XPNPEP2

Summary

XPNPEP2 (X-prolyl aminopeptidase 2, HGNC:12823) is a protein-coding gene on chromosome Xq26.1, encoding Xaa-Pro aminopeptidase 2 (O43895). Membrane-bound metalloprotease which catalyzes the removal of a penultimate prolyl residue from the N-termini of peptides, such as Arg-Pro-Pro.

Aminopeptidase P is a hydrolase specific for N-terminal imido bonds, which are common to several collagen degradation products, neuropeptides, vasoactive peptides, and cytokines. Structurally, the enzyme is a member of the ‘pita bread fold’ family and occurs in mammalian tissues in both soluble and GPI-anchored membrane-bound forms. A membrane-bound and soluble form of this enzyme have been identified as products of two separate genes.

Source: NCBI Gene 7512 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 152 total
• Phenotypes (HPO): 13
• Druggable target: yes
• MANE Select transcript: NM_003399

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12823
Approved symbol	XPNPEP2
Name	X-prolyl aminopeptidase 2
Location	Xq26.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000122121
Ensembl biotype	protein_coding
OMIM	300145
Entrez	7512

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 2 retained_intron

ENST00000371105, ENST00000371106, ENST00000681234, ENST00000880528, ENST00000880529, ENST00000880530, ENST00000880531, ENST00000880532

RefSeq mRNA: 1 — MANE Select: NM_003399 NM_003399

CCDS: CCDS14613

Canonical transcript exons

ENST00000371106 — 21 exons

Exon	Start	End
ENSE00000828153	129767603	129767692
ENSE00000828154	129762694	129762770
ENSE00000828155	129762006	129762065
ENSE00000828156	129761172	129761276
ENSE00000828157	129760512	129760581
ENSE00000828158	129759180	129759240
ENSE00000828159	129756484	129756555
ENSE00000828160	129755294	129755371
ENSE00000828161	129754472	129754581
ENSE00000828162	129753159	129753248
ENSE00000828163	129752150	129752345
ENSE00000828164	129751745	129751826
ENSE00000828165	129750468	129750569
ENSE00000828166	129747607	129747753
ENSE00000828167	129746595	129746681
ENSE00000828168	129746236	129746340
ENSE00000828169	129745203	129745266
ENSE00000828170	129743961	129744071
ENSE00000828171	129742108	129742181
ENSE00001454364	129768291	129769536
ENSE00001912589	129738979	129739262

Expression profiles

Bgee: expression breadth ubiquitous, 146 present calls, max score 98.61.

FANTOM5 (CAGE): breadth broad, TPM avg 2.4560 / max 682.8553, expressed in 325 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
197528	1.8947	271
197532	0.2569	135
197530	0.1453	63
197531	0.0850	50
197529	0.0442	21
197534	0.0298	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	98.61	gold quality
jejunal mucosa	UBERON:0000399	97.59	gold quality
nephron tubule	UBERON:0001231	95.26	gold quality
kidney epithelium	UBERON:0004819	94.04	gold quality
renal glomerulus	UBERON:0000074	92.24	gold quality
adult mammalian kidney	UBERON:0000082	92.23	gold quality
duodenum	UBERON:0002114	92.22	gold quality
metanephric glomerulus	UBERON:0004736	91.98	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.57	gold quality
small intestine	UBERON:0002108	89.44	gold quality
kidney	UBERON:0002113	87.75	gold quality
adult organism	UBERON:0007023	86.94	gold quality
endometrium epithelium	UBERON:0004811	81.99	gold quality
cortex of kidney	UBERON:0001225	81.71	gold quality
metanephros	UBERON:0000081	79.55	gold quality
frontal pole	UBERON:0002795	78.66	gold quality
mucosa of stomach	UBERON:0001199	78.56	gold quality
paraflocculus	UBERON:0005351	78.49	gold quality
middle frontal gyrus	UBERON:0002702	77.81	gold quality
right coronary artery	UBERON:0001625	76.23	gold quality
left coronary artery	UBERON:0001626	75.97	gold quality
right lobe of liver	UBERON:0001114	75.77	gold quality
rectum	UBERON:0001052	75.05	gold quality
coronary artery	UBERON:0001621	74.86	gold quality
jejunum	UBERON:0002115	74.51	gold quality
intestine	UBERON:0000160	74.49	gold quality
subcutaneous adipose tissue	UBERON:0002190	74.12	gold quality
right atrium auricular region	UBERON:0006631	73.22	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	72.74	gold quality
liver	UBERON:0002107	72.58	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	65.32
E-ANND-3	yes	10.76

