PSMA4

Summary

PSMA4 (proteasome 20S subunit alpha 4, HGNC:9533) is a protein-coding gene on chromosome 15q25.1, encoding Proteasome subunit alpha type-4 (P25789). Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. It is a common-essential gene (DepMap: required in 99.7% of cancer cell lines).

This gene encodes a core alpha subunit of the 20S proteosome, which is a highly ordered ring-shaped structure composed of four rings of 28 non-identical subunits. Proteasomes cleave peptides in an ATP- and ubiquitin-dependent manner.

Source: NCBI Gene 5685 — RefSeq curated summary.

At a glance

• GWAS associations: 28 (top 5% of genes corpus-wide)
• Clinical variants (ClinVar): 24 total
• GTEx eGene: eQTL in 41 tissues, sQTL in 25 (q < 0.05)
• ChEMBL bioactivity: 6 clinical-phase molecules tested; no curated mechanism-of-action drug
• Cancer dependency (DepMap): dependent in 99.7% of screened cell lines (common-essential)
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.41 (moderately constrained)
• MANE Select transcript: NM_002789
• Interaction hub: 3,312 STRING partners (top 2% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9533
Approved symbol	PSMA4
Name	proteasome 20S subunit alpha 4
Location	15q25.1
Locus type	gene with protein product
Status	Approved
Aliases	HC9, HsT17706
Ensembl gene	ENSG00000041357
Ensembl biotype	protein_coding
OMIM	176846
Entrez	5685

Gene structure

Transcript identifiers

Ensembl transcripts: 46 — 37 protein_coding, 6 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

MANE Select: ENST00000044462

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 5, TSL 2: 4, TSL 3: 3, TSL 4: 1, TSL 5: 8

ENST00000044462, ENST00000413382, ENST00000557929, ENST00000558094, ENST00000558281, ENST00000558341, ENST00000558635, ENST00000558639, ENST00000559082, ENST00000559146, ENST00000559154, ENST00000559365, ENST00000559437, ENST00000559906, ENST00000559934, ENST00000559948, ENST00000560033, ENST00000560099, ENST00000560217, ENST00000560737, ENST00000560842, ENST00000859802, ENST00000859803, ENST00000859804, ENST00000859805, ENST00000859806, ENST00000859807, ENST00000859808, ENST00000859809, ENST00000920050, ENST00000920051, ENST00000920052, ENST00000992531, ENST00000992532, ENST00001053766, ENST00001053768, ENST00001062648, ENST00001062652, ENST00001062661, ENST00001062663, ENST00001117541, ENST00001117542, ENST00001127593, ENST00001127594, ENST00001127595, ENST00001136214

RefSeq mRNA: 6 — MANE Select: NM_002789 NM_001102667, NM_001102668, NM_001330673, NM_001330675, NM_001330676, NM_002789

CCDS: CCDS10303, CCDS45319, CCDS86478, CCDS86479

Canonical transcript exons

ENST00000044462 — 9 exons

Exon	Start	End
ENSE00001814481	78548790	78552417
ENSE00002554217	78540444	78540539
ENSE00003473522	78544869	78544957
ENSE00003486880	78545634	78545764
ENSE00003526690	78542483	78542645
ENSE00003530356	78542177	78542219
ENSE00003643595	78544190	78544267
ENSE00003689695	78541905	78541930
ENSE00003785334	78546575	78546698

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 99.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 124.2519 / max 3944.4436, expressed in 1821 samples.

