DPEP3

Summary

DPEP3 (dipeptidase 3, HGNC:23029) is a protein-coding gene on chromosome 16q22.1, encoding Dipeptidase 3 (Q9H4B8). Lacks dipeptidase activity and is unable to hydrolyze cystinyl-bis-glycine, leukotriene D4 and the beta-lactam antibiotic imipenem.

This gene encodes a membrane-bound glycoprotein from the family of dipeptidases involved in hydrolytic metabolism of various dipeptides, including penem and carbapenem beta-lactam antibiotics. This gene is located on chromosome 16 in a cluster with another member of this family. Alternatively spliced transcript variants that encode different isoforms have been found for this gene.

Source: NCBI Gene 64180 — RefSeq curated summary.

At a glance

• GWAS associations: 23
• Clinical variants (ClinVar): 85 total
• MANE Select transcript: NM_001370198

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23029
Approved symbol	DPEP3
Name	dipeptidase 3
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000141096
Ensembl biotype	protein_coding
OMIM	609926
Entrez	64180

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000268793, ENST00000574342, ENST00000672962, ENST00000876631

RefSeq mRNA: 2 — MANE Select: NM_001370198 NM_001129758, NM_001370198

CCDS: CCDS10856

Canonical transcript exons

ENST00000268793 — 10 exons

Exon	Start	End
ENSE00000946577	67978267	67978408
ENSE00000946578	67977938	67978007
ENSE00000946581	67976700	67976775
ENSE00000946582	67976093	67976228
ENSE00001294460	67975663	67976001
ENSE00001322074	67980094	67980499
ENSE00001598520	67978497	67978626
ENSE00001664599	67979639	67979765
ENSE00001679349	67977653	67977829
ENSE00001703908	67977270	67977354

Expression profiles

Bgee: expression breadth ubiquitous, 112 present calls, max score 95.11.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4872 / max 284.0760, expressed in 75 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157842	0.3069	50
157841	0.1647	54
157840	0.0156	8

Top tissues by expression

254 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	95.11	gold quality
left testis	UBERON:0004533	93.80	gold quality
testis	UBERON:0000473	91.34	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.75	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.15	gold quality
sperm	CL:0000019	77.02	silver quality
male germ cell	CL:0000015	76.44	silver quality
blood	UBERON:0000178	75.49	gold quality
adult organism	UBERON:0007023	74.46	gold quality
diaphragm	UBERON:0001103	70.45	gold quality
granulocyte	CL:0000094	70.05	gold quality
triceps brachii	UBERON:0001509	69.41	gold quality
tendon of biceps brachii	UBERON:0008188	65.59	gold quality
buccal mucosa cell	CL:0002336	65.46	gold quality
vastus lateralis	UBERON:0001379	65.26	gold quality
gluteal muscle	UBERON:0002000	64.94	gold quality
spleen	UBERON:0002106	64.80	gold quality
biceps brachii	UBERON:0001507	64.64	gold quality
quadriceps femoris	UBERON:0001377	64.49	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	61.20	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	60.84	gold quality
bone marrow	UBERON:0002371	60.31	gold quality
hindlimb stylopod muscle	UBERON:0004252	59.15	gold quality
skeletal muscle tissue	UBERON:0001134	59.10	gold quality
bone marrow cell	CL:0002092	58.42	gold quality
decidua	UBERON:0002450	57.86	gold quality
superficial temporal artery	UBERON:0001614	57.67	gold quality
leukocyte	CL:0000738	57.45	gold quality
myocardium	UBERON:0002349	57.19	gold quality
deltoid	UBERON:0001476	56.77	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-124263	yes	1242.67
E-ANND-3	no	0.95

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

6 targeting DPEP3, 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-3064-3P	100.00	70.09	1254
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-1257	98.97	68.02	1133
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-6805-5P	95.79	64.86	670

Literature-anchored findings (GeneRIF, showing 1)

• This paper describes differences in substrate specificity and tissue distribution of membrane-bound dipeptidase 3 from mouse in comparison to other mouse members of this family. (PMID:12738806)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Dpep3	ENSMUSG00000031898
rattus_norvegicus	Dpep3	ENSRNOG00000019757
drosophila_melanogaster	CG6154	FBGN0039420
drosophila_melanogaster	CG44837	FBGN0266100

