PM20D2

Summary

PM20D2 (peptidase M20 domain containing 2, HGNC:21408) is a protein-coding gene on chromosome 6q15, encoding Xaa-Arg dipeptidase (Q8IYS1). Catalyzes the peptide bond hydrolysis in dipeptides having basic amino acids lysine, ornithine or arginine at C-terminus.

Enables dipeptidase activity and identical protein binding activity. Acts upstream of or within proteolysis and regulation of protein metabolic process. Located in nucleoplasm.

Source: NCBI Gene 135293 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 83 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001010853

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21408
Approved symbol	PM20D2
Name	peptidase M20 domain containing 2
Location	6q15
Locus type	gene with protein product
Status	Approved
Aliases	bA63L7.3
Ensembl gene	ENSG00000146281
Ensembl biotype	protein_coding
OMIM	615913
Entrez	135293

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000275072, ENST00000879768

RefSeq mRNA: 1 — MANE Select: NM_001010853 NM_001010853

CCDS: CCDS34499

Canonical transcript exons

ENST00000275072 — 7 exons

Exon	Start	End
ENSE00000974846	89149265	89149413
ENSE00000974847	89153043	89153185
ENSE00000974848	89154748	89154902
ENSE00001016515	89146055	89146609
ENSE00001016517	89161783	89161890
ENSE00001016518	89158325	89158460
ENSE00001305660	89162109	89165565

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 95.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.6114 / max 225.1369, expressed in 1425 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
68874	7.9202	1381
68873	0.6913	382

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibialis anterior	UBERON:0001385	95.44	gold quality
deltoid	UBERON:0001476	94.51	gold quality
epithelial cell of pancreas	CL:0000083	94.39	gold quality
oviduct epithelium	UBERON:0004804	94.20	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	94.18	gold quality
quadriceps femoris	UBERON:0001377	93.92	gold quality
pigmented layer of retina	UBERON:0001782	93.87	gold quality
vastus lateralis	UBERON:0001379	93.64	gold quality
germinal epithelium of ovary	UBERON:0001304	92.76	gold quality
left ventricle myocardium	UBERON:0006566	92.61	gold quality
cardiac muscle of right atrium	UBERON:0003379	92.02	gold quality
skeletal muscle tissue	UBERON:0001134	91.60	gold quality
thymus	UBERON:0002370	91.23	gold quality
mucosa of paranasal sinus	UBERON:0005030	90.84	gold quality
biceps brachii	UBERON:0001507	90.71	gold quality
muscle tissue	UBERON:0002385	90.52	gold quality
oral cavity	UBERON:0000167	89.98	gold quality
skeletal muscle organ	UBERON:0014892	89.75	gold quality
gastrocnemius	UBERON:0001388	89.48	gold quality
ventricular zone	UBERON:0003053	89.31	gold quality
ileal mucosa	UBERON:0000331	89.27	gold quality
muscle of leg	UBERON:0001383	88.95	gold quality
calcaneal tendon	UBERON:0003701	88.45	gold quality
superficial temporal artery	UBERON:0001614	88.42	gold quality
upper arm skin	UBERON:0004263	88.42	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	87.70	gold quality
myocardium	UBERON:0002349	87.63	gold quality
tongue	UBERON:0001723	87.61	gold quality
trabecular bone tissue	UBERON:0002483	87.53	gold quality
descending thoracic aorta	UBERON:0002345	87.41	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	35.40
E-MTAB-7249	yes	11.03
E-ANND-3	yes	4.71
E-CURD-112	yes	4.13

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

111 targeting PM20D2, 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-3613-3P	100.00	76.36	7965
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4455	100.00	65.48	1587
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-548AJ-3P	99.96	73.38	5345

Literature-anchored findings (GeneRIF, showing 1)

• PM20D2 hydrolyzed beta-alanyl-lysine, beta-alanyl-ornithine, gamma-aminobutyryl-lysine, and gamma-aminobutyryl-ornithine as its best substrates. (PMID:24891507)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pm20d2	ENSMUSG00000054659
rattus_norvegicus	Pm20d2	ENSRNOG00000007755

Protein

Protein identifiers

Xaa-Arg dipeptidase — Q8IYS1 (reviewed: Q8IYS1)

Alternative names: Beta-Ala-Lys dipeptidase

All UniProt accessions (1): Q8IYS1

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the peptide bond hydrolysis in dipeptides having basic amino acids lysine, ornithine or arginine at C-terminus. Postulated to function in a metabolite repair mechanism by eliminating alternate dipeptide by-products formed during carnosine synthesis.