Highest expression (Bgee): monocyte, mononuclear cell, leukocyte, visceral pleura, parietal pleura.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PSMA4 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 41 tissues and its splicing (sQTL) in 25 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 66 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Muscle Skeletal	sqtl	3.6e-124	+1.06	15:78549897:T:C
Muscle Skeletal	eqtl	1.8e-78	+0.30	15:78547058:G:A
Cells Cultured fibroblasts	sqtl	5.5e-49	+0.93	15:78536749:T:C
Heart Left Ventricle	eqtl	1.7e-36	+0.33	15:78550493:G:GT
Esophagus Mucosa	sqtl	1.6e-25	-0.81	15:78528674:G:A
Heart Left Ventricle	sqtl	2.2e-24	+0.79	15:78550493:G:GT
Heart Atrial Appendage	eqtl	6.3e-24	-0.31	15:78550709:C:T
Lung	sqtl	1.5e-23	+0.79	15:78528674:G:A
Cells EBV-transformed lymphocytes	sqtl	3.3e-20	+1.06	15:78528674:G:A
Nerve Tibial	eqtl	8.7e-19	+0.19	15:78543946:A:T
Thyroid	sqtl	1.1e-16	+0.62	15:78510715:C:T
Skin Not Sun Exposed Suprapubic	sqtl	3.0e-16	+0.56	15:78540490:T:C
Whole Blood	eqtl	1.5e-15	-0.13	15:78528674:G:A
Colon Transverse	sqtl	2.4e-15	+0.67	15:78522047:C:T
Whole Blood	sqtl	1.3e-14	+0.42	15:78522047:C:T
Esophagus Muscularis	eqtl	2.1e-13	-0.15	15:78529264:C:T
Artery Tibial	eqtl	3.9e-13	-0.15	15:78550709:C:T
Stomach	sqtl	2.0e-12	+0.68	15:78528674:G:A
Heart Atrial Appendage	sqtl	5.1e-12	+0.69	15:78522047:C:T
Thyroid	eqtl	5.4e-12	+0.14	15:78577237:T:A

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
147912	122.2834	1821
147914	1.8685	1008
147913	0.1000	17

