XPNPEP1

Summary

XPNPEP1 (X-prolyl aminopeptidase 1, HGNC:12822) is a protein-coding gene on chromosome 10q25.1, encoding Xaa-Pro aminopeptidase 1 (Q9NQW7). Metalloaminopeptidase that catalyzes the removal of a penultimate prolyl residue from the N-termini of peptides, such as Arg-Pro-Pro.

This gene encodes the cytosolic form of a metalloaminopeptidase that catalyzes the cleavage of the N-terminal amino acid adjacent to a proline residue. The gene product may play a role in degradation and maturation of tachykinins, neuropeptides, and peptide hormones. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 7511 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 107 total
• Druggable target: yes
• MANE Select transcript: NM_020383

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12822
Approved symbol	XPNPEP1
Name	X-prolyl aminopeptidase 1
Location	10q25.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000108039
Ensembl biotype	protein_coding
OMIM	602443
Entrez	7511

Gene structure

Transcript identifiers

Ensembl transcripts: 46 — 22 protein_coding, 17 protein_coding_CDS_not_defined, 7 retained_intron

ENST00000322238, ENST00000369658, ENST00000369683, ENST00000403138, ENST00000423625, ENST00000430337, ENST00000443078, ENST00000451592, ENST00000460055, ENST00000460523, ENST00000472336, ENST00000475123, ENST00000488118, ENST00000490740, ENST00000494499, ENST00000494564, ENST00000502595, ENST00000502935, ENST00000504664, ENST00000505255, ENST00000506777, ENST00000507328, ENST00000508059, ENST00000508275, ENST00000508525, ENST00000509646, ENST00000510988, ENST00000512582, ENST00000513817, ENST00000891174, ENST00000891175, ENST00000891176, ENST00000891177, ENST00000891178, ENST00000927702, ENST00000927703, ENST00000927704, ENST00000927705, ENST00000942375, ENST00000942376, ENST00000942377, ENST00000942378, ENST00000942379, ENST00000942380, ENST00000942381, ENST00000942382

RefSeq mRNA: 9 — MANE Select: NM_020383 NM_001167604, NM_001324128, NM_001324131, NM_001324132, NM_001324133, NM_001324134, NM_001324135, NM_001324136, NM_020383

CCDS: CCDS53576, CCDS7560, CCDS81498

Canonical transcript exons

ENST00000502935 — 21 exons

Exon	Start	End
ENSE00003464473	109877790	109877867
ENSE00003479024	109907691	109907815
ENSE00003479340	109915011	109915099
ENSE00003481264	109871792	109871861
ENSE00003506415	109884067	109884148
ENSE00003510669	109891722	109891826
ENSE00003514423	109869953	109870029
ENSE00003521262	109880188	109880238
ENSE00003521736	109870731	109870904
ENSE00003529836	109873367	109873427
ENSE00003532698	109864766	109865312
ENSE00003539124	109886246	109886341
ENSE00003543665	109888049	109888192
ENSE00003557542	109875528	109875599
ENSE00003557752	109888503	109888595
ENSE00003574233	109880842	109880931
ENSE00003602257	109878000	109878058
ENSE00003613899	109893012	109893075
ENSE00003646166	109882432	109882642
ENSE00003673385	109868614	109868712
ENSE00003843740	109923402	109923511