Similarity. Belongs to the peptidase M20A family.

RefSeq proteins (1): NP_001010853* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002933	Peptidase_M20	Family
IPR011650	Peptidase_M20_dimer	Domain
IPR017144	Xaa-Arg_dipeptidase	Family
IPR036264	Bact_exopeptidase_dim_dom	Homologous_superfamily
IPR052030	Peptidase_M20/M20A_hydrolases	Family

Pfam: PF01546, PF07687

Catalyzed reactions (Rhea), 5 shown:

• beta-alanyl-L-lysine + H2O = beta-alanine + L-lysine (RHEA:59608)
• beta-alanyl-L-ornithine + H2O = beta-alanine + L-ornithine (RHEA:59612)
• N(2)-(4-aminobutanoyl)-L-lysine + H2O = 4-aminobutanoate + L-lysine (RHEA:59620)
• N(2)-(4-aminobutanoyl)-L-ornithine + H2O = 4-aminobutanoate + L-ornithine (RHEA:59624)
• N(2)-(4-aminobutanoyl)-L-arginine + H2O = 4-aminobutanoate + L-arginine (RHEA:59628)

UniProt features (35 total): helix 14, strand 11, turn 5, sequence conflict 3, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7YH4	X-RAY DIFFRACTION	2.03
8ZEI	X-RAY DIFFRACTION	2.3
8ZEL	X-RAY DIFFRACTION	2.3
8XZC	X-RAY DIFFRACTION	2.35

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IYS1-F1	93.56	0.87

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 88 (showing top): chr6q15, GOBP_MODIFIED_AMINO_ACID_CATABOLIC_PROCESS, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_PTERIDINE_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_CATABOLIC_PROCESS, TTGGAGA_MIR5155P_MIR519E, DODD_NASOPHARYNGEAL_CARCINOMA_UP, CHARAFE_BREAST_CANCER_LUMINAL_VS_BASAL_DN, JAATINEN_HEMATOPOIETIC_STEM_CELL_UP, GOBP_DICARBOXYLIC_ACID_CATABOLIC_PROCESS, GOBP_VITAMIN_METABOLIC_PROCESS, GOBP_FOLIC_ACID_METABOLIC_PROCESS

GO Biological Process (2): proteolysis (GO:0006508), regulation of protein metabolic process (GO:0051246)

GO Molecular Function (6): carboxypeptidase activity (GO:0004180), dipeptidase activity (GO:0016805), identical protein binding (GO:0042802), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (1): nucleoplasm (GO:0005654)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	2
exopeptidase activity	2
regulation of macromolecule metabolic process	1
regulation of primary metabolic process	1
protein binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
nuclear lumen	1
cellular anatomical structure	1

Protein interactions and networks

STRING

703 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PM20D2	MAPK1IP1L	Q8NDC0	520
PM20D2	KLHL33	A6NCF5	515
PM20D2	UBE2J1	Q9Y385	509
PM20D2	MDN1	Q9NU22	486
PM20D2	ZKSCAN8	Q15776	453
PM20D2	PGRMC2	O15173	451
PM20D2	CCDC198	Q9NVL8	447
PM20D2	FAAH	O00519	441
PM20D2	QRSL1	Q9H0R6	436
PM20D2	GABRR2	P28476	429
PM20D2	PM20D1	Q6GTS8	428
PM20D2	PPP4R4	Q6NUP7	425
PM20D2	MAST2	Q6P0Q8	425
PM20D2	INTS5	Q6P9B9	412
PM20D2	CNDP1	Q96KN2	412

IntAct

97 interactions, top by confidence:

A	B	Type	Score
ANG	RNH1	psi-mi:“MI:0914”(association)	0.750
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
PM20D2	CNNM3	psi-mi:“MI:0915”(physical association)	0.560
PM20D2	PM20D2	psi-mi:“MI:0915”(physical association)	0.560
PM20D2	DDIT4L	psi-mi:“MI:0915”(physical association)	0.560
PM20D2	SAXO1	psi-mi:“MI:0915”(physical association)	0.560
PM20D2	HAPLN2	psi-mi:“MI:0915”(physical association)	0.560
PM20D2	DNAJC11	psi-mi:“MI:0915”(physical association)	0.560
MEOX1	PM20D2	psi-mi:“MI:0915”(physical association)	0.560
TDO2	PM20D2	psi-mi:“MI:0915”(physical association)	0.560
REL	PM20D2	psi-mi:“MI:0915”(physical association)	0.560
PM20D2	NAA80	psi-mi:“MI:0915”(physical association)	0.560
PM20D2	TAPBPL	psi-mi:“MI:0915”(physical association)	0.560
PM20D2	CERT1	psi-mi:“MI:0915”(physical association)	0.560
KEL	PM20D2	psi-mi:“MI:0915”(physical association)	0.560
RGS12	PM20D2	psi-mi:“MI:0915”(physical association)	0.560
PM20D2	EPDR1	psi-mi:“MI:0915”(physical association)	0.560
DALRD3	PM20D2	psi-mi:“MI:0915”(physical association)	0.560
RP2	PM20D2	psi-mi:“MI:0915”(physical association)	0.560
POU6F2	PM20D2	psi-mi:“MI:0915”(physical association)	0.560
KRT75	PM20D2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP26-1	PM20D2	psi-mi:“MI:0915”(physical association)	0.560
PM20D2	RUSC1	psi-mi:“MI:0915”(physical association)	0.560
PM20D2	MYOZ3	psi-mi:“MI:0915”(physical association)	0.560
PSMA1	PM20D2	psi-mi:“MI:0915”(physical association)	0.560
SIVA1	PM20D2	psi-mi:“MI:0915”(physical association)	0.560
HAO2	EIF4G3	psi-mi:“MI:0914”(association)	0.530
ANGPTL4	NMT2	psi-mi:“MI:0914”(association)	0.530
DEFB1	NMT2	psi-mi:“MI:0914”(association)	0.530

BioGRID (72): PM20D2 (Affinity Capture-MS), PM20D2 (Affinity Capture-MS), PM20D2 (Affinity Capture-MS), PM20D2 (Affinity Capture-MS), PM20D2 (Affinity Capture-MS), PM20D2 (Affinity Capture-MS), PM20D2 (Affinity Capture-MS), PM20D2 (Proximity Label-MS), PM20D2 (Affinity Capture-MS), PM20D2 (Affinity Capture-MS), PM20D2 (Affinity Capture-MS), KIAA1671 (Affinity Capture-MS), PRIM2 (Affinity Capture-MS), TK1 (Affinity Capture-MS), PM20D2 (Affinity Capture-MS)

ESM2 similar proteins: A3KG59, A4IFH5, B9N1F9, D3ZVR9, O04059, O35331, O35621, O46560, P11172, P24298, P37111, Q03154, Q04609, Q15124, Q17QK3, Q2R483, Q501L1, Q5E9T8, Q5I0K3, Q5NAY4, Q5R514, Q5R5C9, Q5RDE7, Q5RDN7, Q5RFB0, Q5RFI8, Q6AY30, Q6AYS7, Q6K2E8, Q6PTT0, Q6Q0N1, Q6ZV70, Q7TSV4, Q7X7L3, Q8BZF8, Q8CG45, Q8CG76, Q8IYS1, Q8K183, Q8N0X4

Diamond homologs: A3KG59, Q0S8V5, Q501L1, Q8IYS1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	63
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1538 predictions. Top by Δscore:

Variant	Effect	Δscore
6:89149259:TTCTA:T	acceptor_loss	1.0000
6:89149264:GGTA:G	acceptor_gain	1.0000
6:89149409:CATGA:C	donor_gain	1.0000
6:89149410:ATGA:A	donor_gain	1.0000
6:89149410:ATGAG:A	donor_loss	1.0000
6:89149411:TGA:T	donor_gain	1.0000
6:89149412:GA:G	donor_gain	1.0000
6:89149412:GAG:G	donor_gain	1.0000
6:89149412:GAGTG:G	donor_loss	1.0000
6:89149413:AGT:A	donor_loss	1.0000
6:89149414:G:GG	donor_gain	1.0000
6:89149414:GT:G	donor_loss	1.0000
6:89149415:T:G	donor_loss	1.0000
6:89149417:AGT:A	donor_loss	1.0000
6:89153041:A:AG	acceptor_gain	1.0000
6:89153041:AGTGT:A	acceptor_gain	1.0000
6:89153042:G:GA	acceptor_gain	1.0000
6:89153042:GT:G	acceptor_gain	1.0000
6:89153042:GTGT:G	acceptor_gain	1.0000
6:89153042:GTGTG:G	acceptor_gain	1.0000
6:89153176:A:T	donor_gain	1.0000
6:89153182:CATGG:C	donor_loss	1.0000
6:89153183:ATGG:A	donor_loss	1.0000
6:89153185:GGT:G	donor_loss	1.0000
6:89153186:G:GA	donor_loss	1.0000
6:89153186:G:GG	donor_gain	1.0000
6:89153187:T:A	donor_loss	1.0000
6:89154797:T:TA	acceptor_gain	1.0000
6:89154903:G:GG	donor_gain	1.0000
6:89158312:A:AG	acceptor_gain	1.0000

AlphaMissense

2813 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:89154817:G:C	R276P	0.997
6:89149308:A:T	K170I	0.995
6:89149364:C:G	H189D	0.995
6:89146482:A:T	E113V	0.994
6:89153153:G:C	R242T	0.993
6:89153154:A:C	R242S	0.993
6:89153154:A:T	R242S	0.993
6:89154899:C:G	C303W	0.993
6:89161865:T:A	H377Q	0.993
6:89161865:T:G	H377Q	0.993
6:89146403:T:C	F87L	0.992
6:89146405:C:A	F87L	0.992
6:89146405:C:G	F87L	0.992
6:89146525:C:A	N127K	0.992
6:89146525:C:G	N127K	0.992
6:89149291:A:C	E164D	0.992
6:89149291:A:T	E164D	0.992
6:89149309:A:C	K170N	0.992
6:89149309:A:T	K170N	0.992
6:89149366:C:A	H189Q	0.992
6:89149366:C:G	H189Q	0.992
6:89153117:C:A	A230D	0.992
6:89162145:C:A	A398D	0.992
6:89146473:T:C	F110S	0.991
6:89146522:C:A	H126Q	0.991
6:89146522:C:G	H126Q	0.991
6:89149290:A:T	E164V	0.991
6:89149293:A:T	E165V	0.991
6:89153063:G:A	G212E	0.991
6:89153119:G:C	A231P	0.991

dbSNP variants (sampled 300 via entrez): RS1000001820 (6:89141424 G>A), RS1000024219 (6:89137736 A>G), RS1000106183 (6:89115385 C>A,T), RS1000108810 (6:89152570 C>A), RS1000178375 (6:89123214 A>G), RS1000180742 (6:89128613 G>A), RS1000194564 (6:89165137 A>G), RS1000253668 (6:89122851 A>G), RS1000335786 (6:89122471 T>C), RS1000345234 (6:89161370 A>G), RS1000403892 (6:89152979 A>G), RS1000507272 (6:89105718 T>C,G), RS1000517360 (6:89121494 A>AG), RS1000613820 (6:89106262 G>A), RS1000648841 (6:89134577 C>T)

Disease associations

OMIM: gene MIM:615913 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST012020_120	Serum metabolite levels	7.000000e-23
GCST012020_121	Serum metabolite levels	3.000000e-16

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725160 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
5.00	IC50	1e+04	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 6 total; 1 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
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178966: Inhibition of PM20D2 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression, affects expression	3
Valproic Acid	affects expression, decreases expression, increases methylation	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	2
Cyclosporine	decreases expression, increases expression	2
Cadmium Chloride	decreases expression	2
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
lead acetate	decreases expression	1
sodium arsenite	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
monomethylarsonous acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
NSC 689534	affects binding, decreases expression	1
Bortezomib	increases expression	1
Sunitinib	decreases expression	1
Leflunomide	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Ethanol	increases expression	1
Carbamazepine	affects expression	1
Copper	affects binding, decreases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Demecolcine	decreases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Methyl Methanesulfonate	decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697696	Binding	Inhibition of PM20D2 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Clinical trials (associated diseases)

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