Paralogs (2): DPEP1 (ENSG00000015413), DPEP2 (ENSG00000167261)

Protein

Protein identifiers

Dipeptidase 3 — Q9H4B8 (reviewed: Q9H4B8)

All UniProt accessions (2): A0A5F9ZHB4, Q9H4B8

UniProt curated annotations — full annotation on UniProt →

Function. Lacks dipeptidase activity and is unable to hydrolyze cystinyl-bis-glycine, leukotriene D4 and the beta-lactam antibiotic imipenem. The absence of activity may be due to the inability of asparagine (instead of aspartate found in DPEP1/2) at position 359 to function as the acid/base catalyst and activate the nucleophilic water/hydroxide. A tyrosine (instead of histidine) at position 269 reduces affinity for the beta zinc and may cause substrate steric hindrance.

Subunit / interactions. Homodimer; disulfide-linked. Interacts with TEX101; co-localized on the cell surface of spermatocytes, spermatids, and testicular spermatozoa, co-localized only in cytoplasmic droplets of caput and corpus epididymal sperm.

Subcellular location. Membrane.

Similarity. Belongs to the metallo-dependent hydrolases superfamily. Peptidase M19 family.

RefSeq proteins (2): NP_001123230, NP_001357127* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000180	Dipep_AS	Active_site
IPR008257	Pept_M19	Family
IPR032466	Metal_Hydrolase	Homologous_superfamily

Pfam: PF01244

UniProt features (48 total): helix 19, strand 14, turn 4, disulfide bond 3, sequence conflict 2, signal peptide 1, chain 1, propeptide 1, lipid moiety-binding region 1, glycosylation site 1, mutagenesis site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6VGO	X-RAY DIFFRACTION	1.82
6VGR	X-RAY DIFFRACTION	2.84

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H4B8-F1	84.15	0.70

Antibody-complex structures (SAbDab): 1 — 6VGR

Functional residue map

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

Post-translational modifications (1): 463

Disulfide bonds (3): 146–225, 297–329, 434

Glycosylation sites (1): 334

Mutagenesis-validated functional residues (1):

Position	Phenotype
196	loss of zinc binding.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 92 (showing top): chr16q22, GOCC_SECRETORY_GRANULE, GOBP_SULFUR_COMPOUND_CATABOLIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, HELLER_HDAC_TARGETS_SILENCED_BY_METHYLATION_UP, GOBP_SMALL_MOLECULE_CATABOLIC_PROCESS, GOBP_LIPID_CATABOLIC_PROCESS, GOBP_FATTY_ACID_DERIVATIVE_METABOLIC_PROCESS, GOBP_LEUKOTRIENE_METABOLIC_PROCESS, GOCC_SECRETORY_VESICLE, GOCC_SIDE_OF_MEMBRANE, GOBP_PROTEOLYSIS

GO Biological Process (2): proteolysis (GO:0006508), leukotriene D4 catabolic process (GO:1901749)

GO Molecular Function (3): dipeptidase activity (GO:0016805), peptidase activity (GO:0008233), metallodipeptidase activity (GO:0070573)

GO Cellular Component (4): acrosomal vesicle (GO:0001669), plasma membrane (GO:0005886), membrane (GO:0016020), side of membrane (GO:0098552)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
membrane	2
cellular anatomical structure	2
protein metabolic process	1
leukotriene catabolic process	1
sulfur compound catabolic process	1
icosanoid catabolic process	1
exopeptidase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
metalloexopeptidase activity	1
dipeptidase activity	1
secretory granule	1
cell periphery	1
leaflet of membrane bilayer	1

Protein interactions and networks

STRING

686 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DPEP3	TEX101	Q9BY14	751
DPEP3	ANPEP	P15144	446
DPEP3	CNDP2	Q96KP4	430
DPEP3	SMIM12	Q96EX1	411
DPEP3	HSPA5	P11021	409
DPEP3	SPACA4	Q8TDM5	406
DPEP3	ANKEF1	Q9NU02	399
DPEP3	CSNK2A2IP	A0A1B0GTH6	398
DPEP3	XPNPEP2	O43895	397
DPEP3	LY6K	Q17RY6	382
DPEP3	ACE2	Q9BYF1	379
DPEP3	XPNPEP3	Q9NQH7	372
DPEP3	XPNPEP1	Q9NQW7	371
DPEP3	MAGEB17	A8MXT2	368
DPEP3	BEND7	Q8N7W2	365

