PEPD

Summary

PEPD (peptidase D, HGNC:8840) is a protein-coding gene on chromosome 19q13.11, encoding Xaa-Pro dipeptidase (P12955). Dipeptidase that catalyzes the hydrolysis of dipeptides with a prolyl (Xaa-Pro) or hydroxyprolyl residue in the C-terminal position.

This gene encodes a member of the peptidase family. The protein forms a homodimer that hydrolyzes dipeptides or tripeptides with C-terminal proline or hydroxyproline residues. The enzyme serves an important role in the recycling of proline, and may be rate limiting for the production of collagen. Mutations in this gene result in prolidase deficiency, which is characterized by the excretion of large amount of di- and tri-peptides containing proline. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 5184 — RefSeq curated summary.

At a glance

• Gene–disease (curated): prolidase deficiency (Definitive, ClinGen)
• GWAS associations: 172
• Clinical variants (ClinVar): 824 total — 47 pathogenic, 29 likely-pathogenic
• Phenotypes (HPO): 67
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_000285

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8840
Approved symbol	PEPD
Name	peptidase D
Location	19q13.11
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000124299
Ensembl biotype	protein_coding
OMIM	613230
Entrez	5184

Gene structure

Transcript identifiers

Ensembl transcripts: 45 — 25 protein_coding, 10 protein_coding_CDS_not_defined, 6 nonsense_mediated_decay, 4 retained_intron

ENST00000244137, ENST00000397032, ENST00000436370, ENST00000588328, ENST00000588719, ENST00000590408, ENST00000590731, ENST00000590755, ENST00000591968, ENST00000593085, ENST00000593163, ENST00000609145, ENST00000651646, ENST00000651901, ENST00000698359, ENST00000698360, ENST00000698361, ENST00000698362, ENST00000698363, ENST00000698364, ENST00000698365, ENST00000698426, ENST00000698427, ENST00000698428, ENST00000698429, ENST00000698430, ENST00000698431, ENST00000698432, ENST00000698433, ENST00000698434, ENST00000698435, ENST00000698436, ENST00000698437, ENST00000698438, ENST00000698439, ENST00000879072, ENST00000879073, ENST00000879074, ENST00000879075, ENST00000879076, ENST00000879077, ENST00000879078, ENST00000926219, ENST00000947369, ENST00000947370

RefSeq mRNA: 3 — MANE Select: NM_000285 NM_000285, NM_001166056, NM_001166057

CCDS: CCDS42544, CCDS54244, CCDS54245

Canonical transcript exons

ENST00000244137 — 15 exons

Exon	Start	End
ENSE00000896656	33401721	33401869
ENSE00000896666	33511028	33511155
ENSE00000896667	33512593	33512776
ENSE00002928721	33386950	33387481
ENSE00002960601	33521744	33521791
ENSE00003468574	33391295	33391479
ENSE00003585611	33387890	33388081
ENSE00003702654	33493290	33493337
ENSE00003703500	33462995	33463041
ENSE00003703566	33478046	33478090
ENSE00003703603	33500938	33501001
ENSE00003705558	33463987	33464062
ENSE00003706086	33489996	33490057
ENSE00003706192	33413575	33413643
ENSE00003708394	33411672	33411749

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 98.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.8898 / max 386.6368, expressed in 1810 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
180428	37.6513	1810
180419	0.1796	97
180416	0.0377	18
180426	0.0211	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	98.10	gold quality
adult mammalian kidney	UBERON:0000082	97.79	gold quality
right lobe of liver	UBERON:0001114	97.64	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.25	gold quality
jejunal mucosa	UBERON:0000399	97.22	gold quality
nephron tubule	UBERON:0001231	96.70	gold quality
small intestine	UBERON:0002108	96.54	gold quality
kidney epithelium	UBERON:0004819	96.19	gold quality
duodenum	UBERON:0002114	95.85	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.66	gold quality
left adrenal gland cortex	UBERON:0035825	95.57	gold quality
kidney	UBERON:0002113	95.55	gold quality
stromal cell of endometrium	CL:0002255	95.48	gold quality
left adrenal gland	UBERON:0001234	95.48	gold quality
right adrenal gland cortex	UBERON:0035827	95.48	gold quality
right adrenal gland	UBERON:0001233	95.46	gold quality
cortex of kidney	UBERON:0001225	95.25	gold quality
metanephric glomerulus	UBERON:0004736	95.21	gold quality
adult organism	UBERON:0007023	95.21	gold quality
renal glomerulus	UBERON:0000074	95.02	gold quality
adenohypophysis	UBERON:0002196	94.79	gold quality
mucosa of transverse colon	UBERON:0004991	94.63	gold quality
metanephros cortex	UBERON:0010533	94.59	gold quality
liver	UBERON:0002107	94.40	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.34	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.23	gold quality
lower esophagus	UBERON:0013473	94.22	gold quality
omental fat pad	UBERON:0010414	94.09	gold quality
peritoneum	UBERON:0002358	94.01	gold quality
adrenal cortex	UBERON:0001235	93.98	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	654.58
E-MTAB-6701	yes	45.11
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A

miRNA regulators (miRDB)

29 targeting PEPD, 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-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-105-5P	99.54	69.24	2060
HSA-MIR-7853-5P	99.54	69.30	2055
HSA-MIR-4696	99.48	67.48	1040
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-642A-3P	99.23	67.67	1258
HSA-MIR-642B-3P	99.23	67.67	1258
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-6506-5P	99.04	65.66	1386
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-3192-3P	98.62	65.80	970
HSA-MIR-619-5P	98.57	64.97	1988
HSA-MIR-6742-3P	97.95	64.50	1490
HSA-MIR-1279	97.83	67.50	1898
HSA-MIR-3151-3P	97.80	66.16	479
HSA-MIR-5089-3P	97.50	67.82	758
HSA-MIR-5587-3P	82.90	60.79	138

