NPEPPS

Summary

NPEPPS (aminopeptidase puromycin sensitive, HGNC:7900) is a protein-coding gene on chromosome 17q21.32, encoding Puromycin-sensitive aminopeptidase (P55786). Aminopeptidase with broad substrate specificity for several peptides. It is a selective cancer dependency (DepMap: 53.4% of cell lines).

This gene encodes the puromycin-sensitive aminopeptidase, a zinc metallopeptidase which hydrolyzes amino acids from the N-terminus of its substrate. The protein has been localized to both the cytoplasm and to cellular membranes. This enzyme degrades enkaphalins in the brain, and studies in mouse suggest that it is involved in proteolytic events regulating the cell cycle.

Source: NCBI Gene 9520 — RefSeq curated summary.

At a glance

• GWAS associations: 29
• Clinical variants (ClinVar): 109 total
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 53.4% of screened cell lines
• MANE Select transcript: NM_006310

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7900
Approved symbol	NPEPPS
Name	aminopeptidase puromycin sensitive
Location	17q21.32
Locus type	gene with protein product
Status	Approved
Aliases	PSA, MP100
Ensembl gene	ENSG00000141279
Ensembl biotype	protein_coding
OMIM	606793
Entrez	9520

Gene structure

Transcript identifiers

Ensembl transcripts: 43 — 15 retained_intron, 13 nonsense_mediated_decay, 9 protein_coding, 6 protein_coding_CDS_not_defined

ENST00000322157, ENST00000525007, ENST00000525021, ENST00000525037, ENST00000525048, ENST00000525401, ENST00000526247, ENST00000527298, ENST00000527360, ENST00000527824, ENST00000527964, ENST00000528565, ENST00000528751, ENST00000529602, ENST00000530173, ENST00000530514, ENST00000531486, ENST00000532729, ENST00000533538, ENST00000533573, ENST00000534691, ENST00000534807, ENST00000534814, ENST00000602788, ENST00000676492, ENST00000677120, ENST00000677226, ENST00000677370, ENST00000677664, ENST00000677710, ENST00000678262, ENST00000678461, ENST00000678496, ENST00000678902, ENST00000678909, ENST00000700479, ENST00000700480, ENST00000700481, ENST00000700497, ENST00000700498, ENST00000700499, ENST00000922449, ENST00000972331

RefSeq mRNA: 3 — MANE Select: NM_006310 NM_001330257, NM_001411130, NM_006310

CCDS: CCDS45721, CCDS82149, CCDS92355

Canonical transcript exons

ENST00000322157 — 23 exons

Exon	Start	End
ENSE00001138605	47531108	47531555
ENSE00001298576	47621768	47623276
ENSE00003458758	47618350	47618457
ENSE00003468403	47569417	47569494
ENSE00003481577	47605333	47605552
ENSE00003484900	47603915	47604049
ENSE00003504982	47579390	47579511
ENSE00003515312	47586365	47586398
ENSE00003553730	47582742	47582849
ENSE00003579412	47590717	47590881
ENSE00003593059	47587230	47587344
ENSE00003595849	47619009	47619164
ENSE00003596880	47585500	47585700
ENSE00003621987	47545909	47545993
ENSE00003637064	47599676	47599739
ENSE00003642178	47613669	47613725
ENSE00003666015	47586148	47586244
ENSE00003667245	47619737	47619784
ENSE00003670530	47612460	47612602
ENSE00003673693	47591956	47592060
ENSE00003674401	47596353	47596462
ENSE00003674880	47601608	47601747
ENSE00003785912	47592485	47592545

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 98.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.7603 / max 358.8404, expressed in 1812 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161351	8.1519	1767
161349	5.5876	1609
161350	4.3942	1625
161353	2.2254	1295
161352	1.3897	940
208227	0.0116	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
esophagus squamous epithelium	UBERON:0006920	98.65	gold quality
cortical plate	UBERON:0005343	98.49	gold quality
lower esophagus mucosa	UBERON:0035834	98.42	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.34	gold quality
cerebellar hemisphere	UBERON:0002245	98.30	gold quality
esophagus mucosa	UBERON:0002469	98.28	gold quality
cerebellar cortex	UBERON:0002129	98.22	gold quality
vagina	UBERON:0000996	98.09	gold quality
epithelium of esophagus	UBERON:0001976	97.97	gold quality
cerebellum	UBERON:0002037	97.81	gold quality
colonic epithelium	UBERON:0000397	97.74	gold quality
ganglionic eminence	UBERON:0004023	97.65	gold quality
skin of leg	UBERON:0001511	97.60	gold quality
mucosa of stomach	UBERON:0001199	97.55	gold quality
esophagus	UBERON:0001043	97.54	gold quality
skin of abdomen	UBERON:0001416	97.39	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.39	gold quality
left ovary	UBERON:0002119	97.35	gold quality
right ovary	UBERON:0002118	97.34	gold quality
ectocervix	UBERON:0012249	97.34	gold quality
ventricular zone	UBERON:0003053	97.19	gold quality
right uterine tube	UBERON:0001302	97.10	gold quality
ovary	UBERON:0000992	97.03	gold quality
right adrenal gland cortex	UBERON:0035827	97.02	gold quality
gastrocnemius	UBERON:0001388	96.97	gold quality
minor salivary gland	UBERON:0001830	96.92	gold quality
body of uterus	UBERON:0009853	96.90	gold quality
right adrenal gland	UBERON:0001233	96.88	gold quality
left adrenal gland	UBERON:0001234	96.86	gold quality
left adrenal gland cortex	UBERON:0035825	96.82	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	4.69
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR

