DPEP2

Summary

DPEP2 (dipeptidase 2, HGNC:23028) is a protein-coding gene on chromosome 16q22.1, encoding Dipeptidase 2 (Q9H4A9). Dipeptidase that hydrolyzes leukotriene D4 (LTD4) into leukotriene E4 (LTE4).

DPEP2 belongs to the membrane-bound dipeptidase (EC 3.4.13.19) family. These enzymes hydrolyze a variety of dipeptides, including leukotriene D4, the beta-lactam ring of some antibiotics, and cystinyl-bis-glycine (cys-bis-gly) formed during glutathione degradation (Habib et al., 2003 [PubMed 12738806]).

Source: NCBI Gene 64174 — RefSeq curated summary.

At a glance

• GWAS associations: 24
• Clinical variants (ClinVar): 87 total
• MANE Select transcript: NM_022355

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23028
Approved symbol	DPEP2
Name	dipeptidase 2
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000167261
Ensembl biotype	protein_coding
OMIM	609925
Entrez	64174

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 18 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000268795, ENST00000393847, ENST00000572624, ENST00000572888, ENST00000573808, ENST00000574316, ENST00000574865, ENST00000575203, ENST00000575510, ENST00000867043, ENST00000867044, ENST00000867045, ENST00000867046, ENST00000867047, ENST00000867048, ENST00000867049, ENST00000867050, ENST00000970168, ENST00000970169, ENST00000970170, ENST00000970171

RefSeq mRNA: 3 — MANE Select: NM_022355 NM_001324159, NM_001369657, NM_022355

CCDS: CCDS10857

Canonical transcript exons

ENST00000393847 — 11 exons

Exon	Start	End
ENSE00000946604	67991115	67991184
ENSE00000946608	67987852	67987987
ENSE00001204516	67991838	67991979
ENSE00001516676	67987394	67987760
ENSE00001516679	67999375	67999484
ENSE00001661570	67992510	67992636
ENSE00001710371	67992064	67992193
ENSE00001791867	67990821	67990997
ENSE00003538740	67992950	67993257
ENSE00003572663	67989323	67989398
ENSE00003638085	67990047	67990131

Expression profiles

Bgee: expression breadth ubiquitous, 176 present calls, max score 97.46.

FANTOM5 (CAGE): breadth broad, TPM avg 1.8037 / max 111.5097, expressed in 268 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157843	0.9261	209
157845	0.4615	144
157846	0.2626	91
157844	0.1535	64

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	97.46	gold quality
monocyte	CL:0000576	96.44	gold quality
blood	UBERON:0000178	96.35	gold quality
leukocyte	CL:0000738	96.12	gold quality
mononuclear cell	CL:0000842	96.10	gold quality
spleen	UBERON:0002106	91.61	gold quality
right lung	UBERON:0002167	87.07	gold quality
lymph node	UBERON:0000029	84.34	gold quality
small intestine Peyer’s patch	UBERON:0003454	83.87	gold quality
bone marrow	UBERON:0002371	83.24	gold quality
upper lobe of left lung	UBERON:0008952	83.01	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.85	gold quality
vermiform appendix	UBERON:0001154	82.12	gold quality
small intestine	UBERON:0002108	79.90	gold quality
upper lobe of lung	UBERON:0008948	79.88	gold quality
gall bladder	UBERON:0002110	78.67	gold quality
bone marrow cell	CL:0002092	78.43	gold quality
caecum	UBERON:0001153	77.30	gold quality
hindlimb stylopod muscle	UBERON:0004252	77.17	gold quality
tendon of biceps brachii	UBERON:0008188	76.21	gold quality
placenta	UBERON:0001987	75.50	gold quality
omental fat pad	UBERON:0010414	75.35	gold quality
peritoneum	UBERON:0002358	75.25	gold quality
rectum	UBERON:0001052	74.85	gold quality
adipose tissue of abdominal region	UBERON:0007808	74.80	gold quality
right coronary artery	UBERON:0001625	74.59	gold quality
gastrocnemius	UBERON:0001388	73.99	gold quality
subcutaneous adipose tissue	UBERON:0002190	73.99	gold quality
transverse colon	UBERON:0001157	73.40	gold quality
left uterine tube	UBERON:0001303	73.23	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.32
E-GEOD-100618	no	304.82

