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
• Druggable target: yes
• MANE Select transcript: NM_130443

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: 31 — 24 protein_coding, 5 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000525738, ENST00000526250, ENST00000526515, ENST00000526667, ENST00000530165, ENST00000531272, ENST00000531314, ENST00000531354, ENST00000531863, ENST00000532019, ENST00000532677, ENST00000533725, ENST00000533799, ENST00000539085, ENST00000541961, ENST00000544603, ENST00000883956, ENST00000883957, ENST00000883958, ENST00000883959, ENST00000883960, ENST00000883961, ENST00000883962, ENST00000883963, ENST00000883964, ENST00000914249, ENST00000914250, ENST00000914252, ENST00000914253, ENST00000914254, ENST00000962696

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.

FANTOM5 promoters (2 alternative TSS)

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

Top tissues by expression

283 total, 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

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

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

miRNA regulators (miRDB)

51 targeting DPP3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

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

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	Dpp3l1	ENSRNOG00000031485
rattus_norvegicus		ENSRNOG00000067192
drosophila_melanogaster	DppIII	FBGN0037580
caenorhabditis_elegans	dpt-1	WBGENE00008532

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, Q9NY33, E9PNX5, E9PPK9, E9PQ14, E9PQF2, G3V180, G3V1D3

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	Dipeptidyl-peptase3	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 (88 total): helix 38, strand 26, turn 8, 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.

PDB	Method	Resolution (Å)
5E33	X-RAY DIFFRACTION	1.84
3FVY	X-RAY DIFFRACTION	1.9
5E3A	X-RAY DIFFRACTION	2.05
5EHH	X-RAY DIFFRACTION	2.38
3T6B	X-RAY DIFFRACTION	2.4
5E2Q	X-RAY DIFFRACTION	2.4
7OUP	X-RAY DIFFRACTION	2.65
5EGY	X-RAY DIFFRACTION	2.74
5E3C	X-RAY DIFFRACTION	2.77
3T6J	X-RAY DIFFRACTION	2.98

Predicted structure (AlphaFold)

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

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): 451

Ligand- & substrate-binding residues (3): 450; 455; 508

Post-translational modifications (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-8951664	Neddylation
R-HSA-9755511	KEAP1-NFE2L2 pathway

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

Rollup of top-2 pathways:

Category	Pathways
Post-translational protein modification	1
Cellular response to chemical stress	1

GO top-level categories

Rollup of top GO terms by namespace:

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

Protein interactions and networks

STRING

1179 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DPP3	KEAP1	Q14145	919
DPP3	AGT	P01019	697
DPP3	DPP7	Q9UHL4	692
DPP3	PALB2	Q86YC2	685
DPP3	AMER1	Q5JTC6	670
DPP3	RNPEP	Q9H4A4	633
DPP3	PREP	P48147	622
DPP3	THOP1	P52888	603
DPP3	CDK20	Q8IZL9	564
DPP3	CHD6	Q8TD26	555
DPP3	MCM3	P25205	537
DPP3	PGAM5	Q96HS1	522
DPP3	CTSC	P53634	510
DPP3	DPP4	P27487	498
DPP3	CUL3	Q13618	488

IntAct

42 interactions, top by confidence:

A	B	Type	Score
BBS1	BBS9	psi-mi:“MI:0914”(association)	0.940
KEAP1	DPP3	psi-mi:“MI:0915”(physical association)	0.910
DPP3	KEAP1	psi-mi:“MI:0915”(physical association)	0.910
DPP3	TERF1	psi-mi:“MI:0915”(physical association)	0.370
TERF2IP	DPP3	psi-mi:“MI:0915”(physical association)	0.370
DPP3	TINF2	psi-mi:“MI:0915”(physical association)	0.370
POT1	DPP3	psi-mi:“MI:0915”(physical association)	0.370
BBS1	HSPA8	psi-mi:“MI:0914”(association)	0.350
KEAP1	VWA8	psi-mi:“MI:0914”(association)	0.350
OSBPL10	SAP18	psi-mi:“MI:0914”(association)	0.350
KEAP1	SEC16A	psi-mi:“MI:0914”(association)	0.350
KEAP1	ASNS	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
RGS20	KIF3B	psi-mi:“MI:0914”(association)	0.350
APEH	MPRIP	psi-mi:“MI:0914”(association)	0.350
DDX28	UBA6	psi-mi:“MI:0914”(association)	0.350
GAB2	UBA6	psi-mi:“MI:0914”(association)	0.350
ITM2C	UBA6	psi-mi:“MI:0914”(association)	0.350
MRPL49	UBA6	psi-mi:“MI:0914”(association)	0.350
TTC9C		psi-mi:“MI:0914”(association)	0.350
MAPT	PITPNM1	psi-mi:“MI:2364”(proximity)	0.270
MAPT	DCTN6	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (58): DPP3 (Two-hybrid), DPP3 (Co-fractionation), DPP3 (Co-fractionation), TANGO2 (Co-fractionation), DPP3 (Affinity Capture-MS), KEAP1 (Two-hybrid), DPP3 (Affinity Capture-MS), DPP3 (Affinity Capture-MS), KEAP1 (Affinity Capture-Western), DPP3 (Affinity Capture-Western), DPP3 (Proximity Label-MS), DPP3 (Affinity Capture-RNA), DPP3 (Affinity Capture-MS), DPP3 (Two-hybrid), DPP3 (Two-hybrid)

ESM2 similar proteins: A0A4P8DJE6, A5PKH3, A7EI75, A7KAL8, A7RZW4, F7W4M2, G2XR75, I1S0J7, O55096, O74638, O93918, P16930, P25093, P32327, P35505, P38095, P38675, P78820, P80576, Q00770, Q02218, Q09WE7, Q0CLK1, Q0GZS3, Q148N0, Q1RMS2, Q1ZXQ1, Q4WHT8, Q4WJ90, Q4WYN6, Q52CS0, Q5AWA2, Q5RCB8, Q5W915, Q5XI78, Q60597, Q60HE2, Q6H7M1, Q6P6Z8, Q6PEI7

Diamond homologs: A7RZW4, O55096, Q08225, Q557H1, Q99KK7, Q9NY33, Q9VHR8

SIGNOR signaling

2 interactions.