miRNA regulators (miRDB)

109 targeting NPEPPS, 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-4262	100.00	73.26	3931
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-8080	99.82	67.52	1342

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 53.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 10)

• ApPS Y394F exhibited a 3.3-fold lower affinity for RB-3014, a transition state inhibitor, indicating that Tyr394 is involved in transition state stabilization (PMID:14706550)
• PSA gene was downregulated in PC-3 cells that were treated with CoCl(2). PSA is involved in the proliferation, migration, and invasion of PC-3 cells, which are important determinants of metastasis, via a mechanism that involves MMP-9 modulation. (PMID:19494703)
• attenuated proteolysis of FTDP-17 mutant tau may be explained by increased phosphorylation levels, resulting in resistance to proteolysis. (PMID:20377816)
• findings show that by promoting autophagic protein clearance, PSA helps protect against accumulation of aggregation-prone proteins and proteotoxicity (PMID:20829225)
• Elevation of NPEPPS activity blocks accumulation of hyperphosphorylated TAU protein and slows down the progression of Alzheimer’s disease. (PMID:21320871)
• Studies indicate the critical role of M1 aminopeptidases ERAP1, ERAP2 and NPEPPS in immune-mediated diseases. (PMID:25142031)
• MiR-614 inhibited cell invasion and proliferationa targeting PSA in lung cancer cells, PGCL3 (PMID:25342037)
• cytosolic peptidases(puromycin-sensitive aminopeptidase (PSA), aminopeptidase B (APB) and pyroglutamyl-peptidase I (PGI) ) may be involved in colorectal carcinogenesis (PMID:26078706)
• Analysis of 47 Non-MHC Ankylosing Spondylitis Susceptibility Loci Regarding Associated Variants across Whites and Han Chinese. (PMID:31523044)
• PSA controls hepatic lipid metabolism by regulating the NRF2 signaling pathway. (PMID:34048566)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	npepps	ENSDARG00000044943
mus_musculus	Npepps	ENSMUSG00000001441
rattus_norvegicus	Npepps	ENSRNOG00000023095
drosophila_melanogaster	Psa	FBGN0261243
caenorhabditis_elegans		WBGENE00003914

Paralogs (11): TRHDE (ENSG00000072657), LTA4H (ENSG00000111144), LNPEP (ENSG00000113441), ENPEP (ENSG00000138792), RNPEPL1 (ENSG00000142327), AOPEP (ENSG00000148120), ERAP1 (ENSG00000164307), ERAP2 (ENSG00000164308), ANPEP (ENSG00000166825), LVRN (ENSG00000172901), RNPEP (ENSG00000176393)

Protein

Protein identifiers

Puromycin-sensitive aminopeptidase — P55786 (reviewed: P55786)

Alternative names: Cytosol alanyl aminopeptidase

All UniProt accessions (18): A0A7I2V389, A0A7I2V3D7, A0A7I2V3W8, A0A7I2V5D4, A0A7I2V5M8, A0A7I2V604, A0A7I2YQS3, A0A8V8TQ95, P55786, E9PI82, E9PJF9, E9PJY4, E9PLK3, E9PP11, E9PPD4, E9PPZ2, H0YCQ5, H0YDG0

UniProt curated annotations — full annotation on UniProt →

Function. Aminopeptidase with broad substrate specificity for several peptides. Involved in proteolytic events essential for cell growth and viability. May act as regulator of neuropeptide activity. Plays a role in the antigen-processing pathway for MHC class I molecules. Involved in the N-terminal trimming of cytotoxic T-cell epitope precursors. Digests the poly-Q peptides found in many cellular proteins. Digests tau from normal brain more efficiently than tau from Alzheimer disease brain.

Subunit / interactions. Monomer.

Subcellular location. Cytoplasm. Cytosol. Nucleus.