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• FAK-independent regulation of prolidase activity and collagen biosynthesis in MCF-7 cells. (PMID:11820613)
• Carbobenzoxyproline is a potent inhibitor of prolidase in cultured fibroblasts from patients with prolidase deficiency. (PMID:15878628)
• Significant correlation was observed between serum prolidase activity, and total antioxidant capacity, total oxidant status and oxidative stress index (p<0.01, r=-0.367; p<0.05, r=0.283; p<0.01, r=0.379; respectively) in H. pylori-positive subjects. (PMID:16999949)
• oxidative stress and decreased prolidase activity may have a role in pathogenesis of knee osteoarthritis (PMID:17096092)
• Prolidase is viable target for selective activation of melphalan prodrugs in melanoma cells. (PMID:17377743)
• Prolidase deficiency and systemic lupus erythematosus share a number of common immunological features. (PMID:17570078)
• Data show that serum prolidase activity is associated with the presence hypertension independent of left ventricular hypertrophy. (PMID:17604013)
• differential expression of prolidase in 2 breast cancer cell lines showed prolidase-dependent differences in HIF-1 alpha levels (PMID:17999410)
• Serum levels of prolidase were lower in the choldren with joint hypermobility compared with controls; there was significant negative correlation between prolidase level and Beighton score (PMID:18202846)
• Higher prolidase activities in pleural tuberculosis patients might reflect increased collagen turnover in those patients, since prolidase is involved in the final stage of degradation in collagen catabolism. (PMID:18387361)
• presence of atrial fibrillation in patients with severe mitral stenosis may be associated with the plasma prolidase activity, tissue and plasma oxidative parameters (PMID:18514097)
• The kinetics of prodilase enzymatic reaction was analyzed by capillary electrophoresis and electrochemiluminescence with simplicity and efficiency. (PMID:18550075)
• serum prolidase activity is significantly associated with the presence and severity of coronary artery disease, and elevated serum prolidase activity might be an independent predictor of coronary atherosclerosis. (PMID:18607169)
• Serum prolidase enzyme activity can accurately predict the degree and stage of all histological lesions in non-alcoholic fatty liver disease. (PMID:18989777)
• characterization of erythrocyte prolidase I and II; effect of sulfur-containing amino acids on activities of prolidase I & II isolated from erythrocytes of healthy individuals, & a patient with prolidase deficiency were investigated (PMID:19263194)
• Increased serum prolidase activity and oxidative stress may be associated with endometrial cancer, and increased serum prolidase activity may be related to local invasion of endometrial cancer. (PMID:19823062)
• Data shows prolidase activity was significantly increased in patients with thalassemia major compared with controls. (PMID:20087956)
• Data suggest that the presence of ascending aortic aneurysms is associated with low serum prolidase activity. (PMID:20383038)
• In the early pregnancy loss group compared to the control group, serum levels of prolidase activity were significantly lower and placental tissue activity levels were significantly higher. (PMID:20437180)
• Serum prolidase activity seems to be correlated with the level of fibrosis in patients with non-alcoholic steatohepatitis. (PMID:20486204)
• found serum prolidase activity was significantly lower in both Idiopathic and ischemic dilated cardiomyopathies (DCM) groups relative to healthy volunteers and lower in ischemic DCM than idiopathic. (PMID:20626024)
• investigation of role of prolidase in regulation of expression of TGF beta1 & TGF beta1 receptor in skin fibroblasts: down-regulation by prolidase inhibitors (Cbz-Pro & PEP); up-regulation by prolidase products (Pro & HyPro) (PMID:20868675)
• Prolidase activity was positively correlated erum prolidase activity is significantly associated with Legg-Calve-Perthes disease. (PMID:21304409)
• Serum prolidase activity is elevated in patients with pulmonary tuberculosis (PMID:21722016)
• elevated in submucosal uterine fibroids (PMID:22185542)
• Relinoic acid regulates prolidase activity in human dermal cells via IGF receptor signaling in photoaged cells. (PMID:22245250)
• Increased prolidase seems to be associated with increased NO levels and oxidative stress along with decreased antioxidant levels in bladder cancer. (PMID:22258852)
• Assessed the serum prolidase enzyme level and the oxidative-antioxidative status in chronic hepatitis C infection. The prolidase was higher in the chronic hepatitis C group compared to the control group. (PMID:22811354)
• A Mn(II)-Mn(II) center in human prolidase. (PMID:22999980)
• Data suggest that elevated serum prolidase activity and oxidative stress may be associated with increased cardiovascular risk in polycystic ovary syndrome (PCOS) and/or menstrual irregularities associated with this syndrome. (PMID:23163753)
• Varicose venous wall prolidase enzyme activity could be an important factor in progression of azoospermia and infertility in patients with varicocele. (PMID:23171426)
• PEPD is a ligand of EGFR and presents a novel mechanism of EGFR activation (PMID:23212918)
• Serum PEPD activity appears to be higher in patients with diabetic foot ulcers when compared with patients without diabetic foot ulcers and healthy controls. (PMID:23242638)
• Although approximately 70 PEPD gene mutations and polymorphisms have been reported in various ethnic groups, we however report, for the first time, the identification of insertion mutation in human the PEPD gene. (PMID:23287645)
• A diminished prolidase activity may contribute to alteration of collagen metabolism and should be considered a biomarker of myeloproliferative neoplasms progress. (PMID:23457135)
• kinetic and structural evidences on human prolidase pathological mutants (PMID:23516557)
• Prolidase dependent HIF1A expression in breast cancer cells is induced by prolidase substrate peptides. (PMID:23549681)
• Patients with psoriasis exhibit higher serum prolidase activity independent of gender, BMI, disease severity or duration, type of treatments or nitric oxide level. (PMID:23553128)
• prolidase may share an undefined role in fibrosis in heart failure and may have a role in the diffuse fibrosis of heart failure. (PMID:24065222)
• High prolidase activity may indicate critical biological activities relevant to pathological events in Behcet’s disease, and this activity may be a biological indicator of disease. (PMID:24225260)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pepd	ENSDARG00000102249
mus_musculus	Pepd	ENSMUSG00000063931
rattus_norvegicus	Pepd	ENSRNOG00000052945
drosophila_melanogaster	Dip-C	FBGN0000455
caenorhabditis_elegans	K12C11.1	WBGENE00019673

Paralogs (7): XPNPEP1 (ENSG00000108039), METAP2 (ENSG00000111142), XPNPEP2 (ENSG00000122121), METAP1 (ENSG00000164024), PA2G4 (ENSG00000170515), METAP1D (ENSG00000172878), XPNPEP3 (ENSG00000196236)

Protein

Protein identifiers

Xaa-Pro dipeptidase — P12955 (reviewed: P12955)

Alternative names: Imidodipeptidase, Peptidase D, Proline dipeptidase

All UniProt accessions (19): A0A140VJR2, A0A494C165, A0A494C194, A0A8V8TLL9, A0A8V8TLN7, A0A8V8TLP2, A0A8V8TLP4, A0A8V8TLR1, A0A8V8TLR6, A0A8V8TM81, A0A8V8TM86, A0A8V8TN48, A0A8V8TN70, A0A8V8TNF2, A0A8V8TNH5, P12955, K7ES25, V9GYE4, V9GYL0

UniProt curated annotations — full annotation on UniProt →

Function. Dipeptidase that catalyzes the hydrolysis of dipeptides with a prolyl (Xaa-Pro) or hydroxyprolyl residue in the C-terminal position. The preferred dipeptide substrate is Gly-Pro, but other Xaa-Pro dipeptides, such as Ala-Pro, Met-Pro, Phe-Pro, Val-Pro and Leu-Pro, can be cleaved. Plays an important role in collagen metabolism because the high level of iminoacids in collagen.