Top tissues by expression

showing 100 of 300 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.26	gold quality
mononuclear cell	CL:0000842	99.15	gold quality
leukocyte	CL:0000738	99.09	gold quality
visceral pleura	UBERON:0002401	99.03	gold quality
parietal pleura	UBERON:0002400	98.98	gold quality
pleura	UBERON:0000977	98.83	gold quality
ganglionic eminence	UBERON:0004023	98.82	gold quality
islet of Langerhans	UBERON:0000006	98.78	gold quality
rectum	UBERON:0001052	98.78	gold quality
ventricular zone	UBERON:0003053	98.75	gold quality
adrenal tissue	UBERON:0018303	98.58	gold quality
smooth muscle tissue	UBERON:0001135	98.57	gold quality
palpebral conjunctiva	UBERON:0001812	98.57	gold quality
left testis	UBERON:0004533	98.57	gold quality
right testis	UBERON:0004534	98.57	gold quality
esophagus squamous epithelium	UBERON:0006920	98.53	gold quality
vermiform appendix	UBERON:0001154	98.50	gold quality
tongue squamous epithelium	UBERON:0006919	98.50	gold quality
lymph node	UBERON:0000029	98.46	gold quality
granulocyte	CL:0000094	98.41	gold quality
calcaneal tendon	UBERON:0003701	98.41	gold quality
embryo	UBERON:0000922	98.35	gold quality
mucosa of transverse colon	UBERON:0004991	98.33	gold quality
epithelium of nasopharynx	UBERON:0001951	98.31	gold quality
nasopharynx	UBERON:0001728	98.29	gold quality
squamous epithelium	UBERON:0006914	98.28	gold quality
endometrium	UBERON:0001295	98.27	gold quality
gingival epithelium	UBERON:0001949	98.27	gold quality
gall bladder	UBERON:0002110	98.27	gold quality
right adrenal gland	UBERON:0001233	98.22	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.21	gold quality
gastrocnemius	UBERON:0001388	98.19	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.19	gold quality
esophagus mucosa	UBERON:0002469	98.18	gold quality
germinal epithelium of ovary	UBERON:0001304	98.16	gold quality
transverse colon	UBERON:0001157	98.15	gold quality
muscle of leg	UBERON:0001383	98.15	gold quality
metanephros cortex	UBERON:0010533	98.15	gold quality
testis	UBERON:0000473	98.13	gold quality
caecum	UBERON:0001153	98.13	gold quality
left adrenal gland	UBERON:0001234	98.13	gold quality
cortical plate	UBERON:0005343	98.10	gold quality
right adrenal gland cortex	UBERON:0035827	98.09	gold quality
sigmoid colon	UBERON:0001159	98.08	gold quality
mucosa of stomach	UBERON:0001199	98.06	gold quality
esophagus	UBERON:0001043	98.04	gold quality
left adrenal gland cortex	UBERON:0035825	98.04	gold quality
spleen	UBERON:0002106	98.00	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.00	gold quality
lower esophagus	UBERON:0013473	97.99	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.99	gold quality
adrenal cortex	UBERON:0001235	97.98	gold quality
body of uterus	UBERON:0009853	97.98	gold quality
left uterine tube	UBERON:0001303	97.97	gold quality
eye	UBERON:0000970	97.96	gold quality
colon	UBERON:0001155	97.95	gold quality
large intestine	UBERON:0000059	97.94	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.92	gold quality
gingiva	UBERON:0001828	97.90	gold quality
ectocervix	UBERON:0012249	97.89	gold quality
endometrium epithelium	UBERON:0004811	97.88	gold quality
left coronary artery	UBERON:0001626	97.87	gold quality
upper lobe of left lung	UBERON:0008952	97.84	gold quality
intestine	UBERON:0000160	97.83	gold quality
right lung	UBERON:0002167	97.83	gold quality
adrenal gland	UBERON:0002369	97.80	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.79	gold quality
endocervix	UBERON:0000458	97.77	gold quality
descending thoracic aorta	UBERON:0002345	97.77	gold quality
coronary artery	UBERON:0001621	97.75	gold quality
upper lobe of lung	UBERON:0008948	97.75	gold quality
peritoneum	UBERON:0002358	97.73	gold quality
omental fat pad	UBERON:0010414	97.73	gold quality
apex of heart	UBERON:0002098	97.72	gold quality
duodenum	UBERON:0002114	97.72	gold quality
uterus	UBERON:0000995	97.66	gold quality
skin of abdomen	UBERON:0001416	97.62	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	97.61	gold quality
oral cavity	UBERON:0000167	97.61	gold quality
body of stomach	UBERON:0001161	97.61	gold quality
muscle organ	UBERON:0001630	97.61	gold quality
skeletal muscle organ	UBERON:0014892	97.61	gold quality
adipose tissue of abdominal region	UBERON:0007808	97.59	gold quality
body of pancreas	UBERON:0001150	97.57	gold quality
epithelium of esophagus	UBERON:0001976	97.57	gold quality
pylorus	UBERON:0001166	97.53	gold quality
right uterine tube	UBERON:0001302	97.53	gold quality
right coronary artery	UBERON:0001625	97.53	gold quality
artery	UBERON:0001637	97.53	gold quality
right lobe of liver	UBERON:0001114	97.52	gold quality
thoracic aorta	UBERON:0001515	97.52	gold quality
right lobe of thyroid gland	UBERON:0001119	97.51	gold quality
stromal cell of endometrium	CL:0002255	97.50	gold quality
left lobe of thyroid gland	UBERON:0001120	97.50	gold quality
tibial nerve	UBERON:0001323	97.50	gold quality
popliteal artery	UBERON:0002250	97.50	gold quality
tibial artery	UBERON:0007610	97.50	gold quality
jejunal mucosa	UBERON:0000399	97.49	gold quality
aorta	UBERON:0000947	97.49	gold quality
ascending aorta	UBERON:0001496	97.48	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	20.76
E-CURD-46	yes	19.46
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Caudate putamen	tissue	162.6
Frontal cortex	tissue	155.5
Thymus	tissue	145.8
Liver	tissue	132.6	medium
Skeletal muscle	tissue	130.2	not detected
Lymph node	tissue	127.9	medium
Tonsil	tissue	120.4	medium
Tongue	tissue	113.4
Urinary bladder	tissue	111.0	medium
Rectum	tissue	102.9	medium
Duodenum	tissue	102.4	medium
Bone marrow	tissue	101.5	medium
Appendix	tissue	100.3	medium
Colon	tissue	98.5	medium
Small intestine	tissue	95.3	medium
Smooth muscle	tissue	92.7	not detected
Kidney	tissue	90.8	medium
Testis	tissue	89.8	low
Prostate	tissue	81.7	medium
Breast	tissue	81.6	low
Placenta	tissue	80.6	high
Adipose tissue	tissue	78.3	not detected
Vagina	tissue	77.4	not detected
Pons	tissue	75.8
Esophagus	tissue	73.9	medium
Superior colliculi	tissue	73.1
Adrenal gland	tissue	72.7	medium
Ovary	tissue	71.5	not detected
Epididymis	tissue	70.2	medium
Spinal cord	tissue	69.9
Endometrium 1	tissue	69.3	medium
Parathyroid gland	tissue	68.9	medium
Skin 1	tissue	68.0	low
Thalamus	tissue	68.0
Spleen	tissue	68.0	medium
Heart muscle	tissue	67.6	medium
Stomach 1	tissue	67.0	medium
Midbrain	tissue	66.9
Fallopian tube	tissue	66.6	medium
Substantia nigra	tissue	66.0
Lung	tissue	65.7	medium
Hippocampal formation	tissue	65.6
Thyroid gland	tissue	64.7	low
Cervix	tissue	63.2	medium
Putamen	tissue	63.2
Medulla oblongata	tissue	63.1
Gallbladder	tissue	61.9	medium
Periaqueductal gray	tissue	61.7
Hypothalamus	tissue	61.1
Seminal vesicle	tissue	60.4	low
Septum	tissue	59.3
Basal ganglia	tissue	57.2	low
Cerebral cortex	tissue	57.0	low
Occipital cortex	tissue	57.0
Ventral forebrain	tissue	54.4
Corpus callosum	tissue	54.1
Prefrontal cortex	tissue	53.2
Pituitary gland	tissue	52.4
Somatosensory cortex	tissue	52.4
Entorhinal cortex	tissue	49.3