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

11 targeting DPEP2, 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-205-3P	99.92	69.92	3165
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-548V	99.29	69.47	1157
HSA-MIR-5190	99.15	67.76	1234
HSA-MIR-6894-3P	96.73	65.64	798
HSA-MIR-550B-2-5P	96.56	64.61	646
HSA-MIR-6742-5P	96.32	64.01	869
HSA-MIR-6796-5P	95.37	66.08	1120
HSA-MIR-4471	95.11	66.84	755
HSA-MIR-8059	95.11	66.30	646

Literature-anchored findings (GeneRIF, showing 1)

• Dipeptidase-2 is a prognostic marker in lung adenocarcinoma that is correlated with its sensitivity to cisplatin. (PMID:37449493)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	dpep2	ENSDARG00000079216
mus_musculus	Dpep2	ENSMUSG00000053687
mus_musculus	Dpep2	ENSMUSG00000115067
rattus_norvegicus	Dpep2	ENSRNOG00000023303
drosophila_melanogaster	CG6154	FBGN0039420
drosophila_melanogaster	CG44837	FBGN0266100

Paralogs (2): DPEP1 (ENSG00000015413), DPEP3 (ENSG00000141096)

Protein

Protein identifiers

Dipeptidase 2 — Q9H4A9 (reviewed: Q9H4A9)

All UniProt accessions (5): Q9H4A9, I3L348, I3L4H3, J3KSU4, J3QLL2

UniProt curated annotations — full annotation on UniProt →

Function. Dipeptidase that hydrolyzes leukotriene D4 (LTD4) into leukotriene E4 (LTE4). Hydrolyzes cystinyl-bis-glycine. Independently of its dipeptidase activity can also modulate macrophage inflammatory response by acting as a regulator of NF-kappaB inflammatory signaling pathway.

Subunit / interactions. Homodimer; disulfide-linked.

Subcellular location. Membrane.

Activity regulation. Inhibited by L-penicillamine.

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

Isoforms (3)

UniProt ID	Names	Canonical?
Q9H4A9-1	1	yes
Q9H4A9-2	2
Q9H4A9-3	3

RefSeq proteins (3): NP_001311088, NP_001356586, NP_071750* (*=MANE)

Domains & families (InterPro)

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

Pfam: PF01244

Catalyzed reactions (Rhea), 3 shown:

• leukotriene D4 + H2O = leukotriene E4 + glycine (RHEA:48616)
• an L-aminoacyl-L-amino acid + H2O = 2 an L-alpha-amino acid (RHEA:48940)
• L-cystine-bis-glycine + 2 H2O = L-cystine + 2 glycine (RHEA:60520)

UniProt features (24 total): binding site 9, glycosylation site 3, disulfide bond 3, splice variant 3, sequence variant 2, signal peptide 1, chain 1, lipid moiety-binding region 1, propeptide 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H4A9-F1	82.94	0.70

Functional residue map

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

Ligand- & substrate-binding residues (9): 293; 351; 89; 91; 188; 188; 215; 261; 282

Post-translational modifications (1): 463

Disulfide bonds (3): 138–217, 289–321, 426

Glycosylation sites (3): 111, 176, 235

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2142691	Synthesis of Leukotrienes (LT) and Eoxins (EX)
R-HSA-5423646	Aflatoxin activation and detoxification
R-HSA-9664535	LTC4-CYSLTR mediated IL4 production

MSigDB gene sets: 160 (showing top): MULLIGHAN_NPM1_SIGNATURE_3_UP, REACTOME_BIOLOGICAL_OXIDATIONS, chr16q22, GOMF_METALLOPEPTIDASE_ACTIVITY, GNF2_MCL1, GOBP_SULFUR_COMPOUND_CATABOLIC_PROCESS, GNF2_ICAM3, GOBP_AMIDE_METABOLIC_PROCESS, GNF2_S100A4, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, MODULE_301, GOZGIT_ESR1_TARGETS_UP, GOBP_LIPID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, YAMASHITA_METHYLATED_IN_PROSTATE_CANCER