Subunit / interactions. Homodimer.

Disease relevance. Prolidase deficiency (PD) [MIM:170100] A multisystem disorder associated with massive iminodipeptiduria and lack of or reduced prolidase activity in erythrocytes, leukocytes, or cultured fibroblasts. Clinical features include skin ulcers, developmental delay, recurrent infections, and a characteristic facies. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Specifically inhibited by the pseudodipeptide CQ31. Inhibition by CQ31 indirectly activates the CARD8 inflammasome: dipeptide accumulation following PEPD inactivation weaky inhibit dipeptidyl peptidases DDP8 and DPP9, relieving DPP8- and/or DPP9-mediated inhibition of CARD8.

Cofactor. Binds 2 manganese ions per subunit.

Similarity. Belongs to the peptidase M24B family. Eukaryotic-type prolidase subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P12955-1	1	yes
P12955-2	2
P12955-3	3

RefSeq proteins (3): NP_000276, NP_001159528, NP_001159529 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000994	Pept_M24	Domain
IPR001131	Peptidase_M24B_aminopep-P_CS	Conserved_site
IPR007865	Aminopep_P_N	Domain
IPR029149	Creatin/AminoP/Spt16_N	Homologous_superfamily
IPR036005	Creatinase/aminopeptidase-like	Homologous_superfamily
IPR052433	X-Pro_dipept-like	Family

Pfam: PF00557, PF05195

Enzyme classification (BRENDA):

• EC 3.4.13.9 — Xaa-Pro dipeptidase (BRENDA: 28 organisms, 221 substrates, 105 inhibitors, 169 Km, 83 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
MET-PRO	0.8–14.5	36
L-MET-L-PRO	0.81–9.89	13
LEU-PRO	0.2–10.4	13
GLY-L-PRO	0.006–7.1	10
ALA-PRO	0.127–8.3	8
L-LEU-L-PRO	0.395–23.3	8
L-PRO-GLY	6.8–26.9	8
L-PRO-L-MET	4.2–19.1	8
L-PRO-L-VAL	3.2–28.6	8
MET-PRO-ALA	1.8–9	8
GLY-PRO	0.14–11.23	6
PHE-PRO	0.76–25	6
ARG-PRO-ALA	2.1–8.4	4
L-VAL-L-PRO	0.06–0.41	4
MET-ALA-ALA	0.15–0.91	4

Catalyzed reactions (Rhea), 1 shown:

• Xaa-L-Pro dipeptide + H2O = an L-alpha-amino acid + L-proline (RHEA:76407)

UniProt features (80 total): helix 20, strand 17, sequence conflict 14, binding site 11, sequence variant 7, turn 5, modified residue 2, splice variant 2, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
6SRE	X-RAY DIFFRACTION	1.39
5MC1	X-RAY DIFFRACTION	1.43
6H2P	X-RAY DIFFRACTION	1.48
5M4G	X-RAY DIFFRACTION	1.48
5M4L	X-RAY DIFFRACTION	1.49
5MBZ	X-RAY DIFFRACTION	1.5
5MC3	X-RAY DIFFRACTION	1.52
5M4J	X-RAY DIFFRACTION	1.55
5MBY	X-RAY DIFFRACTION	1.55
5MC0	X-RAY DIFFRACTION	1.56
6QSC	X-RAY DIFFRACTION	1.57
5MC2	X-RAY DIFFRACTION	1.7
5M4Q	X-RAY DIFFRACTION	1.73
6H2Q	X-RAY DIFFRACTION	1.78
5MC4	X-RAY DIFFRACTION	1.8
2IW2	X-RAY DIFFRACTION	1.82
6SRF	X-RAY DIFFRACTION	1.85
5MC5	X-RAY DIFFRACTION	1.9
6QSB	X-RAY DIFFRACTION	1.99
2OKN	X-RAY DIFFRACTION	2.45
6SRG	X-RAY DIFFRACTION	2.56

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P12955-F1	97.62	0.97

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 (11): 412; 452; 452; 255; 276; 287; 287; 287; 370; 377; 398

Post-translational modifications (2): 2, 167

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 366 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, MODULE_172, MODULE_52, GRUETZMANN_PANCREATIC_CANCER_DN, GOMF_METALLOPEPTIDASE_ACTIVITY, ENK_UV_RESPONSE_KERATINOCYTE_UP, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_DN, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, CAGCTG_AP4_Q5, MODULE_118, OCT1_06, HOFFMANN_SMALL_PRE_BII_TO_IMMATURE_B_LYMPHOCYTE_UP, SANSOM_APC_TARGETS_DN

GO Biological Process (5): proteolysis (GO:0006508), amino acid metabolic process (GO:0006520), collagen catabolic process (GO:0030574), negative regulation of programmed cell death (GO:0043069), CARD8 inflammasome complex assembly (GO:0140633)

GO Molecular Function (11): metallocarboxypeptidase activity (GO:0004181), peptidase activity (GO:0008233), manganese ion binding (GO:0030145), metalloaminopeptidase activity (GO:0070006), proline dipeptidase activity (GO:0102009), protein binding (GO:0005515), metalloexopeptidase activity (GO:0008235), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), dipeptidase activity (GO:0016805), metal ion binding (GO:0046872)

GO Cellular Component (1): extracellular exosome (GO:0070062)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
metalloexopeptidase activity	2
exopeptidase activity	2
protein metabolic process	1
primary metabolic process	1
catabolic process	1
collagen metabolic process	1
programmed cell death	1
regulation of programmed cell death	1
negative regulation of cellular process	1
canonical inflammasome complex assembly	1
carboxypeptidase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
transition metal ion binding	1
aminopeptidase activity	1
dipeptidase activity	1
binding	1
metallopeptidase activity	1
peptidase activity	1
catalytic activity	1
cation binding	1
extracellular vesicle	1