Tissue specificity. Detected in liver, epithelium of renal tubules, epithelium of small and large intestine, gastric epithelial cells, and alveoli of the lung (at protein level).

Activity regulation. Strongly inhibited by bestatin, leuhistin, actinonin, amastatin, 1,10-phenanthroline, DFP, PCMBS, Zn(2+), Cd(2+), Co(2+), Cu(2+), Hg(2+), EDTA and puromycin. Not inhibited by PMSF, and only slightly inhibited by leupeptin and aprotinin. Activity is increased by Mg(2+) and Ca(2+).

Cofactor. Binds 1 zinc ion per subunit.

Similarity. Belongs to the peptidase M1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P55786-1	1	yes
P55786-2	2

RefSeq proteins (3): NP_001317186, NP_001398059, NP_006301* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001930	Peptidase_M1	Family
IPR014782	Peptidase_M1_dom	Domain
IPR024571	ERAP1-like_C_dom	Domain
IPR027268	Peptidase_M4/M1_CTD_sf	Homologous_superfamily
IPR034016	M1_APN-typ	Family
IPR042097	Aminopeptidase_N-like_N_sf	Homologous_superfamily
IPR045357	Aminopeptidase_N-like_N	Domain
IPR050344	Peptidase_M1_aminopeptidases	Family

Pfam: PF01433, PF11838, PF17900

UniProt features (89 total): helix 38, strand 29, turn 5, binding site 5, mutagenesis site 4, splice variant 2, chain 1, short sequence motif 1, sequence conflict 1, active site 1, site 1, modified residue 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
8SW0	X-RAY DIFFRACTION	2.3
9O5K	ELECTRON MICROSCOPY	3.19
8SW1	X-RAY DIFFRACTION	3.65

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55786-F1	91.53	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.

Catalytic / active sites (2): 353 (proton acceptor); 438 (transition state stabilizer)

Ligand- & substrate-binding residues (5): 180; 316–320; 352; 356; 375

Post-translational modifications (1): 464

Mutagenesis-validated functional residues (4):

Position	Phenotype
353	reduces catalytic activity by 25,000-fold to 100,000-fold.
353	reduces catalytic activity by 5,000-fold to 15,000-fold.
353	reduces catalytic activity by 300,000-fold to 500,000-fold.
438	reduces catalytic activity by 1,000-fold to 2,500-fold.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 174 (showing top): REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOMF_METALLOPEPTIDASE_ACTIVITY, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GCANCTGNY_MYOD_Q6, AREB6_03, GOBP_PROTEIN_TARGETING, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_PEPTIDE_METABOLIC_PROCESS, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_LEVELS, GOBP_RESPONSE_TO_OXYGEN_LEVELS, BLALOCK_ALZHEIMERS_DISEASE_UP, GROSS_HYPOXIA_VIA_HIF1A_DN

GO Biological Process (5): protein polyubiquitination (GO:0000209), proteolysis (GO:0006508), peptide catabolic process (GO:0043171), cellular response to hypoxia (GO:0071456), obsolete positive regulation of protein targeting to mitochondrion (GO:1903955)

GO Molecular Function (8): aminopeptidase activity (GO:0004177), zinc ion binding (GO:0008270), alanyl aminopeptidase activity (GO:0016285), metalloaminopeptidase activity (GO:0070006), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (5): extracellular region (GO:0005576), nucleus (GO:0005634), cytosol (GO:0005829), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
aminopeptidase activity	2
protein ubiquitination	1
protein metabolic process	1
peptide metabolic process	1
catabolic process	1
response to hypoxia	1
cellular response to stress	1
cellular response to decreased oxygen levels	1
exopeptidase activity	1
transition metal ion binding	1
metalloexopeptidase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
cytoplasm	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1985 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NPEPPS	NBPF1	Q3BBV0	829
NPEPPS	HYDIN	Q4G0P3	829
NPEPPS	UGT2B17	O75795	827
NPEPPS	GPRIN2	O60269	826
NPEPPS	SRGAP2	O75044	822
NPEPPS	DRD5	P21918	811
NPEPPS	SRGAP3	O43295	810
NPEPPS	GTF2I	P78347	763
NPEPPS	GGT6	Q6P531	638
NPEPPS	GGT7	Q9UJ14	626
NPEPPS	GGT2P	P36268	598
NPEPPS	BLMH	Q13867	589
NPEPPS	LAP3	P28838	571
NPEPPS	GGT5	P36269	563
NPEPPS	DNPEP	Q9ULA0	557

IntAct

92 interactions, top by confidence:

A	B	Type	Score
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
	XPO1	psi-mi:“MI:0914”(association)	0.530
LRRC8B	SLC25A17	psi-mi:“MI:0914”(association)	0.530
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
	TK2	psi-mi:“MI:0915”(physical association)	0.400
NFKB1	NFKB1	psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
Prkaa1	MYL12B	psi-mi:“MI:0914”(association)	0.350
BCL2L14		psi-mi:“MI:0914”(association)	0.350
P2RY6	ESYT2	psi-mi:“MI:0914”(association)	0.350
CUL3	PXDNL	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
LRRC8E	TBC1D4	psi-mi:“MI:0914”(association)	0.350
OTUD4	KRT36	psi-mi:“MI:0914”(association)	0.350
DMWD	P4HA2	psi-mi:“MI:0914”(association)	0.350

BioGRID (247): NPEPPS (Affinity Capture-MS), NPEPPS (Affinity Capture-MS), NPEPPS (Affinity Capture-MS), EIF6 (Co-fractionation), NPEPPS (Co-fractionation), NPEPPS (Co-fractionation), NPEPPS (Affinity Capture-MS), NPEPPS (Affinity Capture-MS), NPEPPS (Affinity Capture-MS), NPEPPS (Affinity Capture-MS), NPEPPS (Affinity Capture-MS), NPEPPS (Affinity Capture-MS), NPEPPS (Affinity Capture-MS), NPEPPS (Affinity Capture-RNA), NPEPPS (Affinity Capture-MS)

ESM2 similar proteins: A1CSI2, A1DG68, A2QKF8, A3LQI7, A3LRX6, A4QUC1, A5DGF3, A5DME6, A5DSS4, A6RCT2, A6SAG8, A6ZS33, A7EJL9, A7THG7, B7EA73, G5EFT4, O94544, P09960, P19602, P24527, P30349, P32454, P37898, P52922, P55786, Q0CFY9, Q0J5V5, Q0U653, Q10740, Q11011, Q1DVD1, Q2GY21, Q2TZ99, Q3SZH7, Q4TT88, Q4X265, Q59NB8, Q5B0W8, Q6BW21, Q6C3E5

Diamond homologs: A2RI32, A6NEC2, A6QPT7, O93654, O93655, P0C2T8, P37893, P37896, P55786, Q0J2B5, Q0J5V5, Q10730, Q10736, Q11010, Q11011, Q22531, Q2KHK3, Q48656, Q4TT88, Q59KZ1, Q6K4E7, Q6Z6L4, Q7Q2T8, Q8VZH2, Q96ZT9, Q974N6, Q978U3, Q97AJ6, Q9CIQ1, A5HUI5, D3UW23, M3XFH7, O57579, P0DQU2, P15144, P15145, P15541, P15684, P16406, P32454

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
NPEPPS	“down-regulates quantity”	oligopeptide	“chemical modification”
NPEPPS	“up-regulates quantity”	“peptide antigen”	“chemical modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 105 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Transport of vitamins, nucleosides, and related molecules	5	17.2×	5e-03
Defective CFTR causes cystic fibrosis	5	13.9×	7e-03
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	5	12.2×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	63
Likely benign	6
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

4339 predictions. Top by Δscore:

Variant	Effect	Δscore
17:47531552:CCAGG:C	donor_loss	1.0000
17:47531553:CAGG:C	donor_loss	1.0000
17:47531554:AGG:A	donor_loss	1.0000
17:47531556:GTACA:G	donor_loss	1.0000
17:47531557:T:A	donor_loss	1.0000
17:47545905:TTA:T	acceptor_loss	1.0000
17:47545906:TA:T	acceptor_loss	1.0000
17:47545907:A:AG	acceptor_gain	1.0000
17:47545907:AGGT:A	acceptor_gain	1.0000
17:47545908:G:A	acceptor_loss	1.0000
17:47545908:G:GG	acceptor_gain	1.0000
17:47545908:GGT:G	acceptor_gain	1.0000
17:47545908:GGTG:G	acceptor_gain	1.0000
17:47545908:GGTGA:G	acceptor_gain	1.0000
17:47545992:AGGT:A	donor_loss	1.0000
17:47545993:GGT:G	donor_loss	1.0000
17:47545994:G:GG	donor_gain	1.0000
17:47545995:T:G	donor_loss	1.0000
17:47569410:A:AG	acceptor_gain	1.0000
17:47569412:TCCA:T	acceptor_loss	1.0000
17:47569413:CCA:C	acceptor_loss	1.0000
17:47569414:CA:C	acceptor_loss	1.0000
17:47569415:A:AG	acceptor_gain	1.0000
17:47569416:G:GA	acceptor_gain	1.0000
17:47569416:GA:G	acceptor_gain	1.0000
17:47569416:GAA:G	acceptor_gain	1.0000
17:47569416:GAAA:G	acceptor_gain	1.0000
17:47569416:GAAAT:G	acceptor_gain	1.0000
17:47569492:CAGGT:C	donor_loss	1.0000
17:47569493:AGG:A	donor_loss	1.0000