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 98.24.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.2109 / max 338.8246, expressed in 1820 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
111372	31.8226	1820
111371	1.1825	496
111365	0.3337	90
111373	0.3187	133
111366	0.1656	50
111367	0.1637	39
111369	0.1282	28
111368	0.0515	18
111370	0.0442	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	98.24	gold quality
jejunal mucosa	UBERON:0000399	98.22	gold quality
cervix squamous epithelium	UBERON:0006922	97.83	gold quality
epithelium of nasopharynx	UBERON:0001951	97.67	gold quality
stromal cell of endometrium	CL:0002255	97.35	gold quality
duodenum	UBERON:0002114	97.33	gold quality
skin of leg	UBERON:0001511	96.64	gold quality
tongue squamous epithelium	UBERON:0006919	96.63	gold quality
monocyte	CL:0000576	96.54	gold quality
rectum	UBERON:0001052	96.52	gold quality
skin of abdomen	UBERON:0001416	96.45	gold quality
tibia	UBERON:0000979	96.38	gold quality
mononuclear cell	CL:0000842	96.23	gold quality
pancreas	UBERON:0001264	96.18	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.09	gold quality
small intestine	UBERON:0002108	96.03	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.97	gold quality
leukocyte	CL:0000738	95.96	gold quality
zone of skin	UBERON:0000014	95.86	gold quality
squamous epithelium	UBERON:0006914	95.82	gold quality
colonic mucosa	UBERON:0000317	95.77	gold quality
mucosa of stomach	UBERON:0001199	95.67	gold quality
gingival epithelium	UBERON:0001949	95.58	gold quality
gall bladder	UBERON:0002110	95.48	gold quality
left uterine tube	UBERON:0001303	95.40	gold quality
esophagus squamous epithelium	UBERON:0006920	95.19	gold quality
right ovary	UBERON:0002118	95.12	gold quality
oviduct epithelium	UBERON:0004804	95.11	gold quality
tonsil	UBERON:0002372	95.10	gold quality
mucosa of transverse colon	UBERON:0004991	95.10	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

75 targeting XPNPEP1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514
HSA-MIR-450B-5P	99.92	71.48	3175

Literature-anchored findings (GeneRIF, showing 2)

• These data suggest that progesterone-induced increases in AP-P may contribute to the development of oral contraceptive pill-induced hypertension in susceptible Women. (PMID:19126663)
• Alanine replacement of Arg535 destabilizes the AMPP dimer and guanidine hydrochloride restores the native monomer-dimer equilibrium. It is proposed that Arg535 plays an important role in AMMP catalysis and in stabilization of the catalytically active dimeric state (PMID:29351301)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	xpnpep1	ENSDARG00000029011
mus_musculus	Xpnpep1	ENSMUSG00000025027
rattus_norvegicus	Xpnpep1	ENSRNOG00000012084
drosophila_melanogaster	ApepP	FBGN0026150
caenorhabditis_elegans	app-1	WBGENE00000155
caenorhabditis_elegans		WBGENE00021555

Paralogs (7): METAP2 (ENSG00000111142), XPNPEP2 (ENSG00000122121), PEPD (ENSG00000124299), METAP1 (ENSG00000164024), PA2G4 (ENSG00000170515), METAP1D (ENSG00000172878), XPNPEP3 (ENSG00000196236)

Protein

Protein identifiers

Xaa-Pro aminopeptidase 1 — Q9NQW7 (reviewed: Q9NQW7)

Alternative names: Aminoacylproline aminopeptidase, Cytosolic aminopeptidase P, Soluble aminopeptidase P, X-Pro aminopeptidase 1, X-prolyl aminopeptidase 1, soluble

All UniProt accessions (4): Q9NQW7, Q5T6H2, Q5T6H3, Q5T6H7

UniProt curated annotations — full annotation on UniProt →

Function. Metalloaminopeptidase that catalyzes the removal of a penultimate prolyl residue from the N-termini of peptides, such as Arg-Pro-Pro. Contributes to the degradation of bradykinin.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Expressed in all tissues tested, including pancreas, heart, muscle, kidney, liver, lung and brain. Highest levels in pancreas.

