9	0.824	0.970
H450	8	0.995	0.999
H455	8	0.995	0.998
H568	8	0.994	0.998
D320	8	0.991	0.996
F109	8	0.979	0.998
D250	8	0.969	0.987
F314	8	0.965	0.999
D111	8	0.962	0.992
N406	8	0.962	0.997
F499	8	0.959	0.997
F373	8	0.950	0.997
F426	8	0.950	0.995
N411	8	0.942	0.997
F404	8	0.940	0.998
H293	8	0.939	0.988
F381	8	0.935	0.997
F528	8	0.928	0.984
F443	8	0.920	0.990
F285	8	0.918	0.987

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Chromophobe (TCGA)	unfavorable	0.000137
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.00044
Lung Adenocarcinoma (validation)	unfavorable	0.000953

Disease associations

OMIM: gene MIM:606818 | disease phenotypes:

GWAS associations

1 associations:

Study	Trait	p-value
GCST001241_12	Bipolar disorder	2e-7

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4520 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — M49: Dipeptidyl-peptidase III

Binding affinities (BindingDB)

16 measured of 40 human assays (46 total across all organisms); most potent 16 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5193958	IC50	130 nM
2,4-Disubstituted-1,3-di-(5-amidino-2-benzoimidazolyl)-cyclobutane hydrochoride, 1’	KD	200 nM
Naringenin, 18	IC50	710 nM
cid_5280863	IC50	1050 nM
CHEMBL5175079	IC50	1440 nM
CHEMBL5653589	KD	1440 nM
Prunetol	IC50	2210 nM
CHEMBL5182137	IC50	4600 nM
CHEMBL5187966	IC50	7700 nM
CHEMBL5199877	IC50	8500 nM
(3R,4S)-1-[6-(6-METHOXYPYRIDIN-3-YL)PYRIMIDIN-4-YL]-4-(2,4,5-TRIFLUOROPHENYL)PYRROLIDIN-3-AMINE	IC50	19000 nM
CHEMBL5176913	IC50	21000 nM
CHEMBL5191808	IC50	22500 nM
flavone	KD	33900 nM
CHEMBL5193133	IC50	74000 nM
3,7-dihydroxy-2-phenyl-4H-chromen-4-one	IC50	1.25e+07 nM

ChEMBL bioactivities

5 potent at pChembl≥5 of 10 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.89	IC50	130	nM	CHEMBL5193958
5.84	IC50	1440	nM	CHEMBL5175079
5.34	IC50	4600	nM	CHEMBL5182137
5.11	IC50	7700	nM	CHEMBL5187966
5.07	IC50	8500	nM	CHEMBL5199877