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Blood vessel (80.1), Ventral spinal cord (69.9), Dorsal hippocampus (65.6), Dorsal spinal cord (65.0), Ventral hippocampus (59.1).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREM

miRNA regulators (miRDB)

Targeting PSMA4 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

25 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-6757-3P	99.63	66.88	1089
HSA-MIR-6833-5P	99.50	68.93	1161
HSA-MIR-3911	99.38	66.95	1087
HSA-MIR-548V	99.29	69.47	1157
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-4520-3P	98.75	66.55	963
HSA-MIR-147A	98.33	66.40	795
HSA-MIR-5581-5P	97.91	66.50	965
HSA-MIR-10526-3P	97.86	64.97	1342
HSA-MIR-3614-3P	97.81	67.15	582
HSA-MIR-3190-3P	97.61	66.95	1406
HSA-MIR-3189-5P	97.55	66.71	655
HSA-MIR-5699-5P	97.36	67.03	1014
HSA-MIR-711	96.60	65.75	528
HSA-MIR-3169	96.40	67.58	698
HSA-MIR-208A-3P	95.87	66.51	397
HSA-MIR-208B-3P	95.87	66.56	396
HSA-MIR-7975	95.04	66.76	516
HSA-MIR-3130-3P	94.98	66.97	574

Functional genomics

gnomAD constraint: pLI 0.998, LOEUF 0.409, missense Z 2.85 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000044462 splits into 2 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
15:78,541,928–78,546,595	79 / 212.4	0.37	no
15:78,546,596–78,548,941	90 / 92.7	0.97	no
DepMap (CRISPR cell-line fitness): dependent in 99.7% of screened cell lines, common-essential.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): DK-MG (-2.606), MFE-280 (-2.288), SK-MM-2 (-2.268), Hs 852.T (-2.265), AsPC-1 (-2.227), Set-2 (-2.198), LN382 (-2.189), HEL 92.1.7 (-2.175), KASUMI-1 (-2.125), KALS-1 (-2.124), OS-RC-2 (-2.091), SLR 24 (-2.061), SNU-626 (-2.057), NIH:OVCAR-3 (-2.053), RERF-LC-AI (-2.044).

Literature-anchored findings (GeneRIF, showing 7)

• Unexpected interaction between alpha4 and alpha7 subunits may provide a molecular basis for the formation of previously reported 13S and 16S assembly intermediates. (PMID:15225636)
• Parkin interacts with the proteasome subunit alpha4 (PMID:15987638)
• study concludes polymorphisms of TGM5, PPAP2B and PSMA4 are not major contributors tonon-small cell lung cancer susceptibility in never-smoking hinese population, this primarily can be attributed to the significantly distinct genetic background of Asian populations from western populations (PMID:24518713)
• rs12901682 is associated with lung cancer risk in a Chinese Han population. (PMID:25744645)
• Five of these SNPs acted as cis-eQTLs, being associated with the transcription of IREB2 (rs2568494, rs16969968, rs11634351, rs6495309), PSMA4 (rs6495309) and ERCC1 (rs735482), out of 10,821 genes analyzed in lung. For these three genes, we obtained experimental evidence of differential allelic expression in lung tissue, pointing to the existence of in-cis genomic variants that regulate their transcription. (PMID:28181565)
• All four variants were significantly associated (P < 1.4 x 10(-6)) with blood DNA methylation of IREB2, CHRNA3 and PSMA4, of which two, including IREB2 and PSMA4, were also differentially methylated in Chronic obstructive pulmonary disease cases and controls (PMID:29422661)
• Potentially functional genetic variants of VAV2 and PSMA4 in the immune-activation pathway and non-small cell lung cancer survival. (PMID:36039727)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	psma4	ENSDARG00000045928
mus_musculus	Psma4	ENSMUSG00000032301
rattus_norvegicus	Psma4	ENSRNOG00000013493
drosophila_melanogaster	Prosalpha3	FBGN0261394
drosophila_melanogaster	Prosalpha3T	FBGN0261395
caenorhabditis_elegans	pas-3	WBGENE00003924