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

57 targeting XPNPEP2, 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-4283	100.00	66.42	2097
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-4688	99.48	64.68	828
HSA-MIR-6743-5P	99.48	63.60	721
HSA-MIR-4687-3P	99.48	66.41	968
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-3978	99.24	68.39	2201

Literature-anchored findings (GeneRIF, showing 10)

• We found significantly decreased plasma aminopeptidase P activity (P=0.013) in hypersensitivity reactions (HSR+) subjects as well as altered degradation of endogenous des-Arginine(9)-bradykinin. (PMID:17003818)
• Increase in aminopeptidase P levels brought on by androgens could contribute to a more effective control of the kinin accumulation considered to be responsible for the symptoms of angioedema. (PMID:18158172)
• Structural comparisons suggest mechanisms for substrate selectivity in different X-prolyl peptidases. (PMID:18515364)
• females have polymorphisms associated with lower levels of APP & ACE; study suggests multiple genes may contribute to this disease (PMID:19178938)
• XPNPEP2 C-2399A polymorphism associates with angiotensin-converting enzyme inhibitor-associated angioedema in men but not women. (PMID:20625347)
• the genetic regulation of the XPNPEP2 gene and identify the genetic factors contributing to variance in plasma aminopeptidase P activity and ACEi-angioedema (XPNPEP2) (PMID:21898657)
• A C-2399A SNP assay was applied to patients with acute hypotensive transfusion reactions. In a pilot study, 2 patients (50%) were found to possess C-2399A polymorphisms. One was found to be homozygous, and the other was heterozygous. (PMID:23276181)
• The XPNPEP2 c-2399A and the ACE insertion/deletion polymorphisms analyzed in a population of patients with hereditary angioedema with F12 mutation were not a major determinant of disease expression. (PMID:27788882)
• we demonstrated that XPNPEP2 had significant effects on the metastasis of xenografted tumors in vivo. Collectively, our findings identify the novel function of XPNPEP2 in the metastasis of cervical cancer and suggest that XPNPEP2 could be a novel potential therapeutic target for the treatment of cervical cancer (PMID:28670957)
• XPNPEP2 is associated with lymph node metastasis in prostate cancer patients. (PMID:31296901)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	xpnpep2	ENSDARG00000026017
mus_musculus	Xpnpep2	ENSMUSG00000037005
rattus_norvegicus	Xpnpep2	ENSRNOG00000004009
drosophila_melanogaster	und	FBGN0283478
caenorhabditis_elegans	app-1	WBGENE00000155
caenorhabditis_elegans		WBGENE00003130
caenorhabditis_elegans		WBGENE00021555

Paralogs (7): XPNPEP1 (ENSG00000108039), METAP2 (ENSG00000111142), PEPD (ENSG00000124299), METAP1 (ENSG00000164024), PA2G4 (ENSG00000170515), METAP1D (ENSG00000172878), XPNPEP3 (ENSG00000196236)

Protein

Protein identifiers

Xaa-Pro aminopeptidase 2 — O43895 (reviewed: O43895)

Alternative names: Aminoacylproline aminopeptidase, Membrane-bound aminopeptidase P, X-Pro aminopeptidase 2

All UniProt accessions (1): O43895

UniProt curated annotations — full annotation on UniProt →

Function. Membrane-bound metalloprotease which catalyzes the removal of a penultimate prolyl residue from the N-termini of peptides, such as Arg-Pro-Pro. May play a role in the metabolism of the vasodilator bradykinin.

Subunit / interactions. Homotrimer.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in kidney, lung, heart, placenta, liver, small intestine and colon. No expression in brain, skeletal muscle, pancreas, spleen, thymus, prostate, testis and ovary.

Post-translational modifications. N-glycosylated.

Disease relevance. Angioedema induced by ACE inhibitors (AEACEI) [MIM:300909] A potentially life-threatening side effect of ACE inhibitors that appears in a subset of patients taking these drugs for hypertension and cardiovascular disease treatment. AEACEI is characterized by swelling of the face, lips, tongue, and airway that can lead to suffocation and death if severe. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Activity regulation. Inhibited by apstatin and the chelating agent 1,10-phenanthroline. Also inhibited by high concentrations of Zn(2+). Not significantly inhibited by bestatin or phosphoramidon.