Activity regulation. Inhibited by apstatin and the metal ion chelators EDTA and 1,10-phenanthroline. Partially inhibited by dithiothreitol. Not inhibited by enalaprilat or amastatin. 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.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9NQW7-1	1	yes
Q9NQW7-2	2
Q9NQW7-3	3
Q9NQW7-4	4

RefSeq proteins (9): NP_001161076, NP_001311057, NP_001311060, NP_001311061, NP_001311062, NP_001311063, NP_001311064, NP_001311065, NP_065116* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000587	Creatinase_N	Domain
IPR000994	Pept_M24	Domain
IPR001131	Peptidase_M24B_aminopep-P_CS	Conserved_site
IPR029149	Creatin/AminoP/Spt16_N	Homologous_superfamily
IPR032416	Peptidase_M24_C	Domain
IPR033740	Pept_M24B	Domain
IPR036005	Creatinase/aminopeptidase-like	Homologous_superfamily
IPR050422	X-Pro_aminopeptidase_P	Family

Pfam: PF00557, PF01321, PF16188, PF16189

Enzyme classification (BRENDA):

• EC 3.1.8.1 — aryldialkylphosphatase (BRENDA: 49 organisms, 600 substrates, 192 inhibitors, 422 Km, 434 kcat entries)
• EC 3.4.11.9 — Xaa-Pro aminopeptidase (BRENDA: 34 organisms, 218 substrates, 171 inhibitors, 117 Km, 90 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
PARAOXON	0.005–24.25	109
BRADYKININ	0.021–6.7	30
MALATHION	0.001–1.9	27
S-(2-[DI(PROPAN-2-YL)AMINO]ETHYL) O,O-DIETHYL PH	0.22–20	25
DIETHYL-PARAOXON	0.0017–1.586	23
S-(2-[DI(PROPAN-2-YL)AMINO]ETHYL) O,O-DIMETHYL P	0.3–7	20
4-ACETYLPHENYL (S)-2-METHYLPROPYL METHYLPHOSPHON	0.03–4.5	15
4-ACETYLPHENYL (R)-2-METHYLPROPYL METHYLPHOSPHON	0.15–4	14
(S)-[2-[DI(PROPAN-2-YL)AMINO]ETHYL] O,O-DIETHYL	0.35–3.2	13
METHYL PARAOXON	0.05–2.79	12
CHLORPYRIFOS	0.032–0.51	8
DIMETHYL-PARAOXON	0.5–1.3	8
DEMETON-S	0.236–7.6	7
METHYL PARATHION	0.052–0.87	7
PARATHION	0.015–1.7	7

UniProt features (87 total): helix 32, strand 26, binding site 12, sequence conflict 6, turn 4, splice variant 2, mutagenesis site 2, initiator methionine 1, chain 1, modified residue 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3CTZ	X-RAY DIFFRACTION	1.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NQW7-F1	96.99	0.94

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 (12): 523; 523; 537; 537; 77; 395; 415; 426; 426; 489; 489; 498

Post-translational modifications (1): 304

Mutagenesis-validated functional residues (2):

Position	Phenotype
41	reduces activity by 10%.
477	interferes with dimerization and reduces activity by 94%.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 201 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, MODULE_172, RNGTGGGC_UNKNOWN, GOMF_METALLOPEPTIDASE_ACTIVITY, MODULE_151, AP4_Q6, CAGCTG_AP4_Q5, PUJANA_CHEK2_PCC_NETWORK, GOBP_AMIDE_METABOLIC_PROCESS, GROSS_HYPOXIA_VIA_ELK3_AND_HIF1A_UP, HIF1_Q3, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_UP, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, MULLIGHAN_NPM1_SIGNATURE_3_DN, MODULE_209

GO Biological Process (4): proteolysis (GO:0006508), bradykinin catabolic process (GO:0010815), negative regulation of programmed cell death (GO:0043069), CARD8 inflammasome complex assembly (GO:0140633)

GO Molecular Function (9): aminopeptidase activity (GO:0004177), manganese ion binding (GO:0030145), protein homodimerization activity (GO:0042803), metalloaminopeptidase activity (GO:0070006), protein binding (GO:0005515), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), extracellular exosome (GO:0070062)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
protein metabolic process	1
catabolic process	1
programmed cell death	1
regulation of programmed cell death	1
negative regulation of cellular process	1
canonical inflammasome complex assembly	1
exopeptidase activity	1
transition metal ion binding	1
identical protein binding	1
protein dimerization activity	1
aminopeptidase activity	1
metalloexopeptidase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
cytoplasm	1
extracellular vesicle	1