Protein interactions and networks

STRING

2353 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PEPD	APOC2	P02655	794
PEPD	APOC1	P02654	779
PEPD	PGC	P20142	654
PEPD	DPP7	Q9UHL4	632
PEPD	CNDP2	Q96KP4	618
PEPD	SCN9A	Q15858	615
PEPD	ERCC2	P18074	613
PEPD	HARS1	P12081	606
PEPD	HARS2	P49590	606
PEPD	GPI	P06744	585
PEPD	CNDP1	Q96KN2	582
PEPD	SHMT2	P34897	566
PEPD	XPNPEP2	O43895	561
PEPD	XPNPEP1	Q9NQW7	560
PEPD	TPI1	P00938	559

IntAct

23 interactions, top by confidence:

A	B	Type	Score
PEPD	ATXN1	psi-mi:“MI:0915”(physical association)	0.670
PEPD	TERF1	psi-mi:“MI:0915”(physical association)	0.510
PKM	PEPD	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
USP7	PEPD	psi-mi:“MI:0915”(physical association)	0.370
SPP1	PEPD	psi-mi:“MI:0915”(physical association)	0.370
KSR1		psi-mi:“MI:0914”(association)	0.350
ORF69	PEPD	psi-mi:“MI:0914”(association)	0.350
CUL2	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350
TERF1	PEPD	psi-mi:“MI:0915”(physical association)	0.000
tig	PEPD	psi-mi:“MI:0915”(physical association)	0.000
	PEPD	psi-mi:“MI:0915”(physical association)	0.000
acnA	PEPD	psi-mi:“MI:0915”(physical association)	0.000
comEA	PEPD	psi-mi:“MI:0915”(physical association)	0.000
ATXN1	PEPD	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (95): PEPD (Two-hybrid), PEPD (Affinity Capture-RNA), PEPD (Affinity Capture-RNA), GOT1 (Co-fractionation), HSPE1 (Co-fractionation), PEPD (Co-fractionation), PEPD (Co-fractionation), PEPD (Co-fractionation), PEPD (Co-fractionation), PSMG4 (Co-fractionation), TANGO2 (Co-fractionation), PEPD (Affinity Capture-MS), PEPD (Affinity Capture-RNA), PEPD (Proximity Label-MS), PEPD (Affinity Capture-MS)

ESM2 similar proteins: A1CNW6, A1D1S6, A2QAW7, A4RQ11, A6QYF6, A6SL16, A7ENP9, B0XN37, B2AW39, B6HAN0, B6QAW7, B8M2W9, B8MZI5, C0NF18, C0NIF0, C0SDW6, C0SHQ0, C1GD57, C1GHS9, C1H3X3, C1H9Q9, C4JF09, C4JY72, C5FUV0, C5G874, C5GKT2, C5JQ04, C5K0R2, C5PAH2, C5PHM7, C6H7R7, C6HNY5, C9SEV5, D1ZBF6, D4B0B2, D4D6B8, E3Q897, E4V1Q7, E9CY14, E9DDK8

Diamond homologs: A1CNW6, A1CSI0, A1D1S6, A1DG66, A2QAW7, A2QKF6, A4RAE9, A4RQ11, A6QYF6, A6SDE9, A6SL16, A7ENP9, A7EUB3, A7UWH7, B0XN37, B0XW47, B2AFW1, B2AW39, B2WKR4, B2WMQ2, B4EWE3, B4SZ86, B4TBS6, B4TNZ2, B5BIZ1, B5EZW1, B5FNX9, B5QW86, B5RFL5, B6H2M0, B6HAN0, B6Q8T5, B6QAW7, B8M0Z4, B8M2W9, B8MZI5, B8NC10, C0NF18, C0NIF0, C0Q3F4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	47
Likely pathogenic	29
Uncertain significance	245
Likely benign	385
Benign	52

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1299535	NM_000285.4(PEPD):c.2T>G (p.Met1Arg)	Pathogenic
1299536	NM_000285.4(PEPD):c.549-1G>T	Pathogenic
1433659	NC_000019.9:g.(?34012630)(34012666_?)del	Pathogenic
1439106	NM_000285.4(PEPD):c.340A>T (p.Lys114Ter)	Pathogenic
1440927	NM_000285.4(PEPD):c.550C>T (p.Arg184Ter)	Pathogenic
1454838	NC_000019.9:g.(?33902558)(33904569_?)del	Pathogenic
1470569	NC_000019.9:g.(?33968932)(33969016_?)del	Pathogenic
208	NM_000285.4(PEPD):c.826G>A (p.Asp276Asn)	Pathogenic
209	NM_000285.3(PEPD):c.1153_1344del (p.Gly385_Gly448del)	Pathogenic
211	NM_000285.4(PEPD):c.551G>A (p.Arg184Gln)	Pathogenic
2146250	NM_000285.4(PEPD):c.1086_1087del (p.Phe363fs)	Pathogenic
215	NM_000285.4(PEPD):c.793C>T (p.Arg265Ter)	Pathogenic
216	NM_000285.4(PEPD):c.1234G>A (p.Glu412Lys)	Pathogenic
217	NM_000285.4(PEPD):c.611_623dup (p.Glu208_Val209insGlyProProTer)	Pathogenic
218	NM_000285.4(PEPD):c.605C>T (p.Ser202Phe)	Pathogenic
2580569	NM_000285.4(PEPD):c.769G>T (p.Gly257Ter)	Pathogenic
2705436	NM_000285.4(PEPD):c.650_653del (p.Met217fs)	Pathogenic
2731784	NM_000285.4(PEPD):c.504-1G>T	Pathogenic
2736862	NM_000285.4(PEPD):c.504-2A>G	Pathogenic
2749223	NM_000285.4(PEPD):c.1060_1094dup (p.His366fs)	Pathogenic
2752938	NM_000285.4(PEPD):c.297del (p.Arg99fs)	Pathogenic
2761059	NM_000285.4(PEPD):c.379C>T (p.Gln127Ter)	Pathogenic
2761247	NM_000285.4(PEPD):c.838_841del (p.Glu280fs)	Pathogenic
2775572	NM_000285.4(PEPD):c.1302_1305del (p.Phe434fs)	Pathogenic
2817935	NM_000285.4(PEPD):c.163C>T (p.Gln55Ter)	Pathogenic
2822380	NM_000285.4(PEPD):c.953dup (p.Ala319fs)	Pathogenic
2841577	NM_000285.4(PEPD):c.738_739insGT (p.Ser247fs)	Pathogenic
2853264	NM_000285.4(PEPD):c.199C>T (p.Gln67Ter)	Pathogenic
2866451	NM_000285.4(PEPD):c.217dup (p.Trp73fs)	Pathogenic
2869763	NM_000285.4(PEPD):c.1305_1306insCTTT (p.Asn436delinsLeuTer)	Pathogenic