Paralogs (18): PSMB1 (ENSG00000008018), PSMA3 (ENSG00000100567), PSMB5 (ENSG00000100804), PSMA6 (ENSG00000100902), PSMA7 (ENSG00000101182), PSMA2 (ENSG00000106588), PSMB2 (ENSG00000126067), PSMA1 (ENSG00000129084), PSMB7 (ENSG00000136930), PSMB6 (ENSG00000142507), PSMA5 (ENSG00000143106), PSMA8 (ENSG00000154611), PSMB4 (ENSG00000159377), PSMB8 (ENSG00000204264), PSMB10 (ENSG00000205220), PSMB11 (ENSG00000222028), PSMB9 (ENSG00000240065), PSMB3 (ENSG00000277791)

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Oryza sativa Indica Group	A2Y9X7	100.0%	Diamond
Oryza sativa Japonica Group	P0DKK3	100.0%	Diamond
Bos taurus	Q2YDE4	100.0%	Diamond
Macaca fascicularis	Q4R932	99.6%	Diamond
Methanococcus maripaludis C5	A4FZT6	99.2%	Diamond
Methanococcus maripaludis C7	A6VIP0	99.2%	Diamond
Arabidopsis thaliana	O23708	99.1%	Diamond
Methanococcus maripaludis C6	A9A846	98.5%	Diamond
Solanum lycopersicum	O24030	93.8%	Diamond
Carassius auratus	Q9PTW9	91.4%	Diamond
Spinacia oleracea	P52427	90.8%	Diamond
Petunia x hybrida	O82530	89.2%	Diamond
Saccharomyces cerevisiae S288C	P23639	74.0%	Diamond
Dictyostelium discoideum	P34119	66.0%	Diamond
Schizosaccharomyces pombe 972h-	Q09682	63.7%	Diamond
Pyrobaculum aerophilum str. IM2	Q8ZVM1	54.7%	Diamond
Aeropyrum pernix K1	Q9YC01	53.0%	Diamond
Trypanosoma brucei brucei	Q9GU37	40.1%	Diamond
Encephalitozoon cuniculi GB-M1	Q8SRU7	38.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
CHRNA5	protein-coding	1138
CHRNB4	protein-coding	1143
HYKK	protein-coding	123688
CHRNA3	protein-coding	1136
IREB2	protein-coding	3658

Protein

Protein identifiers

Proteasome subunit alpha type-4 — P25789 (reviewed: P25789)

Alternative names: Macropain subunit C9, Multicatalytic endopeptidase complex subunit C9, Proteasome component C9, Proteasome subunit L, Proteasome subunit alpha-3

All UniProt accessions (11): P25789, H0YKS0, H0YKT8, H0YL69, H0YLC2, H0YLS6, H0YMA1, H0YMI6, H0YMV3, H0YMZ1, H0YN18

UniProt curated annotations — full annotation on UniProt →

Function. Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).

Subunit / interactions. The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. (Microbial infection) Interaction with HTLV-1 TAX protein favors NFKB1 activation.

Subcellular location. Cytoplasm. Nucleus.

Induction. Down-regulated by antioxidants BO-653 and probucol.

Similarity. Belongs to the peptidase T1A family.