Protein interactions and networks

STRING

1990 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
XPNPEP1	LAP3	P28838	956
XPNPEP1	XPNPEP3	Q9NQH7	891
XPNPEP1	KNG1	P01042	808
XPNPEP1	ADD3	Q9UEY8	655
XPNPEP1	VCF1	Q969W3	633
XPNPEP1	PEPD	P12955	560
XPNPEP1	CCDC127	Q96BQ5	548
XPNPEP1	AARS1	P49588	541
XPNPEP1	KLK4	Q9Y5K2	534
XPNPEP1	ALMS1	Q8TCU4	502
XPNPEP1	APP	P05067	481
XPNPEP1	RABEPK	Q7Z6M1	481
XPNPEP1	CNOT10	Q9H9A5	481
XPNPEP1	GPC1	P35052	463
XPNPEP1	DNPEP	Q9ULA0	460

IntAct

56 interactions, top by confidence:

A	B	Type	Score
RHOA	ARHGEF11	psi-mi:“MI:0914”(association)	0.900
RHOA	CTSA	psi-mi:“MI:0914”(association)	0.730
CD27	TCAF2	psi-mi:“MI:0914”(association)	0.640
GDE1	GAPDHS	psi-mi:“MI:0914”(association)	0.530
SPIN2B	WDHD1	psi-mi:“MI:0914”(association)	0.530
RAB30	UBB	psi-mi:“MI:0914”(association)	0.530
MPHOSPH6	ZFC3H1	psi-mi:“MI:0914”(association)	0.530
TPD52L1	TPD52L2	psi-mi:“MI:0914”(association)	0.530
VGLL4	YAP1	psi-mi:“MI:0914”(association)	0.530
SBDS	DNM1L	psi-mi:“MI:0914”(association)	0.480
CSRP3	XPNPEP1	psi-mi:“MI:0915”(physical association)	0.400
GSK3B	XPNPEP1	psi-mi:“MI:0915”(physical association)	0.370
NUDT3	XPNPEP1	psi-mi:“MI:0915”(physical association)	0.370
XPNPEP1	UBE2D3	psi-mi:“MI:0915”(physical association)	0.370
PRNP	CARNS1	psi-mi:“MI:0914”(association)	0.350
PRNP	WDR91	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
MYLK	ACOT7	psi-mi:“MI:0914”(association)	0.350
RHOA	TAX1BP3	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
PHF20L1	KANSL1L	psi-mi:“MI:0914”(association)	0.350
CD6	CIBAR1	psi-mi:“MI:0914”(association)	0.350
FGB	KIF2A	psi-mi:“MI:0914”(association)	0.350
STXBP6	SNAP23	psi-mi:“MI:0914”(association)	0.350
SDC1	ARVCF	psi-mi:“MI:0914”(association)	0.350
RPL35A	SMCHD1	psi-mi:“MI:0914”(association)	0.350
VWC2L	CHEK1	psi-mi:“MI:0914”(association)	0.350

BioGRID (123): XPNPEP1 (Affinity Capture-RNA), XPNPEP1 (Affinity Capture-RNA), XPNPEP1 (Affinity Capture-MS), ATP6V1A (Co-fractionation), C12orf10 (Co-fractionation), CSE1L (Co-fractionation), DARS (Co-fractionation), DMGDH (Co-fractionation), IRGQ (Co-fractionation), MARS (Co-fractionation), NAGK (Co-fractionation), NUTF2 (Co-fractionation), PUF60 (Co-fractionation), TARDBP (Co-fractionation), TCEB1 (Co-fractionation)