Similarity. Belongs to the peptidase M24B family.

RefSeq proteins (1): NP_003390* (*=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 3.4.11.9 — Xaa-Pro aminopeptidase (BRENDA: 34 organisms, 218 substrates, 171 inhibitors, 117 Km, 90 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
BRADYKININ	0.021–6.7	30
ARG-PRO-PRO	0.16–1.4	7
MET-PRO-ALA	1.9–9	7
L-ALA-L-PRO-4-NITROANILIDE	0.51–16.9	5
ARG-PRO-ALA	2.1–8.4	4
GLY-PRO-HYP	0.32–40.4	4
MET-ALA-ALA	0.15–0.46	3
MET-PRO	6.3–11.9	3
2-AMINOBENZOYL-L-LYS-L-PRO-L-PRO-4-NITROANILIDE	0.087–0.14	2
ABZ-L-LYS-L-PRO-L-PRO-4-NITROANILIDE	0.087–0.14	2
ARG-PRO-PRO-GLY-PHE	0.048–0.34	2
ARG-PRO-PRO-GLY-PHE-SER	0.032–0.15	2
ARG-PRO-PRO-GLY-PHE-SER-PRO	0.051–0.25	2
ARG-PRO-PRO-GLY-PHE-SER-PRO-PHE	0.039–0.15	2
FPHFD	0.51–0.86	2

UniProt features (26 total): binding site 12, glycosylation site 5, sequence variant 3, sequence conflict 2, signal peptide 1, chain 1, lipid moiety-binding region 1, propeptide 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43895-F1	91.91	0.86

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): 533; 555; 555; 569; 569; 116; 430; 450; 461; 461; 524; 524

Post-translational modifications (1): 649

Glycosylation sites (5): 35, 49, 65, 278, 291

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-163125	Post-translational modification: synthesis of GPI-anchored proteins

MSigDB gene sets: 110 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, GOMF_METALLOPEPTIDASE_ACTIVITY, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, CROONQUIST_NRAS_SIGNALING_UP, MODULE_88, FLECHNER_BIOPSY_KIDNEY_TRANSPLANT_REJECTED_VS_OK_DN, SABATES_COLORECTAL_ADENOMA_DN, MORF_WNT1, MODULE_95, SHEN_SMARCA2_TARGETS_DN, TGGAAA_NFAT_Q4_01, AGCYRWTTC_UNKNOWN, GOCC_SIDE_OF_MEMBRANE, MODULE_55, GOBP_PROTEOLYSIS

GO Biological Process (1): proteolysis (GO:0006508)

GO Molecular Function (6): aminopeptidase activity (GO:0004177), metal ion binding (GO:0046872), metalloaminopeptidase activity (GO:0070006), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787)

GO Cellular Component (5): extracellular region (GO:0005576), plasma membrane (GO:0005886), membrane (GO:0016020), extracellular exosome (GO:0070062), side of membrane (GO:0098552)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
membrane	2
protein metabolic process	1
exopeptidase activity	1
cation binding	1
aminopeptidase activity	1
metalloexopeptidase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
cell periphery	1
extracellular vesicle	1
leaflet of membrane bilayer	1

Protein interactions and networks

STRING

2102 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
XPNPEP2	XPNPEP3	Q9NQH7	916
XPNPEP2	LAP3	P28838	890
XPNPEP2	APP	P05067	815
XPNPEP2	KNG1	P01042	791
XPNPEP2	APBA3	O96018	766
XPNPEP2	APBA1	Q02410	649
XPNPEP2	APBA2	Q99767	649
XPNPEP2	ACE	P12821	615
XPNPEP2	PEPD	P12955	561
XPNPEP2	APBB1	O00213	560
XPNPEP2	APBB2	Q92870	560
XPNPEP2	KLK4	Q9Y5K2	530
XPNPEP2	ACE2	Q9BYF1	508
XPNPEP2	CASK	O14936	500
XPNPEP2	KIF17	Q9P2E2	497

IntAct

2 interactions, top by confidence:

A	B	Type	Score
XPNPEP2	H1-5	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (3): XPNPEP2 (Co-fractionation), HIST1H1B (Proximity Label-MS), XPNPEP2 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A2Z5GDY5, A1CAQ1, A1DF27, A6RK67, A8P5H7, B0DZL3, B1AVD1, B2AWV6, B6QG01, B8M9W2, C5P7J2, C6HSY3, E3QCU0, E9E9B2, E9EUE6, F4HZG9, F4JQH3, O43451, O43895, O44750, O54975, P12955, P14740, P15287, P22411, P27487, P28843, P58780, P58781, Q07825, Q09795, Q0CDB3, Q10439, Q11136, Q1JPJ2, Q2H8T2, Q2M2H8, Q2VQV9, Q55E60, Q5AVF0

Diamond homologs: A0A144A2H0, A0A2Z5GDY5, A1CAQ1, A1DF27, A2QGR5, A4RF35, A6R035, A6RK67, A7E4T8, A8P5H7, B0DZL3, B0Y3V7, B1AVD1, B2AWV6, B2VUU7, 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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	79
Likely benign	14
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

3083 predictions. Top by Δscore:

Variant	Effect	Δscore
X:129739140:G:GT	donor_gain	1.0000
X:129744069:ATGGT:A	donor_loss	1.0000
X:129744070:TGGTA:T	donor_loss	1.0000
X:129744071:GGTAA:G	donor_loss	1.0000
X:129744072:G:GC	donor_loss	1.0000
X:129744073:T:A	donor_loss	1.0000
X:129746233:CAG:C	acceptor_loss	1.0000
X:129746234:A:C	acceptor_loss	1.0000
X:129746298:GC:G	donor_gain	1.0000
X:129746336:GGAAG:G	donor_gain	1.0000
X:129746337:GAAGG:G	donor_gain	1.0000
X:129746338:A:T	donor_gain	1.0000
X:129750565:GGCCT:G	donor_gain	1.0000
X:129750566:GCCT:G	donor_gain	1.0000
X:129750566:GCCTG:G	donor_gain	1.0000
X:129750570:G:GG	donor_gain	1.0000
X:129751743:AG:A	acceptor_gain	1.0000
X:129751744:GG:G	acceptor_gain	1.0000
X:129753244:GCCAC:G	donor_gain	1.0000
X:129753246:CACG:C	donor_loss	1.0000
X:129753247:ACG:A	donor_loss	1.0000
X:129753248:CG:C	donor_loss	1.0000
X:129753249:G:GG	donor_gain	1.0000
X:129753250:TAAG:T	donor_loss	1.0000
X:129754467:TCCAG:T	acceptor_loss	1.0000
X:129754468:CCAGG:C	acceptor_loss	1.0000
X:129754469:CAGGT:C	acceptor_loss	1.0000
X:129754471:G:GA	acceptor_loss	1.0000
X:129754580:GG:G	donor_gain	1.0000
X:129754581:GG:G	donor_gain	1.0000

AlphaMissense

4401 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:129755322:T:C	F416L	0.992
X:129755324:T:A	F416L	0.992
X:129755324:T:G	F416L	0.992
X:129755319:A:C	S415R	0.991
X:129755321:T:A	S415R	0.991
X:129755321:T:G	S415R	0.991
X:129755338:C:A	A421D	0.991
X:129760531:T:C	L483P	0.991
X:129759204:A:C	R464S	0.990
X:129759204:A:T	R464S	0.990
X:129755337:G:C	A421P	0.989
X:129756531:T:C	L448P	0.989
X:129756538:C:A	D450E	0.989
X:129756538:C:G	D450E	0.989
X:129762695:A:C	E555D	0.989
X:129762695:A:T	E555D	0.989
X:129761196:G:C	R508P	0.988
X:129762724:G:A	G565E	0.988
X:129754481:G:C	A373P	0.987
X:129751757:T:C	L251P	0.986
X:129759203:G:C	R464T	0.986
X:129762060:C:T	S553F	0.986
X:129762720:T:C	F564L	0.986
X:129762722:T:A	F564L	0.986
X:129762722:T:G	F564L	0.986
X:129762723:G:T	G565W	0.986
X:129756537:A:T	D450V	0.985
X:129762700:G:A	G557D	0.985
X:129751760:G:C	R252P	0.984
X:129756537:A:C	D450A	0.984