PubChem BioAssay actives

10 with measured affinity, of 48 total; 10 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]-3-phenylpropanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoic acid	1873652: Inhibition of DPP3 (unknown origin)	ic50	0.1300	uM
6,7-dihydroxy-3-methylbenzo[a]fluorene-1,4,11-trione	1873651: Competitive inhibition of DPP3 (unknown origin) using Arg-Arg-2-naphthylamide as substrate	ic50	1.4400	uM
6-(4,5-dihydro-1H-imidazol-3-ium-2-yl)-2-[3-[6-(4,5-dihydro-1H-imidazol-3-ium-2-yl)-1H-benzimidazol-2-yl]-2,4-diphenylcyclobutyl]-1H-benzimidazole	1799651: Enzyme Inhibition Assay from Article 10.1016/j.bioorg.2006.11.002: “Novel amidino-substituted benzimidazoles: synthesis of compounds and inhibition of dipeptidyl peptidase III.”	ic50	2.8000	uM
(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-1-fluoro-3-methylbutylidene]amino]-3-phenylpropanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoic acid	1873650: Inhibition of human DPP3 using Arg-Arg-2-naphthylamide as substrate assessed as reduction in release of 2-naphthylamine preincubated for 10 mins followed by substrate addition and measured for 30 mins by fluorescence based analysis	ic50	4.6000	uM
[amino-[2-[3-[6-[amino(azaniumylidene)methyl]-1H-benzimidazol-2-yl]-2,4-diphenylcyclobutyl]-3H-benzimidazol-5-yl]methylidene]azanium	1799651: Enzyme Inhibition Assay from Article 10.1016/j.bioorg.2006.11.002: “Novel amidino-substituted benzimidazoles: synthesis of compounds and inhibition of dipeptidyl peptidase III.”	ic50	5.6000	uM
[amino-[2-[3-[6-[amino(propan-2-ylazaniumylidene)methyl]-1H-benzimidazol-2-yl]-2,4-bis(2-chlorophenyl)cyclobutyl]-3H-benzimidazol-5-yl]methylidene]-propan-2-ylazanium	1799651: Enzyme Inhibition Assay from Article 10.1016/j.bioorg.2006.11.002: “Novel amidino-substituted benzimidazoles: synthesis of compounds and inhibition of dipeptidyl peptidase III.”	ic50	6.0000	uM
[amino-[2-[3-[6-[amino(azaniumylidene)methyl]-1H-benzimidazol-2-yl]-2,4-bis(2-chlorophenyl)cyclobutyl]-3H-benzimidazol-5-yl]methylidene]azanium	1799651: Enzyme Inhibition Assay from Article 10.1016/j.bioorg.2006.11.002: “Novel amidino-substituted benzimidazoles: synthesis of compounds and inhibition of dipeptidyl peptidase III.”	ic50	7.0000	uM
(2S)-2-[[(2S)-1-[(Z,2R,5S)-5-[[(2S)-2-amino-3-methylbutanoyl]amino]-2-benzyl-4-fluoro-6-methylhept-3-enoyl]piperidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoic acid	1873650: Inhibition of human DPP3 using Arg-Arg-2-naphthylamide as substrate assessed as reduction in release of 2-naphthylamine preincubated for 10 mins followed by substrate addition and measured for 30 mins by fluorescence based analysis	ic50	7.7000	uM
6-(4,5-dihydro-1H-imidazol-3-ium-2-yl)-2-[3-[6-(4,5-dihydro-1H-imidazol-3-ium-2-yl)-1H-benzimidazol-2-yl]-2,4-bis(furan-2-yl)cyclobutyl]-1H-benzimidazole	1799651: Enzyme Inhibition Assay from Article 10.1016/j.bioorg.2006.11.002: “Novel amidino-substituted benzimidazoles: synthesis of compounds and inhibition of dipeptidyl peptidase III.”	ic50	8.0000	uM
(2S)-2-[[(2S)-1-[(2S)-2-[[(1S,2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-1-hydroxy-3-methylbutyl]amino]-3-phenylpropanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoic acid	1873652: Inhibition of DPP3 (unknown origin)	ic50	8.5000	uM

CTD chemical–gene interactions

43 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation	2
Smoke	decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Valproic Acid	affects expression, decreases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
bisphenol F	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression, decreases expression	1
tetrahydropalmatine	decreases expression	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression	1
Ro 31-8220	decreases reaction, increases expression	1
di-n-butylphosphoric acid	affects expression	1
spinorphin	decreases reaction, increases cleavage	1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases reaction, increases expression	1
tynorphin	decreases reaction, increases cleavage	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
jinfukang	increases expression	1
(+)-JQ1 compound	increases expression	1
bisphenol AF	increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Vehicle Emissions	decreases expression, decreases reaction	1
Benztropine	affects cotreatment, decreases expression	1
Cisplatin	decreases expression, decreases reaction	1
Clozapine	affects cotreatment, decreases expression	1
Cuprizone	affects cotreatment, decreases expression	1
Doxorubicin	affects expression	1
Enkephalin, Leucine	increases cleavage, decreases reaction	1
Furaldehyde	affects cotreatment, affects localization, increases expression	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1010598	Binding	Inhibition of DPP3 in human erythrocytes	(3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone: a potent, selective, orally active dipeptidyl peptidase IV inhibitor. — *Bioorg Med Chem Lett*

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_ER17	IMR-32_pCMV-DPP3	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for DPP3 across ~30M SureChEMBL compounds — explore on Sugi Predict.