AlphaMissense

6020 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:47579420:G:A	G150E	1.000
17:47579443:G:C	G158R	1.000
17:47579444:G:A	G158D	1.000
17:47579495:C:A	A175D	1.000
17:47579511:G:C	E180D	1.000
17:47579511:G:T	E180D	1.000
17:47582752:C:A	A184D	1.000
17:47582771:C:G	C190W	1.000
17:47582775:G:C	D192H	1.000
17:47582776:A:T	D192V	1.000
17:47582782:C:A	P194H	1.000
17:47582846:C:A	N215K	1.000
17:47582846:C:G	N215K	1.000
17:47585576:C:T	S242F	1.000
17:47585585:T:C	L245P	1.000
17:47586218:T:C	L307P	1.000
17:47586224:C:A	A309D	1.000
17:47586235:T:C	F313L	1.000
17:47586236:T:C	F313S	1.000
17:47586237:T:A	F313L	1.000
17:47586237:T:G	F313L	1.000
17:47586368:C:A	A317D	1.000
17:47586368:C:T	A317V	1.000
17:47586372:G:A	M318I	1.000
17:47586372:G:C	M318I	1.000
17:47586372:G:T	M318I	1.000
17:47586373:G:A	E319K	1.000
17:47586374:A:C	E319A	1.000
17:47586374:A:T	E319V	1.000
17:47586375:G:C	E319D	1.000

dbSNP variants (sampled 300 via entrez): RS1000008167 (17:47607161 C>T), RS1000013668 (17:47599684 T>C), RS1000087408 (17:47616531 A>G), RS1000096907 (17:47556741 T>C), RS1000163592 (17:47543213 A>G), RS1000234299 (17:47600071 G>A,C), RS1000303867 (17:47588252 G>T), RS1000349398 (17:47537426 G>A,T), RS1000378651 (17:47584449 C>G), RS1000441521 (17:47550012 G>A), RS1000526490 (17:47606959 C>G), RS1000552982 (17:47594736 C>G,T), RS1000567072 (17:47601341 ATTAAGT>A), RS1000597998 (17:47604643 C>G,T), RS1000608362 (17:47592711 C>A,G)

Disease associations

OMIM: gene MIM:606793 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

29 associations (top):

Study	Trait	p-value
GCST002274_1	Multiple sclerosis or amyotrophic lateral sclerosis	5.000000e-07
GCST002690_12	Very long-chain saturated fatty acid levels (fatty acid 20:0)	4.000000e-07
GCST004599_126	Mean platelet volume	3.000000e-12
GCST005529_24	Ankylosing spondylitis	2.000000e-12
GCST005529_42	Ankylosing spondylitis	6.000000e-15
GCST005531_16	Multiple sclerosis	1.000000e-13
GCST005537_33	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	2.000000e-14
GCST005951_16	Body mass index	4.000000e-08
GCST006034_3	Total cholesterol levels	3.000000e-09
GCST008163_269	Height	1.000000e-06
GCST008295_47	Number of decayed, missing and filled tooth surfaces or use of dentures	1.000000e-08
GCST008306_11	Dentures	7.000000e-09
GCST008839_330	Height	1.000000e-11
GCST008916_117	Asthma	1.000000e-09
GCST008954_4	High chromosomal aberration frequency (chromosome type)	3.000000e-06
GCST009597_307	Multiple sclerosis	2.000000e-27
GCST010204_18	Low density lipoprotein cholesterol levels	2.000000e-46
GCST010241_337	Apolipoprotein A1 levels	3.000000e-08
GCST010243_179	Apolipoprotein B levels	2.000000e-43
GCST010245_194	LDL cholesterol levels	1.000000e-36
GCST010703_72	Brain morphology (MOSTest)	3.000000e-08
GCST011347_54	Low density lipoprotein cholesterol levels	3.000000e-09
GCST90002395_262	Mean platelet volume	6.000000e-21
GCST90002395_263	Mean platelet volume	8.000000e-34
GCST90002397_575	Mean spheric corpuscular volume	4.000000e-16
GCST90002400_219	Plateletcrit	4.000000e-10
GCST90002401_550	Platelet distribution width	4.000000e-12
GCST90011770_79	Glaucoma (primary open-angle)	3.000000e-07
GCST90020028_1389	Hip circumference adjusted for BMI	1.000000e-08