SpliceAI

4294 predictions. Top by Δscore:

Variant	Effect	Δscore
19:33387479:GACC:G	acceptor_loss	1.0000
19:33387480:ACCTG:A	acceptor_loss	1.0000
19:33387481:CCTG:C	acceptor_loss	1.0000
19:33387885:CTCA:C	donor_loss	1.0000
19:33387886:TCACC:T	donor_loss	1.0000
19:33387887:CACCC:C	donor_loss	1.0000
19:33387888:A:AC	donor_gain	1.0000
19:33387888:AC:A	donor_gain	1.0000
19:33387888:ACC:A	donor_gain	1.0000
19:33387888:ACCC:A	donor_gain	1.0000
19:33387889:C:CC	donor_gain	1.0000
19:33387889:CC:C	donor_gain	1.0000
19:33387889:CCC:C	donor_gain	1.0000
19:33387889:CCCC:C	donor_gain	1.0000
19:33387889:CCCCG:C	donor_gain	1.0000
19:33388077:ACGCC:A	acceptor_gain	1.0000
19:33388078:CGCC:C	acceptor_gain	1.0000
19:33388078:CGCCC:C	acceptor_gain	1.0000
19:33388079:GCC:G	acceptor_gain	1.0000
19:33388080:CC:C	acceptor_gain	1.0000
19:33388080:CCCTG:C	acceptor_gain	1.0000
19:33388081:CCT:C	acceptor_loss	1.0000
19:33388081:CCTG:C	acceptor_gain	1.0000
19:33388082:C:CA	acceptor_loss	1.0000
19:33388082:C:CC	acceptor_gain	1.0000
19:33388082:C:T	acceptor_gain	1.0000
19:33391290:CTGA:C	donor_loss	1.0000
19:33391291:TGA:T	donor_loss	1.0000
19:33391292:GACCT:G	donor_loss	1.0000
19:33391293:A:AG	donor_loss	1.0000

AlphaMissense

3247 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:33387470:C:A	E452D	0.999
19:33387470:C:G	E452D	0.999
19:33391318:G:C	H377D	0.999
19:33401827:G:C	D287E	0.999
19:33401827:G:T	D287E	0.999
19:33401828:T:A	D287V	0.999
19:33401828:T:G	D287A	0.999
19:33401861:T:A	D276V	0.999
19:33464050:C:A	K187N	0.999
19:33464050:C:G	K187N	0.999
19:33387471:T:A	E452V	0.998
19:33387998:C:A	E412D	0.998
19:33387998:C:G	E412D	0.998
19:33391316:G:C	H377Q	0.998
19:33391316:G:T	H377Q	0.998
19:33391318:G:T	H377N	0.998
19:33391337:G:C	H370Q	0.998
19:33391337:G:T	H370Q	0.998
19:33391339:G:C	H370D	0.998
19:33401829:C:G	D287H	0.998
19:33401831:G:A	S286F	0.998
19:33401831:G:T	S286Y	0.998
19:33401860:G:C	D276E	0.998
19:33401860:G:T	D276E	0.998
19:33401861:T:G	D276A	0.998
19:33413580:G:C	C245W	0.998
19:33463995:G:C	H206D	0.998
19:33387999:T:A	E412V	0.997
19:33388005:G:A	T410I	0.997
19:33388042:G:T	R398S	0.997

dbSNP variants (sampled 300 via entrez): RS1000013286 (19:33410925 C>A,T), RS1000041841 (19:33505907 C>T), RS1000071313 (19:33520046 A>G), RS1000087228 (19:33479346 A>C,G), RS1000112426 (19:33436897 T>C), RS1000121256 (19:33406322 A>G), RS1000128524 (19:33514056 C>T), RS1000145363 (19:33456912 C>T), RS1000147649 (19:33518393 G>C), RS1000156493 (19:33482961 C>T), RS1000214430 (19:33477052 A>G), RS1000233719 (19:33474135 C>T), RS1000247091 (19:33477361 C>T), RS1000270124 (19:33519576 C>T), RS1000274186 (19:33401255 A>G)

Disease associations

OMIM: gene MIM:613230 | disease phenotypes: MIM:170100, MIM:602541, MIM:107100

GenCC curated gene-disease

Disease	Classification	Inheritance
prolidase deficiency	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
prolidase deficiency	Definitive	AR

Mondo (3): prolidase deficiency (MONDO:0008221), megaconial type congenital muscular dystrophy (MONDO:0011246), hereditary anorectal anomalies (MONDO:0007136)

Orphanet (3): Prolidase deficiency (Orphanet:742), Megaconial congenital muscular dystrophy (Orphanet:280671), Non-syndromic anorectal malformation (Orphanet:557)

HPO phenotypes

67 total (30 of 67 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000294	Low anterior hairline
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000370	Abnormality of the middle ear
HP:0000457	Depressed nasal ridge
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000520	Proptosis
HP:0000670	Carious teeth
HP:0000958	Dry skin
HP:0000962	Hyperkeratosis
HP:0000963	Thin skin
HP:0000964	Eczematoid dermatitis
HP:0000967	Petechiae
HP:0000982	Palmoplantar keratoderma
HP:0000989	Pruritus
HP:0000992	Cutaneous photosensitivity
HP:0001007	Hirsutism
HP:0001166	Arachnodactyly
HP:0001231	Abnormal fingernail morphology
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay
HP:0001508	Failure to thrive
HP:0001744	Splenomegaly
HP:0001873	Thrombocytopenia
HP:0001903	Anemia
HP:0001999	Abnormal facial shape

GWAS associations

172 associations (top):