IntAct

13 interactions, top by confidence:

A	B	Type	Score
DPEP3	HSPA5	psi-mi:“MI:0914”(association)	0.530
TEX101	DPEP3	psi-mi:“MI:2364”(proximity)	0.420
DPEP3	PDIA6	psi-mi:“MI:0915”(physical association)	0.400
TEX101	NDUFA4	psi-mi:“MI:0914”(association)	0.350
TEX101	ITGB1	psi-mi:“MI:0914”(association)	0.350
TEX101	GGT3P	psi-mi:“MI:0914”(association)	0.350
TEX101	ACE	psi-mi:“MI:0914”(association)	0.350
DPEP2	QSOX1	psi-mi:“MI:0914”(association)	0.350

BioGRID (14): DPEP3 (Affinity Capture-MS), DPEP2 (Affinity Capture-MS), CANX (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), DPEP3 (Protein-RNA), DPEP3 (Affinity Capture-MS), DPEP3 (Affinity Capture-Luminescence), TEX101 (Affinity Capture-Luminescence), DPEP3 (Proximity Label-MS), HSPA5 (Affinity Capture-MS), CANX (Affinity Capture-MS), DPEP2 (Affinity Capture-MS), DPEP3 (Affinity Capture-MS), DPEP3 (Affinity Capture-MS)

ESM2 similar proteins: A0JPF9, A2VE29, A6QPN6, A8T658, B3SP85, E7E2N8, F1QVU0, H2N4I1, O00391, O08841, O95479, P06802, P07911, P13284, P20062, P23276, P48733, P55104, P56201, P59996, Q13219, Q16549, Q499T2, Q4R7M2, Q5R5C1, Q5REL7, Q5RER0, Q5RJG7, Q5U2X4, Q5XWD5, Q62849, Q6IUU3, Q6P6S4, Q80W65, Q86UX2, Q8BND5, Q8CFX1, Q8NCG5, Q92179, Q924C3

Diamond homologs: A0A1U9YI27, B8LWT1, C4JQN7, C5FK77, C5PCN6, C5PCZ0, C7ZIE1, D4B2N2, D4DEJ7, E5R2Q7, E9CV02, E9D269, M1VV65, O14124, O59832, P16444, P22412, P31428, P31429, P31430, P43477, Q0CS61, Q2UPB0, Q3SZM7, Q4R7M2, Q4WMJ8, Q5M872, Q5U2X4, Q6Q886, Q8C255, Q9DA79, Q9H4A9, Q9H4B8, P27509

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	79
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1488 predictions. Top by Δscore:

Variant	Effect	Δscore
16:67975998:TCACC:T	acceptor_loss	1.0000
16:67976087:GCTTA:G	donor_loss	1.0000
16:67976088:CTTA:C	donor_loss	1.0000
16:67976089:TTA:T	donor_loss	1.0000
16:67976090:TACC:T	donor_loss	1.0000
16:67976091:ACCT:A	donor_loss	1.0000
16:67976092:C:CG	donor_loss	1.0000
16:67977265:CTTA:C	donor_loss	1.0000
16:67977266:TTACC:T	donor_loss	1.0000
16:67977267:TA:T	donor_loss	1.0000
16:67977268:A:AC	donor_gain	1.0000
16:67977268:ACCT:A	donor_loss	1.0000
16:67977268:ACCTG:A	donor_gain	1.0000
16:67977269:C:CC	donor_gain	1.0000
16:67977269:CCTG:C	donor_gain	1.0000
16:67977269:CCTGC:C	donor_gain	1.0000
16:67977350:TTCTT:T	acceptor_gain	1.0000
16:67977352:CTT:C	acceptor_gain	1.0000
16:67977353:TT:T	acceptor_gain	1.0000
16:67977355:C:CC	acceptor_gain	1.0000
16:67977826:CTTT:C	acceptor_gain	1.0000
16:67977828:TTC:T	acceptor_loss	1.0000
16:67977830:C:CC	acceptor_gain	1.0000
16:67977830:CTGCA:C	acceptor_loss	1.0000
16:67977936:A:C	donor_loss	1.0000
16:67978004:TGCCC:T	acceptor_loss	1.0000
16:67978008:C:CA	acceptor_loss	1.0000
16:67978009:T:G	acceptor_loss	1.0000
16:67978262:CTCA:C	donor_loss	1.0000
16:67978263:TCACC:T	donor_loss	1.0000