ESM2 similar proteins: A0A2Z5GDY5, A1CAQ1, A1DF27, A2QGR5, A4RF35, A6R035, A6RK67, A7E4T8, A8P5H7, B0DZL3, B0Y3V7, B2AWV6, B6HQC9, B6QG01, B8M9W2, B8NEI6, C0NDZ7, C0SCV1, C1GEY4, C1H978, C5FHR9, C5GXZ9, C5K105, C5P7J2, C6HSY3, C7Z9Z7, C9SR45, D1ZKF3, D4ARJ9, D4D891, D5GAC6, E3QCU0, E3S7K9, E4USI8, E9CTR7, E9E9B2, E9EUE6, F4JQH3, O44750, Q09795

Diamond homologs: A0A144A2H0, A0A2Z5GDY5, A1CAQ1, A1DF27, A2QGR5, A4RF35, A6R035, A6RK67, A7E4T8, A8P5H7, B0DZL3, B0Y3V7, B2AWV6, B2VUU7, B6HAN0, B6HQC9, B6QG01, B8M9W2, B8NEI6, C0NDZ7, C0SCV1, C1GEY4, C1H978, C5FHR9, C5GXZ9, C5K105, C5P7J2, C6HSY3, C7Z9Z7, C9SR45, D1ZKF3, D4ARJ9, D4D891, D5GAC6, E3QCU0, E3S7K9, E4USI8, E5ABQ8, E9CTR7, E9E9B2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	75
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

4008 predictions. Top by Δscore:

Variant	Effect	Δscore
10:109865311:CA:C	acceptor_gain	1.0000
10:109865313:C:CC	acceptor_gain	1.0000
10:109868708:TTATA:T	acceptor_gain	1.0000
10:109868709:TATA:T	acceptor_gain	1.0000
10:109868711:TA:T	acceptor_gain	1.0000
10:109868713:C:CC	acceptor_gain	1.0000
10:109869947:CCTCA:C	donor_loss	1.0000
10:109869948:CTCAC:C	donor_loss	1.0000
10:109869949:TCA:T	donor_loss	1.0000
10:109869950:CAC:C	donor_loss	1.0000
10:109869952:C:G	donor_loss	1.0000
10:109870027:GCTC:G	acceptor_loss	1.0000
10:109870028:CT:C	acceptor_gain	1.0000
10:109870030:C:CC	acceptor_gain	1.0000
10:109870030:C:T	acceptor_loss	1.0000
10:109870031:T:A	acceptor_loss	1.0000
10:109870724:CACTT:C	donor_loss	1.0000
10:109870725:ACTT:A	donor_loss	1.0000
10:109870726:CTTA:C	donor_loss	1.0000
10:109870727:TTAC:T	donor_loss	1.0000
10:109870728:T:TG	donor_loss	1.0000
10:109870729:A:AC	donor_gain	1.0000
10:109870729:A:AG	donor_loss	1.0000
10:109870730:C:CC	donor_gain	1.0000
10:109870730:C:T	donor_loss	1.0000
10:109870730:CCAT:C	donor_gain	1.0000
10:109870902:GACC:G	acceptor_loss	1.0000
10:109870905:CT:C	acceptor_loss	1.0000
10:109870906:T:C	acceptor_loss	1.0000
10:109877653:ATTT:A	donor_gain	1.0000

AlphaMissense

4393 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000025674 (10:109868326 G>C), RS1000046369 (10:109905093 A>C), RS1000063193 (10:109868021 C>T), RS1000121621 (10:109917762 G>T), RS1000125487 (10:109874270 A>G,T), RS1000134159 (10:109905267 G>A), RS1000217443 (10:109889583 A>G), RS1000256475 (10:109873745 A>C), RS1000307585 (10:109892825 G>C), RS1000310690 (10:109874078 T>C), RS1000391581 (10:109891111 C>A), RS1000427953 (10:109886690 T>C), RS1000453106 (10:109905868 C>T), RS1000481968 (10:109914797 C>A), RS1000505088 (10:109906153 G>A)