Study	Trait	p-value
GCST001351_8	Type 2 diabetes	1.000000e-08
GCST001463_10	Adiponectin levels	2.000000e-08
GCST001465_21	Adiponectin levels	8.000000e-12
GCST001526_13	Fasting blood insulin (BMI interaction)	9.000000e-08
GCST002216_18	Triglycerides	3.000000e-09
GCST002223_68	HDL cholesterol	3.000000e-09
GCST002233_6	Adiponectin levels	4.000000e-12
GCST002831_13	Lead levels in blood	9.000000e-07
GCST003048_326	Schizophrenia	3.000000e-08
GCST004063_154	Waist circumference adjusted for body mass index	2.000000e-07
GCST004063_168	Waist circumference adjusted for body mass index	9.000000e-09
GCST004064_59	Waist-hip ratio	3.000000e-07
GCST004064_63	Waist-hip ratio	4.000000e-11
GCST004064_66	Waist-hip ratio	3.000000e-06
GCST004232_78	HDL cholesterol levels	4.000000e-08
GCST004237_14	Triglyceride levels	3.000000e-09
GCST004500_48	Waist circumference adjusted for BMI (adjusted for smoking behaviour)	1.000000e-07
GCST004501_122	Waist circumference adjusted for BMI (joint analysis main effects and smoking interaction)	3.000000e-07
GCST004562_158	Waist circumference adjusted for body mass index	1.000000e-09
GCST004562_4	Waist circumference adjusted for body mass index	1.000000e-08
GCST004563_140	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	8.000000e-08
GCST004563_35	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	5.000000e-09
GCST004564_45	Waist circumference adjusted for BMI in active individuals	7.000000e-07
GCST004564_46	Waist circumference adjusted for BMI in active individuals	3.000000e-08
GCST004567_121	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	5.000000e-12
GCST004567_33	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	5.000000e-12
GCST004576_18	Waist-to-hip ratio adjusted for body mass index	3.000000e-12
GCST004576_36	Waist-to-hip ratio adjusted for body mass index	2.000000e-13
GCST004576_37	Waist-to-hip ratio adjusted for body mass index	1.000000e-06
GCST004578_135	Waist-to-hip ratio adjusted for BMI in active individuals	2.000000e-06

EFO canonical traits (25, from GWAS)

EFO ID	Trait name
EFO:0004502	adiponectin measurement
EFO:0004340	body mass index
EFO:0004530	triglyceride measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0004343	waist-hip ratio
EFO:0004318	smoking behavior
EFO:0008002	physical activity measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004344	birth weight
EFO:0004534	creatine kinase measurement
EFO:0006335	systolic blood pressure
EFO:0004329	alcohol drinking
EFO:0010092	bitter alcoholic beverage consumption measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0007800	body fat percentage
EFO:0008039	BMI-adjusted hip circumference
EFO:0004980	appendicular lean mass
EFO:0007986	reticulocyte count
EFO:0004587	lymphocyte count
EFO:0004527	mean corpuscular hemoglobin
EFO:0007989	monocyte percentage of leukocytes
EFO:0010701	mean reticulocyte volume
EFO:0004833	neutrophil count
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D056732	Prolidase Deficiency	C16.131.077.735; C16.131.831.720; C16.320.565.100.794; C16.320.850.746
C566527	Muscular Dystrophy, Congenital, Megaconial Type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4185 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 584,453 (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
CHEMBL1560	CAPTOPRIL	4	66,415
CHEMBL178	DAUNORUBICIN	4	203,756
CHEMBL53463	DOXORUBICIN	4	314,282
CHEMBL6067485	GENTAMICIN	4

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — M24: Methionyl aminopeptidase

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
phosphoenolpyruvic acid	Inhibition	9.62	pKi

Binding affinities (BindingDB)

44 measured of 44 human assays (44 total across all organisms); most potent 44 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
US20250368624, Compound CQ79	IC50	720 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
US20250368624, Compound CQ119	IC50	1700 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
US20250368624, Compound CQ118	IC50	2000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
US20250368624, Compound CQ117	IC50	2200 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
US20250368624, Compound CQ113	IC50	2900 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
US20250368624, Compound CQ116	IC50	3400 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
methyl (2S)-1-[(2S,3R)-3-amino-3-cyclopropyl-2-hydroxypropanoyl]pyrrolidine-2-carboxylate	IC50	4200 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
US20250368624, Compound CQ114	IC50	7000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
methyl (2S)-1-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl]pyrrolidine-2-carboxylate	IC50	7600 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
US20250368624, Compound CQ50	IC50	8100 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
US20250368624, Compound CQ96	IC50	10000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
US20250368624, Compound CQ109	IC50	11000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
N-[[(2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]pyrrolidin-2-yl]methyl]methanesulfonamide	IC50	12000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
US20250368624, Compound CQ110	IC50	14000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
US20250368624, Compound CQ115	IC50	14000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
(S)-1-[(S)-1-((2S,3R)-3-Amino-2-hydroxy-4-phenyl-butyryl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carboxylic acid ((S)-1-carbamoyl-ethyl)-amide	IC50	18000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
US20250368624, Compound CQ81	IC50	23000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
methyl (2S)-1-[(2S,3R)-3-(1-adamantyl)-3-amino-2-hydroxypropanoyl]pyrrolidine-2-carboxylate	IC50	33000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
(2S,3R)-3-amino-2-hydroxy-5-methyl-1-pyrrolidin-1-ylhexan-1-one	IC50	38000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
US20250368624, Compound CQ78	IC50	41000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
US20250368624, Compound CQ80	IC50	43000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
methyl (2S)-1-[(2S,3R)-3-amino-3-(1-benzofuran-6-yl)-2-hydroxypropanoyl]pyrrolidine-2-carboxylate	IC50	47000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
(2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]pyrrolidine-2-carboxamide	IC50	53000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
methyl (2S)-2-[[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]amino]-4-methylpentanoate	IC50	57000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
methyl (2S)-1-[(2S,3R)-3-amino-2-hydroxy-5,5-dimethylhexanoyl]pyrrolidine-2-carboxylate	IC50	57000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
methyl (2S)-1-[(2S,3S)-3-amino-2-hydroxy-3-thiophen-2-ylpropanoyl]pyrrolidine-2-carboxylate	IC50	65000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
(2S,3R)-3-amino-2-hydroxy-5-methyl-1-[(2S)-2-(2H-tetrazol-5-yl)pyrrolidin-1-yl]hexan-1-one	IC50	67000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
methyl (2S)-1-[(2S,3S)-3-amino-3-(furan-2-yl)-2-hydroxypropanoyl]pyrrolidine-2-carboxylate	IC50	69000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
methyl (2S,4S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-4-fluoropyrrolidine-2-carboxylate	IC50	74000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
US20250368624, Compound CQ111	IC50	84000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
methyl (2S)-1-[(2S,3R)-3-amino-2-hydroxyheptanoyl]pyrrolidine-2-carboxylate	IC50	92000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
US20250368624, Compound CQ112	IC50	95000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
methyl (2S)-2-[[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]amino]-3-phenylpropanoate	IC50	96000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
Name not given	IC50	100000 nM
US20250368624, Compound CQ43	IC50	115000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
methyl (2S)-1-[(2S,3R)-3-amino-2,7-dihydroxyheptanoyl]pyrrolidine-2-carboxylate	IC50	115000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
methyl (2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]pyrrolidine-2-carboxylate	IC50	122000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
US20250368624, Compound CQ95	IC50	140000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
methyl (2S,4S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-4-methylpyrrolidine-2-carboxylate	IC50	154000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
methyl (2S,4S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-4-hydroxypyrrolidine-2-carboxylate	IC50	190000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
methyl (2S)-1-[(2S,3R)-3-amino-2-hydroxy-4-methylpentanoyl]pyrrolidine-2-carboxylate	IC50	190000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
methyl (2S)-1-[(2S,3R)-3-amino-2-hydroxy-3-phenylpropanoyl]pyrrolidine-2-carboxylate	IC50	203000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
(2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-N-methoxypyrrolidine-2-carboxamide	IC50	303000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION
methyl (6S)-5-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-5-azaspiro[2.4]heptane-6-carboxylate	IC50	324000 nM	US-20250368624: M24B AMINOPEPTIDASE INHIBITORS FOR CARD8 INFLAMMASOME ACTIVATION