dbSNP variants (sampled 300 via entrez): RS1000287494 (X:129763171 G>A), RS1000382321 (X:129743862 TG>T), RS1000459444 (X:129753446 C>T), RS1000492216 (X:129753887 C>T), RS1000665987 (X:129764333 C>A), RS1000744887 (X:129740232 G>A,T), RS1000794328 (X:129739868 G>A,T), RS1001154670 (X:129755023 A>G), RS1001251817 (X:129751104 A>C,T), RS1001394441 (X:129747097 T>A), RS1001519730 (X:129742911 A>G), RS1001629394 (X:129750887 A>G), RS1001662030 (X:129742640 G>A), RS1001827008 (X:129758059 T>C), RS1001896187 (X:129749882 C>T)

Disease associations

OMIM: gene MIM:300145 | disease phenotypes: MIM:300909

GenCC curated gene-disease

Mondo (2): susceptibility to angioedema induced by ACE inhibitors (MONDO:0100003), primary ovarian failure (MONDO:0005387)

Orphanet (3): Renin-angiotensin-aldosterone system-blocker-induced angioedema (Orphanet:100057), Acquired angioedema (Orphanet:91385), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

13 total (13 of 13 shown, HPO-id order):

HPO	Term
HP:0000282	Facial edema
HP:0000989	Pruritus
HP:0001025	Urticaria
HP:0002098	Respiratory distress
HP:0002781	Upper airway obstruction
HP:0010783	Erythema
HP:0011855	Pharyngeal edema
HP:0012027	Laryngeal edema
HP:0025018	Abnormal capillary physiology
HP:0031244	Swollen lip
HP:0040315	Tongue edema
HP:0100540	Palpebral edema
HP:0100665	Angioedema

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST009731_38	Blood protein levels in cardiovascular risk	2.000000e-68
GCST90002393_532	Monocyte count	3.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0010625	xaa‐pro aminopeptidase 2 measurement
EFO:0005091	monocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3831223 (PROTEIN FAMILY), CHEMBL4610 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs3788853	Toxicity	3	Ace Inhibitors;Plain	Angioedema

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2050011	XPNPEP2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — M24: Methionyl aminopeptidase

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
compound 6 [PMID: 10395480]	Inhibition	6.64	pIC50
apstatin	Inhibition	5.54	pIC50

Binding affinities (BindingDB)

4 measured of 4 human assays (4 total across all organisms); most potent 4 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2S)-2-[methyl-[(2S)-1-[(2S)-1-[(2S)-4-methyl-2-sulfanylpentanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]propanoic acid	IC50	640 nM	US-9212206: 4-Fluoro-Thio-containing inhibitors of APP2, compositions thereof and method of use
(2R)-1-[(2S)-1-[(2S)-1-[(2S)-4-methyl-2-sulfanylpentanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carboxylic acid	IC50	12000 nM	US-9212206: 4-Fluoro-Thio-containing inhibitors of APP2, compositions thereof and method of use
(3S)-1-[(2S)-1-[(2S)-1-[(2S)-4-methyl-2-sulfanylpentanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]pyrrolidine-3-carboxylic acid	IC50	49000 nM	US-9212206: 4-Fluoro-Thio-containing inhibitors of APP2, compositions thereof and method of use
(3R)-1-[(2S)-1-[(2S,4S)-4-fluoro-1-[(2S)-4-methyl-2-sulfanylpentanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]pyrrolidine-3-carboxylic acid	IC50	68000 nM	US-9212206: 4-Fluoro-Thio-containing inhibitors of APP2, compositions thereof and method of use

ChEMBL bioactivities

14 potent at pChembl≥5 of 26 total, top 14 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.43	IC50	3.7	nM	CHEMBL4110944
8.41	IC50	3.9	nM	CHEMBL3954917
8.01	IC50	9.7	nM	CHEMBL3932740
7.58	IC50	26	nM	CHEMBL3960222
6.89	IC50	130	nM	CHEMBL2369868
6.64	IC50	230	nM	CHEMBL2369858
6.64	IC50	230	nM	CHEMBL2369868
6.37	IC50	430	nM	CHEMBL2369858
5.58	IC50	2600	nM	CHEMBL311925
5.55	IC50	2800	nM	CHEMBL78505
5.54	IC50	2900	nM	CHEMBL311875
5.47	IC50	3400	nM	CHEMBL78505
5.21	IC50	6100	nM	CHEMBL311875
5.08	IC50	8400	nM	CHEMBL311925