Disease associations

OMIM: gene MIM:602443 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000681_1	Biliary atresia	7.000000e-09
GCST003962_6	Bipolar disorder	3.000000e-08
GCST007328_64	Alcohol consumption (drinks per week)	2.000000e-09
GCST008103_19	Bipolar disorder	1.000000e-08
GCST010002_224	Refractive error	2.000000e-14

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3782 (SINGLE PROTEIN), CHEMBL3831223 (PROTEIN FAMILY)

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
apstatin	Inhibition	4.68	pIC50

Binding affinities (BindingDB)

43 measured of 43 human assays (43 total across all organisms); most potent 43 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
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

17 potent at pChembl≥5 of 48 total, top 17 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.81	Kd	155.1	nM	CHEMBL5653589
6.76	ED50	173.2	nM	CHEMBL5653589
5.96	IC50	1100	nM	CHEMBL2369858
5.92	IC50	1200	nM	CHEMBL2369868
5.77	IC50	1700	nM	CHEMBL5397935
5.70	IC50	2000	nM	CHEMBL5402862
5.66	IC50	2200	nM	CHEMBL5438224
5.57	IC50	2700	nM	CHEMBL78505
5.54	IC50	2900	nM	CHEMBL5433668
5.47	IC50	3400	nM	CHEMBL5400780
5.24	IC50	5700	nM	CHEMBL311925
5.20	IC50	6300	nM	CHEMBL79083
5.20	IC50	6300	nM	CHEMBL2369868
5.17	IC50	6800	nM	CHEMBL78505
5.16	IC50	7000	nM	CHEMBL5393876
5.09	IC50	8100	nM	CHEMBL5435178
5.00	IC50	1e+04	nM	CHEMBL5403523