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0006796	very long-chain saturated fatty acid measurement
EFO:0004340	body mass index
EFO:0004574	total cholesterol measurement
EFO:0010078	dentures
EFO:0009861	chromosome-type aberration frequency
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004615	apolipoprotein B measurement
EFO:0004346	neuroimaging measurement
EFO:0007985	platelet crit
EFO:0007984	platelet component distribution width
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2264 (SINGLE PROTEIN), CHEMBL3831223 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 174,981 (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
CHEMBL2103847	TOSEDOSTAT	2	328
CHEMBL29292	UBENIMEX	2	38,430
CHEMBL469912	PUROMYCIN	2	136,223

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — M1: Aminopeptidase N

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

Ligand	Action	Affinity	Parameter
puromycin	Inhibition	5.61	pIC50
ANTAQ	Inhibition	5.54	pIC50

ChEMBL bioactivities

34 potent at pChembl≥5 of 47 total, top 30 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.30	IC50	5	nM	CHEMBL5590634
8.15	IC50	7	nM	CHEMBL5595970
8.15	IC50	7	nM	CHEMBL3244800
8.13	IC50	7.4	nM	CHEMBL3244800
7.13	IC50	74	nM	CHEMBL5591455
7.06	Kd	86.31	nM	CHEMBL3752910
7.06	ED50	86.31	nM	CHEMBL3752910
7.04	Kd	90.69	nM	CHEMBL5653589
7.04	ED50	90.69	nM	CHEMBL5653589
6.58	IC50	260	nM	TOSEDOSTAT
6.03	IC50	940	nM	CHEMBL3244799
5.85	IC50	1400	nM	CHEMBL4165328
5.75	IC50	1790	nM	CHEMBL516021
5.64	IC50	2300	nM	CHEMBL5591560
5.61	IC50	2450	nM	PUROMYCIN
5.54	IC50	2900	nM	ANTAQ
5.47	IC50	3400	nM	CHEMBL168510
5.46	IC50	3500	nM	UBENIMEX
5.42	IC50	3800	nM	CHEMBL169458
5.41	IC50	3900	nM	CHEMBL5590074
5.34	IC50	4600	nM	DAMPAQ
5.32	IC50	4800	nM	CHEMBL4161892
5.30	IC50	5000	nM	CHEMBL4161496
5.23	IC50	5900	nM	CHEMBL5594450
5.17	IC50	6700	nM	CHEMBL5593353
5.11	IC50	7800	nM	CHEMBL88645
5.09	IC50	8040	nM	CHEMBL3740370
5.08	IC50	8400	nM	CHEMBL5594248
5.07	IC50	8530	nM	CHEMBL3741560
5.01	IC50	9700	nM	PUROMYCIN