AlphaMissense

3133 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:67978268:A:G	W229R	0.975
16:67978268:A:T	W229R	0.975
16:67978623:A:G	W140R	0.972
16:67978623:A:T	W140R	0.972
16:67978007:C:A	W229C	0.967
16:67978007:C:G	W229C	0.967
16:67976175:A:G	L383S	0.951
16:67977807:C:G	R260P	0.950
16:67978382:A:G	C191R	0.945
16:67978624:G:C	F139L	0.939
16:67978624:G:T	F139L	0.939
16:67978626:A:G	F139L	0.939
16:67978309:C:A	G215V	0.936
16:67978310:C:A	G215W	0.936
16:67978327:C:G	R209P	0.934
16:67978006:C:G	A230P	0.927
16:67978303:C:G	R217P	0.921
16:67977801:C:A	G262V	0.919
16:67977998:A:C	S232R	0.919
16:67977998:A:T	S232R	0.919
16:67978000:T:G	S232R	0.919
16:67978297:A:G	L219P	0.919
16:67976145:A:G	L393P	0.916
16:67977942:C:T	G251D	0.915
16:67976123:G:C	N400K	0.914
16:67976123:G:T	N400K	0.914
16:67978380:G:C	C191W	0.913
16:67978328:G:T	R209S	0.911
16:67977944:A:C	F250L	0.910
16:67977944:A:T	F250L	0.910

dbSNP variants (sampled 300 via entrez): RS1000294362 (16:67980516 G>GC), RS1000948786 (16:67982491 T>C,G), RS1001148203 (16:67977188 G>A,T), RS1002243074 (16:67977445 C>T), RS1002646570 (16:67978968 G>A), RS1002906056 (16:67980313 A>G), RS1002937116 (16:67980541 C>T), RS1003013044 (16:67978698 T>A), RS1003244615 (16:67978988 T>C), RS1003274119 (16:67979231 G>A), RS1003346818 (16:67977186 G>A,C,T), RS1003802864 (16:67978168 C>A,T), RS1005806510 (16:67975362 C>G,T), RS1006054450 (16:67978122 C>T), RS1006415523 (16:67981643 C>T)

Disease associations

OMIM: gene MIM:609926 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST002539_84	Schizophrenia	2.000000e-08
GCST006803_42	Schizophrenia	4.000000e-08
GCST008070_114	HDL cholesterol levels	4.000000e-06
GCST008070_120	HDL cholesterol levels	1.000000e-17
GCST008070_49	HDL cholesterol levels	2.000000e-35
GCST008070_81	HDL cholesterol levels	4.000000e-10
GCST008075_133	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	1.000000e-10
GCST008075_14	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	4.000000e-39
GCST008075_142	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	5.000000e-81
GCST008075_209	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	3.000000e-23
GCST008075_92	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	2.000000e-16
GCST008084_111	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	2.000000e-50
GCST008084_138	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	3.000000e-11
GCST008084_148	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	2.000000e-99
GCST008084_57	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	5.000000e-19
GCST008084_72	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	4.000000e-24
GCST008085_115	HDL cholesterol levels in current drinkers	3.000000e-14
GCST008085_12	HDL cholesterol levels in current drinkers	6.000000e-08
GCST008085_125	HDL cholesterol levels in current drinkers	3.000000e-23
GCST008085_45	HDL cholesterol levels in current drinkers	7.000000e-54
GCST008085_78	HDL cholesterol levels in current drinkers	5.000000e-17
GCST008087_9	Triglyceride levels in current drinkers	9.000000e-06
GCST010002_113	Refractive error	2.000000e-14

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004329	alcohol drinking
EFO:0004530	triglyceride measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
entinostat	increases expression, affects cotreatment	2
Air Pollutants	affects expression, increases abundance, increases expression	2
testosterone enanthate	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
cetrorelix	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Benzo(a)pyrene	decreases methylation	1
Estradiol	affects binding, increases expression	1
Ozone	affects expression, increases abundance	1
Valproic Acid	increases methylation	1
Desogestrel	affects cotreatment, decreases expression	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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