ChEMBL bioactivities

44 potent at pChembl≥5 of 56 total, top 44 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.07	Ki	8.5	nM	PHOSPHOENOLPYRUVATE
6.57	Ki	270	nM	CHEMBL96505
6.55	IC50	280	nM	CHEMBL5419166
6.54	IC50	290	nM	CHEMBL5433567
6.52	IC50	300	nM	CHEMBL5435351
6.52	IC50	300	nM	DAUNORUBICIN
6.52	Ki	300	nM	PHOSPHOENOLPYRUVATE
6.28	IC50	530	nM	CHEMBL5429139
6.26	Kd	547.3	nM	CHEMBL5653589
6.26	ED50	547.3	nM	CHEMBL5653589
6.25	IC50	560	nM	CHEMBL5433668
6.18	IC50	660	nM	CHEMBL2369858
6.17	IC50	670	nM	CHEMBL5437413
6.14	IC50	720	nM	CHEMBL5419034
6.14	IC50	720	nM	CHEMBL5393876
6.08	IC50	840	nM	CHEMBL5407130
6.08	IC50	840	nM	CHEMBL5401781
6.04	IC50	910	nM	CHEMBL5410658
6.00	IC50	1000	nM	CHEMBL5403940
5.92	IC50	1200	nM	CHEMBL5399924
5.89	IC50	1300	nM	CHEMBL5396150
5.82	IC50	1500	nM	CHEMBL5438777
5.82	IC50	1500	nM	CHEMBL5436435
5.80	IC50	1600	nM	CHEMBL5396773
5.77	IC50	1700	nM	CHEMBL5398054
5.75	IC50	1800	nM	CHEMBL5394915
5.75	IC50	1800	nM	CHEMBL5421036
5.70	IC50	2000	nM	CHEMBL5404330
5.66	IC50	2200	nM	CHEMBL5433606
5.66	IC50	2200	nM	CHEMBL78699
5.66	IC50	2200	nM	CHEMBL2369868
5.55	IC50	2800	nM	CHEMBL5406619
5.43	IC50	3700	nM	CHEMBL5419938
5.40	IC50	4000	nM	CHEMBL5430934
5.38	IC50	4200	nM	CHEMBL5403929
5.31	IC50	4900	nM	CHEMBL311875
5.24	IC50	5700	nM	CHEMBL5400780
5.21	IC50	6200	nM	CHEMBL5432938
5.12	IC50	7600	nM	CHEMBL5403681
5.12	IC50	7500	nM	CHEMBL5403523
5.12	IC50	7600	nM	CHEMBL5438224
5.01	Ki	9730	nM	CHEMBL5592090
5.00	IC50	1e+04	nM	CHEMBL5402862
5.00	IC50	1e+04	nM	DOXORUBICIN