PubChem BioAssay actives

10 with measured affinity, of 40 total; 5 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]-N-[(2S)-1-amino-1-oxopropan-2-yl]pyrrolidine-2-carboxamide	38385: Inhibition against membrane bound monkey aminopeptidase P	ic50	0.1300	uM
(2S)-1-[(2R,3S)-3-amino-2-hydroxy-5-methylhexanoyl]-N-[(2S)-1-amino-1-oxopropan-2-yl]pyrrolidine-2-carboxamide	38385: Inhibition against membrane bound monkey aminopeptidase P	ic50	0.2300	uM
2-[(2S)-2-[[(2S)-1-amino-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-4-phenylbutanoic acid	38390: Inhibition against membrane bound human aminopeptidase P	ic50	2.6000	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	38390: Inhibition against membrane bound human aminopeptidase P	ic50	2.8000	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	38390: Inhibition against membrane bound human aminopeptidase P	ic50	2.9000	uM

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	decreases expression, increases methylation	2
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
benzo(e)pyrene	affects methylation	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
bisphenol S	increases methylation	1
Acetaminophen	decreases expression	1
Amiodarone	increases expression	1
Amphotericin B	increases expression	1
Angiotensin-Converting Enzyme Inhibitors	affects response to substance	1
Ascorbic Acid	affects cotreatment, decreases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Latex	decreases expression	1
Methapyrilene	affects methylation	1
Progesterone	increases expression	1
Quercetin	affects cotreatment, decreases expression	1
Valproic Acid	decreases expression	1
Cyclosporine	decreases expression	1
Antirheumatic Agents	increases expression	1
Palmitic Acid	decreases expression	1
Okadaic Acid	decreases expression	1

ChEMBL screening assays

7 unique, capped per target: 4 binding, 3 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
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
CHEMBL1821051	Binding	Inhibition of aminopeptidase P	2-({6-[(3R)-3-amino-3-methylpiperidine-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidine-5-yl}methyl)-4-fluorobenzonitrile (DSR-12727): a potent, orally active dipeptidyl peptidase IV inhibitor without mechanism-based inactivation of CYP3A. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	PHASE1/PHASE2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	PHASE1/PHASE2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	PHASE1/PHASE2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	PHASE1/PHASE2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	PHASE1/PHASE2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF
NCT03069209	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Premature Ovarian Failure (POF)
NCT03985462	PHASE1/PHASE2	WITHDRAWN	Very Small Embryonic-like Stem Cells for Ovary
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT04071574	PHASE1/PHASE2	COMPLETED	Comparative Study on the Efficacy of Ovarian Stimulation Protocols on the Success Rate of ICSI in Female Infertility
NCT04922398	PHASE1/PHASE2	UNKNOWN	Ovarian Injection of PRP (Platelet -Rich Plasma) Vs Normal Saline in Premature Ovarian Insufficiency
NCT05462379	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Autologous Heterotopic Fresh Ovarian Graft in Woman With LACC Eligible for Pelvic Radiotherapy Treatment.
NCT06202547	PHASE1/PHASE2	UNKNOWN	Intra-ovarian Injection of MSC-EVs in Idiopathic Premature Ovarian Failure
NCT01129947	EARLY_PHASE1	WITHDRAWN	The Use of DHEA in Women With Premature Ovarian Failure
NCT05522634	EARLY_PHASE1	UNKNOWN	A Clinical Study of Chinese Herbal Compound TJAOA101 in the Treatment of Premature Ovarian Insufficiency
NCT07308327	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	The Influence of Gut Microbiota on Ovarian Function: A Single-center, Randomized,Double Blind, Parallel-controlled, Exploratory Clinical Trial
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00001306	Not specified	COMPLETED	Steroid Therapy in Autoimmune Premature Ovarian Failure
NCT00006156	Not specified	COMPLETED	Feasibility Study for Development of an Early Test for Ovarian Failure
NCT00119925	Not specified	UNKNOWN	‘SPRING’-Study: Subfertility Guidelines: Patient Related Implementation in the Netherlands Among Gynaecologists