PubChem BioAssay actives

32 with measured affinity, of 53 total; 26 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
(2R)-3-(1-adamantylsulfanyl)-2-amino-N-[(2S,3S,4R,5R)-2-(chloromethyl)-5-[6-(dimethylamino)purin-9-yl]-4-hydroxyoxolan-3-yl]propanamide	2116773: Inhibition of human N-terminal His-tagged Puromycin-sensitive aminopeptidase extracted from Escherichia coli BL21 STAR (DE3) using alanine-4-methoxy-2-naphthylamide as substrate incubated for 30 mins by SpectraMax microplate reader analysis	ic50	0.0050	uM
(2R)-2-amino-3-benzhydrylsulfanyl-N-[(2S,3S,4R,5R)-2-(chloromethyl)-5-[6-(dimethylamino)purin-9-yl]-4-hydroxyoxolan-3-yl]propanamide	2116773: Inhibition of human N-terminal His-tagged Puromycin-sensitive aminopeptidase extracted from Escherichia coli BL21 STAR (DE3) using alanine-4-methoxy-2-naphthylamide as substrate incubated for 30 mins by SpectraMax microplate reader analysis	ic50	0.0070	uM
(2R)-2-amino-3-benzhydrylsulfanyl-N-[(2S,3S,4R,5R)-5-[6-(dimethylamino)purin-9-yl]-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]propanamide	2116773: Inhibition of human N-terminal His-tagged Puromycin-sensitive aminopeptidase extracted from Escherichia coli BL21 STAR (DE3) using alanine-4-methoxy-2-naphthylamide as substrate incubated for 30 mins by SpectraMax microplate reader analysis	ic50	0.0070	uM
(2R)-3-(1-adamantylsulfanyl)-2-amino-N-[(2S,3S,4R,5R)-5-[6-(dimethylamino)purin-9-yl]-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]propanamide	2116773: Inhibition of human N-terminal His-tagged Puromycin-sensitive aminopeptidase extracted from Escherichia coli BL21 STAR (DE3) using alanine-4-methoxy-2-naphthylamide as substrate incubated for 30 mins by SpectraMax microplate reader analysis	ic50	0.0740	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148884: Binding affinity to human NPEPPS incubated for 45 mins by Kinobead based pull down assay	kd	0.0863	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148884: Binding affinity to human NPEPPS incubated for 45 mins by Kinobead based pull down assay	kd	0.0907	uM
cyclopentyl (2S)-2-[[(2R)-2-[(1S)-1-hydroxy-2-(hydroxyamino)-2-oxoethyl]-4-methylpentanoyl]amino]-2-phenylacetate	1500910: Inhibition of recombinant human N-terminal His6-MBP-tagged PSA expressed in Escherichia coli BL21 STAR (DE3) using 4-Ala-MNA as substrate measured for 30 mins by thefluorescence assay	ic50	0.2600	uM
(2R)-2-amino-3-benzylsulfanyl-N-[(2S,3S,4R,5R)-5-[6-(dimethylamino)purin-9-yl]-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]propanamide	1500910: Inhibition of recombinant human N-terminal His6-MBP-tagged PSA expressed in Escherichia coli BL21 STAR (DE3) using 4-Ala-MNA as substrate measured for 30 mins by thefluorescence assay	ic50	0.9400	uM
(2R)-2-amino-N-[(2S,3S,4R,5R)-5-[6-(dimethylamino)purin-9-yl]-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]-3-tritylsulfanylpropanamide	1500910: Inhibition of recombinant human N-terminal His6-MBP-tagged PSA expressed in Escherichia coli BL21 STAR (DE3) using 4-Ala-MNA as substrate measured for 30 mins by thefluorescence assay	ic50	1.4000	uM
ethyl 4-anilino-1-phenyl-2,6-dipyridin-3-yl-3,6-dihydro-2H-pyridine-5-carboxylate	1264919: Inhibition of recombinant human puromycin sensitive aminopeptidase using Leu-pNA as substrate after 30 mins	ic50	1.7900	uM
tert-butyl N-[(2R)-3-(1-adamantylsulfanyl)-1-[[(2S,3S,4R,5R)-2-(chloromethyl)-5-[6-(dimethylamino)purin-9-yl]-4-hydroxyoxolan-3-yl]amino]-1-oxopropan-2-yl]carbamate	2116773: Inhibition of human N-terminal His-tagged Puromycin-sensitive aminopeptidase extracted from Escherichia coli BL21 STAR (DE3) using alanine-4-methoxy-2-naphthylamide as substrate incubated for 30 mins by SpectraMax microplate reader analysis	ic50	2.3000	uM
(2S)-2-amino-N-[(2S,3S,4R,5R)-5-[6-(dimethylamino)purin-9-yl]-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]-3-(4-methoxyphenyl)propanamide	1264919: Inhibition of recombinant human puromycin sensitive aminopeptidase using Leu-pNA as substrate after 30 mins	ic50	2.4500	uM
3-anthracen-9-yl-1H-quinazoline-2,4-dione	162817: Puromycin sensitive aminopeptidase inhibitory activity by the use of L-Ala AMC with MOLT-4	ic50	2.9000	uM
3-(2,6-diethylphenyl)-1-methylquinazoline-2,4-dione	162817: Puromycin sensitive aminopeptidase inhibitory activity by the use of L-Ala AMC with MOLT-4	ic50	3.4000	uM
(2S)-2-[[(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl]amino]-4-methylpentanoic acid	1500910: Inhibition of recombinant human N-terminal His6-MBP-tagged PSA expressed in Escherichia coli BL21 STAR (DE3) using 4-Ala-MNA as substrate measured for 30 mins by thefluorescence assay	ic50	3.5000	uM
3-(2,6-diethylphenyl)-1H-quinazoline-2,4-dione	162817: Puromycin sensitive aminopeptidase inhibitory activity by the use of L-Ala AMC with MOLT-4	ic50	3.8000	uM