GO Biological Process (4): proteolysis (GO:0006508), leukotriene metabolic process (GO:0006691), leukotriene D4 catabolic process (GO:1901749), lipid metabolic process (GO:0006629)

GO Molecular Function (6): dipeptidase activity (GO:0016805), metal ion binding (GO:0046872), metallodipeptidase activity (GO:0070573), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787)

GO Cellular Component (3): plasma membrane (GO:0005886), membrane (GO:0016020), side of membrane (GO:0098552)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Arachidonate metabolism	1
Biological oxidations	1
Anti-inflammatory response favouring Leishmania parasite infection	1

GO top-level categories

Rollup of top GO terms by namespace:

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

Protein interactions and networks

STRING

1180 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DPEP2	CNDP2	Q96KP4	560
DPEP2	TRIML1	Q8N9V2	500
DPEP2	BEND5	Q7L4P6	479
DPEP2	ANPEP	P15144	436
DPEP2	ATP10D	Q9P241	418
DPEP2	OR6S1	Q8NH40	400
DPEP2	S4R3Q2	S4R3Q2	398
DPEP2	ZNF227	Q86WZ6	398
DPEP2	C16orf54	Q6UWD8	396
DPEP2	DPP8	Q6V1X1	393
DPEP2	LTC4S	Q16873	391
DPEP2	CNDP1	Q96KN2	384
DPEP2	LTA4H	P09960	383
DPEP2	CTSC	P53634	377
DPEP2	CTSZ	Q9UBR2	376

IntAct

8 interactions, top by confidence:

A	B	Type	Score
DPEP3	HSPA5	psi-mi:“MI:0914”(association)	0.530
DPEP2	NLGN3	psi-mi:“MI:0915”(physical association)	0.370
DPEP2	GET1	psi-mi:“MI:0914”(association)	0.350
DPEP2	QSOX1	psi-mi:“MI:0914”(association)	0.350
TAF1D	MAGEB2	psi-mi:“MI:0914”(association)	0.350
uvrA	DPEP2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (74): PAM (Affinity Capture-MS), METTL9 (Affinity Capture-MS), ITGAV (Affinity Capture-MS), GALNS (Affinity Capture-MS), KDELR3 (Affinity Capture-MS), OS9 (Affinity Capture-MS), CHPF2 (Affinity Capture-MS), GFPT2 (Affinity Capture-MS), FUT11 (Affinity Capture-MS), YIF1A (Affinity Capture-MS), POGLUT1 (Affinity Capture-MS), CHST12 (Affinity Capture-MS), WRB (Affinity Capture-MS), EMILIN3 (Affinity Capture-MS), CNTNAP3B (Affinity Capture-MS)

ESM2 similar proteins: A0JMP0, A4IG42, A5PJN5, A6QLU7, A6QQ07, F1N2K1, O00462, O18835, O43280, O77695, O95479, O97524, P08236, P10253, P12265, P19813, P70699, P82450, Q3U4H6, Q4FAT7, Q4FZV0, Q5E985, Q5FVF9, Q5R5N6, Q5R7A9, Q5R8R3, Q5RFU0, Q5XHI4, Q641Z7, Q6P6V7, Q6P7A9, Q6QR59, Q6RHW4, Q76HN1, Q865R1, Q8BFW6, Q8BNE1, Q8BP56, Q8C0L6, Q8CFX1

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	76
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2039 predictions. Top by Δscore:

Variant	Effect	Δscore
16:67989319:TCA:T	donor_loss	1.0000
16:67989320:CACT:C	donor_loss	1.0000
16:67989321:A:AC	donor_gain	1.0000
16:67989321:AC:A	donor_loss	1.0000
16:67989322:C:CT	donor_gain	1.0000
16:67989322:CTTG:C	donor_gain	1.0000
16:67989394:GTGAT:G	acceptor_gain	1.0000
16:67989395:TGAT:T	acceptor_gain	1.0000
16:67989396:GAT:G	acceptor_gain	1.0000
16:67989398:TCTG:T	acceptor_loss	1.0000
16:67989399:C:CC	acceptor_gain	1.0000
16:67989399:CTGG:C	acceptor_loss	1.0000
16:67990132:C:CC	acceptor_gain	1.0000
16:67991008:A:C	acceptor_gain	1.0000
16:67991880:C:CA	donor_gain	1.0000
16:67991975:CAGAG:C	acceptor_gain	1.0000
16:67991980:C:CC	acceptor_gain	1.0000
16:67992060:CTAC:C	donor_loss	1.0000
16:67992062:ACCTT:A	donor_loss	1.0000
16:67992063:C:CT	donor_loss	1.0000
16:67992189:CAGAA:C	acceptor_gain	1.0000
16:67989315:GCACT:G	donor_loss	0.9900
16:67989317:ACTCA:A	donor_loss	0.9900
16:67989397:AT:A	acceptor_gain	0.9900
16:67990129:CTT:C	acceptor_gain	0.9900
16:67990817:T:TA	donor_loss	0.9900
16:67990818:CA:C	donor_loss	0.9900
16:67990819:A:AC	donor_gain	0.9900
16:67990819:ACCAG:A	donor_loss	0.9900
16:67990820:C:CC	donor_gain	0.9900

AlphaMissense

3128 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:67991839:A:G	W221R	0.976
16:67991839:A:T	W221R	0.976
16:67992190:A:G	W132R	0.975
16:67992190:A:T	W132R	0.975
16:67991175:G:C	S224R	0.969
16:67991175:G:T	S224R	0.969
16:67991177:T:G	S224R	0.969
16:67991183:C:G	A222P	0.967
16:67991184:C:A	W221C	0.966
16:67991184:C:G	W221C	0.966
16:67990958:C:G	D258H	0.964
16:67987934:A:G	L375S	0.963
16:67991850:C:T	C217Y	0.962
16:67992171:C:G	C138S	0.962
16:67992172:A:G	C138R	0.962
16:67992172:A:T	C138S	0.962
16:67990975:C:G	R252P	0.961
16:67991850:C:G	C217S	0.960
16:67991851:A:T	C217S	0.960
16:67992191:G:C	F131L	0.956
16:67992191:G:T	F131L	0.956
16:67992193:A:G	F131L	0.956
16:67991868:A:G	L211P	0.955
16:67992171:C:T	C138Y	0.954
16:67990957:T:G	D258A	0.953
16:67991851:A:G	C217R	0.953
16:67991849:G:C	C217W	0.952
16:67990957:T:A	D258V	0.950
16:67990848:A:C	N294K	0.949
16:67990848:A:T	N294K	0.949

dbSNP variants (sampled 300 via entrez): RS1000123953 (16:67996734 C>T), RS1000304032 (16:67993778 G>A,C,T), RS1000311175 (16:67996778 T>C), RS1000362235 (16:67998863 C>A,G,T), RS1000487317 (16:67988650 T>G), RS1000648296 (16:67995396 G>T), RS1000700678 (16:67997972 G>A,C), RS1000729893 (16:67998212 G>A,C), RS1000888647 (16:67991209 T>C), RS1001007501 (16:68000687 T>C), RS1001021632 (16:68000914 G>A,T), RS1001640780 (16:68001241 C>A,T), RS1001706267 (16:67993864 C>T), RS1001715996 (16:67990462 GT>G,GTT), RS1001733091 (16:67990725 A>C)

Disease associations

OMIM: gene MIM:609925 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST002539_84	Schizophrenia	2.000000e-08
GCST006005_48	High density lipoprotein cholesterol levels	3.000000e-19
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)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Leukotriene and lipoxin metabolism

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
bisphenol S	affects cotreatment, decreases methylation	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants	affects expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Diuron	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Nickel	increases expression	1
Ozone	affects expression, increases abundance	1
Phthalic Acids	increases methylation	1
Tetrachlorodibenzodioxin	affects cotreatment, increases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	increases expression	1

Clinical trials (associated diseases)

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