PubChem BioAssay actives

16 with measured affinity, of 133 total; 14 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149785: Binding affinity to human XPNPEP1 incubated for 45 mins by Kinobead based pull down assay	kd	0.1551	uM
(2S)-1-[(2R,3S)-3-amino-2-hydroxy-5-methylhexanoyl]-N-[(2S)-1-amino-1-oxopropan-2-yl]pyrrolidine-2-carboxamide	38388: Inhibition against Aminopeptidase P from human platelets.	ic50	1.1000	uM
(2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-N-[(2S)-1-amino-1-oxopropan-2-yl]pyrrolidine-2-carboxamide	38388: Inhibition against Aminopeptidase P from human platelets.	ic50	1.2000	uM
(2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-N-[(2S)-4-methyl-1-oxo-1-[2-(4-phenylphenyl)ethylamino]pentan-2-yl]pyrrolidine-2-carboxamide	2027390: Inhibition of 6-His tagged XPNPEP1 (unknown origin) expressed in Escherichia coli Rosetta DE3 cells using H-Lys(abz)-Pro-Pro-pNA as substrate incubated for 60 mins by fluorescence based analysis	ic50	1.7000	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	2027390: Inhibition of 6-His tagged XPNPEP1 (unknown origin) expressed in Escherichia coli Rosetta DE3 cells using H-Lys(abz)-Pro-Pro-pNA as substrate incubated for 60 mins by fluorescence based analysis	ic50	2.0000	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	2027390: Inhibition of 6-His tagged XPNPEP1 (unknown origin) expressed in Escherichia coli Rosetta DE3 cells using H-Lys(abz)-Pro-Pro-pNA as substrate incubated for 60 mins by fluorescence based analysis	ic50	2.2000	uM
(2S)-1-[(2S)-1-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl]pyrrolidine-2-carbonyl]-N-[(2S)-1-[[(2S)-1-[[(2R)-1-amino-1-oxo-3-sulfanylpropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]pyrrolidine-2-carboxamide	38389: Inhibition against cytosolic Aminopeptidase P from human heart.	ic50	2.7000	uM
(2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-N-[(2S)-1-(dimethylsulfamoylamino)-4-methyl-1-oxopentan-2-yl]pyrrolidine-2-carboxamide	2027390: Inhibition of 6-His tagged XPNPEP1 (unknown origin) expressed in Escherichia coli Rosetta DE3 cells using H-Lys(abz)-Pro-Pro-pNA as substrate incubated for 60 mins by fluorescence based analysis	ic50	2.9000	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	2027390: Inhibition of 6-His tagged XPNPEP1 (unknown origin) expressed in Escherichia coli Rosetta DE3 cells using H-Lys(abz)-Pro-Pro-pNA as substrate incubated for 60 mins by fluorescence based analysis	ic50	3.4000	uM
2-[(2S)-2-[[(2S)-1-amino-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-4-phenylbutanoic acid	38388: Inhibition against Aminopeptidase P from human platelets.	ic50	5.7000	uM
(2S)-N-[(2S)-1-amino-1-oxopropan-2-yl]-1-(2-sulfanylcyclopentanecarbonyl)pyrrolidine-2-carboxamide	38389: Inhibition against cytosolic Aminopeptidase P from human heart.	ic50	6.3000	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	2027390: Inhibition of 6-His tagged XPNPEP1 (unknown origin) expressed in Escherichia coli Rosetta DE3 cells using H-Lys(abz)-Pro-Pro-pNA as substrate incubated for 60 mins by fluorescence based analysis	ic50	7.0000	uM
methyl (2S)-2-[[(2S)-1-[(2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]propanoate	2027390: Inhibition of 6-His tagged XPNPEP1 (unknown origin) expressed in Escherichia coli Rosetta DE3 cells using H-Lys(abz)-Pro-Pro-pNA as substrate incubated for 60 mins by fluorescence based analysis	ic50	8.1000	uM
(2S)-1-[(2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl]-N-[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]pyrrolidine-2-carboxamide	2027390: Inhibition of 6-His tagged XPNPEP1 (unknown origin) expressed in Escherichia coli Rosetta DE3 cells using H-Lys(abz)-Pro-Pro-pNA as substrate incubated for 60 mins by fluorescence based analysis	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol F	increases expression, affects cotreatment, decreases expression	2
bisphenol A	decreases expression, increases expression	2
Acetaminophen	decreases expression, increases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, affects expression	2
Ozone	affects expression, affects cotreatment, increases oxidation, increases abundance	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Valproic Acid	affects expression, increases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
sodium arsenate	decreases expression	1
salinomycin	decreases expression	1
beta-lapachone	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
isobutyl alcohol	decreases expression, increases abundance, affects cotreatment	1
S 1 (combination)	increases response to substance	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	increases expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
picoxystrobin	decreases expression	1
bisphenol AF	increases expression	1
Arsenic Trioxide	increases expression	1
Acrolein	increases abundance, affects cotreatment, increases oxidation	1

ChEMBL screening assays

10 unique, capped per target: 9 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5381508	Binding	Inhibition of 6-His tagged XPNPEP1 (unknown origin) expressed in Escherichia coli Rosetta DE3 cells using H-Lys(abz)-Pro-Pro-pNA as substrate incubated for 60 mins by fluorescence based analysis	Optimized M24B Aminopeptidase Inhibitors for CARD8 Inflammasome Activation. — J Med Chem
CHEMBL4334276	ADMET	Stability in pH 2 HCl assessed as aminopeptidase (unknown origin)-mediated compound hydrolysis by measuring parent compound remaining at 200 uM up to 6 hrs by RP-HPLC analysis	Astratides: Insulin-Modulating, Insecticidal, and Antifungal Cysteine-Rich Peptides from Astragalus membranaceus. — J Nat Prod

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1RE	Abcam K-562 XPNPEP1 KO	Cancer cell line	Female
CVCL_D2N1	Abcam Raji XPNPEP1 KO	Cancer cell line	Male
CVCL_WQ83	Abcam Jurkat XPNPEP1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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