(2S)-2-amino-N-[(2S,3S,4R,5R)-2-(chloromethyl)-5-[6-(dimethylamino)purin-9-yl]-4-hydroxyoxolan-3-yl]-3-(4-methoxyphenyl)propanamide	2116773: Inhibition of human N-terminal His-tagged Puromycin-sensitive aminopeptidase extracted from Escherichia coli BL21 STAR (DE3) using alanine-4-methoxy-2-naphthylamide as substrate incubated for 30 mins by SpectraMax microplate reader analysis	ic50	3.9000	uM
N-[3,5-diethyl-4-(1-methyl-2,4-dioxoquinazolin-3-yl)phenyl]-5-(dimethylamino)naphthalene-2-sulfonamide	162817: Puromycin sensitive aminopeptidase inhibitory activity by the use of L-Ala AMC with MOLT-4	ic50	4.6000	uM
(2S)-2-amino-3-benzhydrylsulfanyl-N-[(2S,3S,4R,5R)-5-[6-(dimethylamino)purin-9-yl]-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]propanamide	1500910: Inhibition of recombinant human N-terminal His6-MBP-tagged PSA expressed in Escherichia coli BL21 STAR (DE3) using 4-Ala-MNA as substrate measured for 30 mins by thefluorescence assay	ic50	4.8000	uM
(2S)-2-amino-N-[(2S,3S,4R,5R)-5-[6-(dimethylamino)purin-9-yl]-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]-3-phenylpropanamide	1500910: Inhibition of recombinant human N-terminal His6-MBP-tagged PSA expressed in Escherichia coli BL21 STAR (DE3) using 4-Ala-MNA as substrate measured for 30 mins by thefluorescence assay	ic50	5.0000	uM
tert-butyl N-[(2R)-3-benzhydrylsulfanyl-1-[[(2S,3S,4R,5R)-2-(chloromethyl)-5-[6-(dimethylamino)purin-9-yl]-4-hydroxyoxolan-3-yl]amino]-1-oxopropan-2-yl]carbamate	2116773: Inhibition of human N-terminal His-tagged Puromycin-sensitive aminopeptidase extracted from Escherichia coli BL21 STAR (DE3) using alanine-4-methoxy-2-naphthylamide as substrate incubated for 30 mins by SpectraMax microplate reader analysis	ic50	5.9000	uM
tert-butyl N-[(2S)-3-benzhydrylsulfanyl-1-[[(2S,3S,4R,5R)-2-(chloromethyl)-5-[6-(dimethylamino)purin-9-yl]-4-hydroxyoxolan-3-yl]amino]-1-oxopropan-2-yl]carbamate	2116773: Inhibition of human N-terminal His-tagged Puromycin-sensitive aminopeptidase extracted from Escherichia coli BL21 STAR (DE3) using alanine-4-methoxy-2-naphthylamide as substrate incubated for 30 mins by SpectraMax microplate reader analysis	ic50	6.7000	uM
2-(2,6-diethylphenyl)-4H-isoquinoline-1,3-dione	162817: Puromycin sensitive aminopeptidase inhibitory activity by the use of L-Ala AMC with MOLT-4	ic50	7.8000	uM
ethyl 4-oxo-1-phenyl-2,6-dipyridin-3-ylpiperidine-3-carboxylate	1264919: Inhibition of recombinant human puromycin sensitive aminopeptidase using Leu-pNA as substrate after 30 mins	ic50	8.0400	uM
(2S)-2-amino-3-benzhydrylsulfanyl-N-[(2S,3S,4R,5R)-2-(chloromethyl)-5-[6-(dimethylamino)purin-9-yl]-4-hydroxyoxolan-3-yl]propanamide	2116773: Inhibition of human N-terminal His-tagged Puromycin-sensitive aminopeptidase extracted from Escherichia coli BL21 STAR (DE3) using alanine-4-methoxy-2-naphthylamide as substrate incubated for 30 mins by SpectraMax microplate reader analysis	ic50	8.4000	uM
ethyl 4-(4-methylanilino)-1-(4-methylphenyl)-2-phenyl-6-pyridin-2-yl-3,6-dihydro-2H-pyridine-5-carboxylate	1264919: Inhibition of recombinant human puromycin sensitive aminopeptidase using Leu-pNA as substrate after 30 mins	ic50	8.5300	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Tretinoin	increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
bisphenol F	affects cotreatment, increases expression	1
TAK-243	increases sumoylation	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	decreases expression, affects localization, affects cotreatment	1
beta-lapachone	decreases expression	1
arsenite	affects binding, increases reaction	1
afimoxifene	decreases reaction, increases expression	1
sodium arsenite	decreases expression, increases abundance	1
perfluorooctanoic acid	increases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
artenimol	affects binding	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
nutlin 3	affects cotreatment, increases secretion	1
torcetrapib	increases expression	1
ICG 001	decreases expression	1
bisphenol S	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1

ChEMBL screening assays

9 unique, capped per target: 8 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3744907	Binding	Inhibition of recombinant human puromycin sensitive aminopeptidase using Leu-pNA as substrate after 30 mins	Highly functionalized tetrahydropyridines are cytotoxic and selective inhibitors of human puromycin sensitive aminopeptidase. — Eur 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

6 cell lines: 6 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1PC	Abcam K-562 NPEPPS KO	Cancer cell line	Female
CVCL_D2KY	Abcam Raji NPEPPS KO	Cancer cell line	Male
CVCL_E2EG	HAP1 NPEPPS (-) 1	Cancer cell line	Male
CVCL_E2EH	HAP1 NPEPPS (-) 2	Cancer cell line	Male
CVCL_E2EI	HAP1 NPEPPS (-) 3	Cancer cell line	Male
CVCL_WQ15	Abcam Jurkat NPEPPS KO	Cancer cell line	Male

Clinical trials (associated diseases)

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