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

Disease & clinical

Clinical variants and AI predictions

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

2850 predictions. Top by Δscore:

Variant	Effect	Δscore
11:66482466:ATCAG:A	donor_loss	1.0000
11:66482467:TCAGG:T	donor_loss	1.0000
11:66482469:AGGT:A	donor_loss	1.0000
11:66482471:G:GA	donor_loss	1.0000
11:66482472:T:G	donor_loss	1.0000
11:66485167:CCTCA:C	acceptor_loss	1.0000
11:66485168:CTCA:C	acceptor_loss	1.0000
11:66485169:TCAGG:T	acceptor_loss	1.0000
11:66485170:CAGG:C	acceptor_loss	1.0000
11:66485171:A:AG	acceptor_gain	1.0000
11:66485171:A:G	acceptor_loss	1.0000
11:66485171:AG:A	acceptor_gain	1.0000
11:66485172:G:GG	acceptor_gain	1.0000
11:66485172:GG:G	acceptor_gain	1.0000
11:66485172:GGC:G	acceptor_gain	1.0000
11:66485259:CAAGG:C	donor_loss	1.0000
11:66485260:AAGG:A	donor_loss	1.0000
11:66485261:AGG:A	donor_loss	1.0000
11:66485262:GGT:G	donor_loss	1.0000
11:66485263:GT:G	donor_loss	1.0000
11:66485264:T:A	donor_loss	1.0000
11:66486534:TTGCA:T	acceptor_loss	1.0000
11:66486536:GCAG:G	acceptor_loss	1.0000
11:66486537:CA:C	acceptor_loss	1.0000
11:66486538:A:C	acceptor_loss	1.0000
11:66486539:GGAA:G	acceptor_gain	1.0000
11:66486539:GGAAA:G	acceptor_gain	1.0000
11:66486674:GGAG:G	donor_gain	1.0000
11:66486675:GAGG:G	donor_gain	1.0000
11:66486676:AGGTG:A	donor_loss	1.0000

AlphaMissense

4908 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:66491708:T:C	F314L	0.999
11:66491710:C:A	F314L	0.999
11:66491710:C:G	F314L	0.999
11:66491715:A:T	E316V	0.999
11:66491716:G:C	E316D	0.999
11:66491716:G:T	E316D	0.999
11:66491724:G:C	R319P	0.999
11:66493592:C:G	H450D	0.999
11:66493596:A:T	E451V	0.999
11:66493597:G:C	E451D	0.999
11:66493597:G:T	E451D	0.999
11:66495435:A:T	E508V	0.999
11:66495436:G:C	E508D	0.999
11:66495436:G:T	E508D	0.999
11:66485227:T:C	F109L	0.998
11:66485229:T:A	F109L	0.998
11:66485229:T:G	F109L	0.998
11:66487936:G:C	R199P	0.998
11:66491706:G:A	G313E	0.998
11:66492900:C:A	N391K	0.998
11:66492900:C:G	N391K	0.998
11:66493093:T:C	F404L	0.998
11:66493095:T:A	F404L	0.998
11:66493095:T:G	F404L	0.998
11:66493098:G:C	K405N	0.998
11:66493098:G:T	K405N	0.998
11:66493592:C:A	H450N	0.998
11:66493595:G:A	E451K	0.998
11:66493596:A:C	E451A	0.998
11:66493605:G:A	G454D	0.998

dbSNP variants (sampled 300 via entrez): RS1000017758 (11:66491501 C>T), RS1000170720 (11:66492053 G>A,C), RS1000234996 (11:66493998 G>C), RS1000334444 (11:66487943 C>G,T), RS1000388080 (11:66488087 C>A,G), RS1000433824 (11:66491782 TCA>T), RS1000621950 (11:66492969 C>T), RS1000724825 (11:66486840 A>G), RS1000775561 (11:66487127 T>G), RS1000782398 (11:66498081 C>T), RS1001029622 (11:66498345 G>A,C), RS1001081719 (11:66499128 C>T), RS1001086521 (11:66505038 G>A), RS1001089306 (11:66480434 A>G), RS1001456699 (11:66487541 A>G)

Disease associations

OMIM: gene MIM:606818 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001241_12	Bipolar disorder	2.000000e-07

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4520 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — M49: Dipeptidyl-peptidase III

Binding affinities (BindingDB)

4 measured of 27 human assays (27 total across all organisms); most potent 4 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
2,4-Disubstituted-1,3-di-(5-amidino-2-benzoimidazolyl)-cyclobutane hydrochoride, 1’	KD	200 nM
2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4H-chromen-4-one	KI	2200 nM
5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one	IC50	64300 nM
2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one	IC50	72800 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 47 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 localization, increases expression, decreases expression, affects cotreatment	1
tetrahydropalmatine	decreases expression	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression	1
Ro 31-8220	increases expression, decreases reaction	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)

0 trials via MONDO — disease-level, not drug-specific.