PubChem BioAssay actives

40 with measured affinity, of 140 total; 40 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)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]pyrrolidine-2-carboxamide	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	0.2800	uM
(2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-N-(3-methylbutyl)pyrrolidine-2-carboxamide	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	0.2900	uM
methyl (2S)-1-[(2S,3R)-3-amino-2,7-dihydroxyheptanoyl]pyrrolidine-2-carboxylate	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	0.3000	uM
Daunorubicin	2113102: Inhibition of prolidase (unknown origin)	ic50	0.3000	uM
methyl (2S)-1-[(2S,3R)-3-amino-2-hydroxyheptanoyl]pyrrolidine-2-carboxylate	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	0.5300	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148977: Binding affinity to human PEPD incubated for 45 mins by Kinobead based pull down assay	kd	0.5473	uM
(2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-N-[(2S)-1-(dimethylsulfamoylamino)-4-methyl-1-oxopentan-2-yl]pyrrolidine-2-carboxamide	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	0.5600	uM
(2S)-1-[(2R,3S)-3-amino-2-hydroxy-5-methylhexanoyl]-N-[(2S)-1-amino-1-oxopropan-2-yl]pyrrolidine-2-carboxamide	162622: Inhibition against Prolidase from pig kidney.	ic50	0.6600	uM
methyl (2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]pyrrolidine-2-carboxylate	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	0.6700	uM
(2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-N-[(2S)-1-(2-fluoroethylamino)-4-methyl-1-oxopentan-2-yl]pyrrolidine-2-carboxamide	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	0.7200	uM
methyl (2S)-2-[[(2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]pyrrolidine-2-carbonyl]amino]-3-phenylpropanoate	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	0.7200	uM
methyl (2S,4S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-4-fluoropyrrolidine-2-carboxylate	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	0.8400	uM
methyl (2S,3S)-2-[[(2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]pyrrolidine-2-carbonyl]amino]-3-methylpentanoate	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	0.8400	uM
methyl (2S)-2-[[(2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]pyrrolidine-2-carbonyl]amino]-4-methylpentanoate	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	0.9100	uM
methyl (6S)-5-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-5-azaspiro[2.4]heptane-6-carboxylate	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	1.0000	uM
methyl (2S)-2-[[(2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoate	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	1.2000	uM
methyl (2S)-1-[(2S,3R)-3-amino-6,6,6-trifluoro-2-hydroxyhexanoyl]pyrrolidine-2-carboxylate	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	1.3000	uM
(2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-N-[(2S)-4-methyl-1-(3-methylbutylamino)-1-oxopentan-2-yl]pyrrolidine-2-carboxamide	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	1.5000	uM
methyl (2S)-1-[(2S,3R)-3-amino-2-hydroxy-5,5-dimethylhexanoyl]pyrrolidine-2-carboxylate	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	1.5000	uM
(2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-N-methoxypyrrolidine-2-carboxamide	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	1.6000	uM
methyl (2S)-1-[(2S,3R)-3-amino-3-(furan-2-yl)-2-hydroxypropanoyl]pyrrolidine-2-carboxylate	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	1.7000	uM
methyl (2S)-1-[(2S,3R)-3-amino-2-hydroxy-4-methylpentanoyl]pyrrolidine-2-carboxylate	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	1.8000	uM
methyl (2S)-1-[(2S,3R)-3-amino-3-(1-benzofuran-6-yl)-2-hydroxypropanoyl]pyrrolidine-2-carboxylate	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	1.8000	uM
methyl (2S)-1-[(2S,3R)-3-amino-2-hydroxy-3-thiophen-2-ylpropanoyl]pyrrolidine-2-carboxylate	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	2.0000	uM
(2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-N-[(2S)-1-amino-1-oxopropan-2-yl]pyrrolidine-2-carboxamide	162622: Inhibition against Prolidase from pig kidney.	ic50	2.2000	uM
(2S)-1-[(2S)-1-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carboxamide	162622: Inhibition against Prolidase from pig kidney.	ic50	2.2000	uM
methyl (2S,4S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-4-methylpyrrolidine-2-carboxylate	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	2.2000	uM
methyl (2S)-1-[(2S,3R)-3-amino-2-hydroxy-3-phenylpropanoyl]pyrrolidine-2-carboxylate	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	2.8000	uM
(2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-N-[(2S)-1-(tert-butylamino)-4-methyl-1-oxopentan-2-yl]pyrrolidine-2-carboxamide	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	3.7000	uM
(2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-N-[(2S)-1-(dimethylamino)-4-methyl-1-oxopentan-2-yl]pyrrolidine-2-carboxamide	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	4.0000	uM
methyl (2S)-1-[(2S,3R)-3-amino-3-cyclopropyl-2-hydroxypropanoyl]pyrrolidine-2-carboxylate	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	4.2000	uM
(2S)-1-[(2S)-1-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl]pyrrolidine-2-carbonyl]-N-[(2S)-1-amino-1-oxopropan-2-yl]pyrrolidine-2-carboxamide	162622: Inhibition against Prolidase from pig kidney.	ic50	4.9000	uM
(2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-N-[(2S)-4-methyl-1-oxo-1-(2-phenylethylamino)pentan-2-yl]pyrrolidine-2-carboxamide	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	5.7000	uM
(2S,3R)-3-amino-2-hydroxy-5-methyl-1-[(2S)-2-(2H-tetrazol-5-yl)pyrrolidin-1-yl]hexan-1-one	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	6.2000	uM
(2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-N-[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]pyrrolidine-2-carboxamide	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	7.5000	uM
(2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-N-[(2S)-4-methyl-1-(2-naphthalen-2-ylethylamino)-1-oxopentan-2-yl]pyrrolidine-2-carboxamide	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	7.6000	uM
methyl (2S)-1-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl]pyrrolidine-2-carboxylate	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	7.6000	uM
(4-hydroxyphenyl)urea	2113105: Competitive inhibition of prolidase (unknown origin) in erythrocytes assessed as inhibition constant	ki	9.7300	uM
(2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-N-[(2S)-1-[2-(1H-indol-6-yl)ethylamino]-4-methyl-1-oxopentan-2-yl]pyrrolidine-2-carboxamide	2027389: Inhibition of recombinant human PEPD using Ala-Pro as substrate assessed as alanine release by measuring increase in fluorescense signal by fluorescence based analysis	ic50	10.0000	uM
Doxorubicin	2113102: Inhibition of prolidase (unknown origin)	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects expression, decreases expression, affects methylation, affects cotreatment	4
Isoflurophate	increases hydrolysis, decreases response to substance	4
Aflatoxin B1	decreases methylation, increases methylation, affects expression, decreases expression	4
bisphenol A	decreases expression, increases expression	3
tabun	increases hydrolysis	3
Sarin	increases hydrolysis	3
Soman	increases hydrolysis	3
Valproic Acid	affects expression, increases expression	3
cyclohexyl methylphosphonofluoridate	increases hydrolysis	2
Acetaminophen	decreases activity, decreases expression	2
Hydrogen Peroxide	increases activity, affects expression	2
Smoke	decreases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	increases expression	1
2,4,6-tribromophenol	decreases expression	1
methyleugenol	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
benzo(b)fluoranthene	affects cotreatment, affects expression	1
deoxynivalenol	decreases expression	1
sodium arsenate	decreases expression	1
VX-agent	increases hydrolysis	1
decabromobiphenyl ether	decreases expression	1
methylparaben	decreases activity	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
benzo(e)pyrene	affects methylation	1
aflatoxin B2	increases methylation	1
nivalenol	decreases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	1
CGP 52608	affects binding, increases reaction	1

ChEMBL screening assays

31 unique, capped per target: 31 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1110130	Binding	Inhibition of prolidase	Inhibitors of prolyl oligopeptidases for the therapy of human diseases: defining diseases and inhibitors. — J Med Chem

Cellosaurus cell lines

7 cell lines: 6 finite cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_0E57	WG1077	Finite cell line	Male
CVCL_0E64	WG1625	Finite cell line	Female
CVCL_D0H6	KMUGMCi007-A	Induced pluripotent stem cell	Male
CVCL_UH76	WG1082	Finite cell line	Male
CVCL_UH78	WG1194	Finite cell line	Female
CVCL_UH79	WG1298	Finite cell line	Female
CVCL_UH80	WG1343	Finite cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03334968	Not specified	COMPLETED	Prolidase Enzyme Activity in Stroke Patients