Isoforms (2)

UniProt ID	Names	Canonical?
P25789-1	1	yes
P25789-2	2

RefSeq proteins (6): NP_001096137, NP_001096138, NP_001317602, NP_001317604, NP_001317605, NP_002780* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000426	Proteasome_asu_N	Domain
IPR001353	Proteasome_sua/b	Family
IPR016050	Proteasome_bsu_CS	Conserved_site
IPR023332	Proteasome_alpha-type	Family
IPR029055	Ntn_hydrolases_N	Homologous_superfamily
IPR050115

Pfam: PF00227, PF10584

Enzyme classification (BRENDA)

• EC 3.4.25.1 — proteasome endopeptidase complex (BRENDA: 45 organisms, 202 substrates, 283 inhibitors, 33 Km, 33 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
BENZYLOXYCARBONYL-GPAFG-4-AMINOBENZOATE	0.38–3.3	3
ACETYL-EPFD-7-AMIDO-4-CARBAMOYLCOUMARIN	0.032–0.088	2
ACETYL-NORLEUCINE-ARG-NORLEUCINE-ARG-7-AMIDO-4-C	0.11–0.67	2
ACETYL-YWTQ-7-AMIDO-4-CARBAMOYLCOUMARIN	0.027–0.038	2
BENZYLOXYCARBONYL-GPALG-4-AMINOBENZOATE	0.14–0.57	2
ABZ-VAL-VAL-SER-(4-GUANIDINO-PHE)-ALA-MET-GLY-TY	0.0042	1
ABZ-VAL-VAL-SER-ARG-SER-LEU-GLY-TYR(3-NO2)-NH2	0.0177	1
ACETYL-ARG-HSER-THR-ARG-7-AMIDO-4-METHYLCOUMARIN	0.0094	1
ACETYL-BETAALA-MET(SULFONE)-THR-ARG-7-AMIDO-4-ME	0.051	1
ACETYL-HARG-PRO-2-FLUORO-PHE-ASP-7-AMIDO-4-METHY	0.0159	1
ACETYL-HARG-PRO-ABU-ASP-7-AMIDO-4-METHYLCOUMARIN	0.0432	1
ACETYL-HHSL-7-AMIDO-4-CARBAMOYLCOUMARIN	0.36	1
BENZOYL-VGR-7-AMIDO-4-METHYLCOUMARIN	0.1	1
BENZYLOXYCARBONYL-ARR-7-AMIDO-4-METHYLCOUMARIN	0.248	1
BENZYLOXYCARBONYL-GGF-4-AMINOBENZOATE	2.29	1

UniProt features (39 total): strand 13, helix 11, turn 7, modified residue 5, chain 1, region of interest 1, splice variant 1

Structure

Experimental structures (PDB)

showing 30 of 177 structures by resolution:

PDB	Title	Method	Resolution (Å)
5LE5	Native human 20S proteasome at 1.8 Angstrom	X-RAY DIFFRACTION	1.8
5LEY	Human 20S proteasome complex with Oprozomib at 1.9 Angstrom	X-RAY DIFFRACTION	1.9
5LF4	Human 20S proteasome complex with Delanzomib at 2.0 Angstrom	X-RAY DIFFRACTION	1.99
5LF1	Human 20S proteasome complex with Dihydroeponemycin at 2.0 Angstrom	X-RAY DIFFRACTION	2
5LF7	Human 20S proteasome complex with Ixazomib at 2.0 Angstrom	X-RAY DIFFRACTION	2
8UD9	Structure of human constitutive 20S proteasome complexed with the inhibitor TDI-8304	ELECTRON MICROSCOPY	2.04
5LF6	Human 20S proteasome complex with Z-LLY-ketoaldehyde at 2.1 Angstrom	X-RAY DIFFRACTION	2.07
5LF3	Human 20S proteasome complex with Bortezomib at 2.1 Angstrom	X-RAY DIFFRACTION	2.1
8BZL	Human 20S Proteasome in complex with peptide activator peptide BLM42	X-RAY DIFFRACTION	2.14
5LEZ	Human 20S proteasome complex with Oprozomib in Mg-Acetate at 2.2 Angstrom	X-RAY DIFFRACTION	2.19
5LEX	Native human 20S proteasome in Mg-Acetate at 2.2 Angstrom	X-RAY DIFFRACTION	2.2
7AWE	HUMAN IMMUNOPROTEASOME 20S PARTICLE IN COMPLEX WITH …	X-RAY DIFFRACTION	2.29
5LF0	Human 20S proteasome complex with Epoxomicin at 2.4 Angstrom	X-RAY DIFFRACTION	2.41
7B12	HUMAN IMMUNOPROTEASOME 20S PARTICLE IN COMPLEX WITH …	X-RAY DIFFRACTION	2.43
9K53	Structure of substrate-engaged human 26S proteasome RP-CP subcomplex in state ED2.1	ELECTRON MICROSCOPY	2.5
9HMN	CryoEM structure of human 20S proteasome in complex with proteasome inhibitor …	ELECTRON MICROSCOPY	2.55
4R3O	Human Constitutive 20S Proteasome	X-RAY DIFFRACTION	2.6
6RGQ	Human 20S Proteasome	ELECTRON MICROSCOPY	2.6
9YUZ	Structure of the human 20S proteasome in complex with a beta5-selective covalent …	ELECTRON MICROSCOPY	2.6
8QYL	Human 20S proteasome assembly intermediate structure 2	ELECTRON MICROSCOPY	2.67
8CVR	Human 20S proteasome with MG-132	ELECTRON MICROSCOPY	2.7
6KWY	human PA200-20S complex	ELECTRON MICROSCOPY	2.72
8QYJ	Human 20S proteasome assembly structure 1	ELECTRON MICROSCOPY	2.73
8QYM	Human 20S proteasome assembly intermediate structure 3	ELECTRON MICROSCOPY	2.73
8USB	Non-substrate-engaged human 26S proteasome with Nub1/FAT10 bound to Rpn1	ELECTRON MICROSCOPY	2.73
9MBP	Substrate-engaged human 26S proteasome bound to midnolin with RPT1 at top of spiral …	ELECTRON MICROSCOPY	2.75
9PDL	Nub1/Fat10-processing human 26S proteasome with Rpt5 at top of spiral staircase (AAA+ …	ELECTRON MICROSCOPY	2.76
6E5B	Human Immunoproteasome 20S particle in complex with compound 1	X-RAY DIFFRACTION	2.77
7NAN	Human 20S proteasome core particle	ELECTRON MICROSCOPY	2.8
8TM6	Human premature 20S proteasome assembly intermediate	ELECTRON MICROSCOPY	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P25789-F1	93.17	0.84

Human Protein Atlas

Protein class: Enzymes, Peptidases, Threonine-type peptidases, Predicted intracellular proteins, Plasma proteins, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; nucleoplasm; connecting piece; flagellar centriole; mid piece; vesicles

Antibody reliability (HPA): IH supported · IF supported

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (5)

Type	Positions
Phosphoserine	13, 75, 173
N6-acetyllysine	127, 176

Function

Pathways and Gene Ontology

Reactome pathways

58 curated (TAS) of 172; 13 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

showing 60 of 172 pathways:

ID	Pathway	Evidence
R-HSA-5678895	Defective CFTR causes cystic fibrosis ⚕	curated
R-HSA-5362768	Hh mutants are degraded by ERAD ⚕	curated
R-HSA-180585	Vif-mediated degradation of APOBEC3G ⚕	curated
R-HSA-180534	Vpu mediated degradation of CD4 ⚕	curated
R-HSA-382556	ABC-family protein mediated transport	curated
R-HSA-9931269	AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	curated
R-HSA-174154	APC/C:Cdc20 mediated degradation of Securin	curated
R-HSA-174178	APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1	curated
R-HSA-450408	AUF1 (hnRNP D0) binds and destabilizes mRNA	curated
R-HSA-1169091	Activation of NF-kappaB in B cells	curated
R-HSA-9912633	Antigen processing: Ub, ATP-independent proteasomal degradation	curated
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation	curated
R-HSA-68867	Assembly of the pre-replicative complex	curated
R-HSA-4608870	Asymmetric localization of PCP proteins	curated
R-HSA-174084	Autodegradation of Cdh1 by Cdh1:APC/C	curated
R-HSA-349425	Autodegradation of the E3 ubiquitin ligase COP1	curated
R-HSA-69017	CDK-mediated phosphorylation and removal of Cdc6	curated
R-HSA-5607764	CLEC7A (Dectin-1) signaling	curated
R-HSA-174184	Cdc20:Phospho-APC/C mediated degradation of Cyclin A	curated
R-HSA-1236978	Cross-presentation of soluble exogenous antigens (endosomes)	curated
R-HSA-5607761	Dectin-1 mediated noncanonical NF-kB signaling	curated
R-HSA-4641257	Degradation of AXIN	curated
R-HSA-9766229	Degradation of CDH1	curated
R-HSA-4641258	Degradation of DVL	curated
R-HSA-5610780	Degradation of GLI1 by the proteasome	curated
R-HSA-195253	Degradation of beta-catenin by the destruction complex	curated
R-HSA-202424	Downstream TCR signaling	curated
R-HSA-8854050	FBXL7 down-regulates AURKA during mitotic entry and in early mitosis	curated
R-HSA-2871837	FCERI mediated NF-kB activation	curated
R-HSA-69481	G2/M Checkpoints	curated
R-HSA-5610785	GLI3 is processed to GLI3R by the proteasome	curated
R-HSA-9762114	GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2	curated
R-HSA-9929356	GSK3B-mediated proteasomal degradation of PD-L1(CD274)	curated
R-HSA-5632684	Hedgehog ‘on’ state	curated
R-HSA-5358346	Hedgehog ligand biogenesis	curated
R-HSA-9020702	Interleukin-1 signaling	curated
R-HSA-9755511	KEAP1-NFE2L2 pathway	curated
R-HSA-5687128	MAPK6/MAPK4 signaling	curated
R-HSA-5676590	NIK–>noncanonical NF-kB signaling	curated
R-HSA-8951664	Neddylation	curated
R-HSA-9974237	Negative Regulation of DNA Double Strand Break Response	curated
R-HSA-68949	Orc1 removal from chromatin	curated
R-HSA-1234176	Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	curated
R-HSA-8939236	RUNX1 regulates transcription of genes involved in differentiation of HSCs	curated
R-HSA-8948751	Regulation of PTEN stability and activity	curated
R-HSA-5658442	Regulation of RAS by GAPs	curated
R-HSA-8941858	Regulation of RUNX3 expression and activity	curated
R-HSA-350562	Regulation of ornithine decarboxylase (ODC)	curated
R-HSA-187577	SCF(Skp2)-mediated degradation of p27/p21	curated
R-HSA-174113	SCF-beta-TrCP mediated degradation of Emi1	curated
R-HSA-9929491	SPOP-mediated proteasomal degradation of PD-L1(CD274)	curated
R-HSA-2467813	Separation of Sister Chromatids	curated
R-HSA-5668541	TNFR2 non-canonical NF-kB pathway	curated
R-HSA-8852276	The role of GTSE1 in G2/M progression after G2 checkpoint	curated
R-HSA-5689603	UCH proteinases	curated
R-HSA-5689880	Ub-specific processing proteases	curated
R-HSA-69601	Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A	curated
R-HSA-75815	Ubiquitin-dependent degradation of Cyclin D	curated
R-HSA-5619084	ABC transporter disorders ⚕	—
R-HSA-1643685	Disease ⚕	—

MSigDB gene sets: 508 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, REACTOME_DNA_REPLICATION, REACTOME_SIGNALING_BY_NOTCH, MODULE_52, REACTOME_APC_C_CDH1_MEDIATED_DEGRADATION_OF_CDC20_AND_OTHER_APC_C_CDH1_TARGETED_PROTEINS_IN_LATE_MITOSIS_EARLY_G1, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_10, REACTOME_INNATE_IMMUNE_SYSTEM, MORF_MBD4, TGCGCANK_UNKNOWN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, KEGG_PROTEASOME

GO Biological Process (25): immune system process (GO:0002376), DNA repair (GO:0006281), apoptotic process (GO:0006915), DNA damage response (GO:0006974), response to oxidative stress (GO:0006979), spermatogenesis (GO:0007283), proteasomal protein catabolic process (GO:0010498), proteasomal ubiquitin-independent protein catabolic process (GO:0010499), flagellated sperm motility (GO:0030317), positive regulation of type II interferon production (GO:0032729), positive regulation of interleukin-2 production (GO:0032743), positive regulation of tumor necrosis factor production (GO:0032760), response to type II interferon (GO:0034341), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), CD8-positive, alpha-beta T cell differentiation (GO:0043374), thymic T cell selection (GO:0045061), T-helper 1 cell differentiation (GO:0045063), negative regulation of regulatory T cell differentiation (GO:0045590), meiotic cell cycle (GO:0051321), regulation of proteasomal protein catabolic process (GO:0061136), cellular response to type I interferon (GO:0071357), T-helper 17 cell differentiation (GO:0072539), CD8-positive, alpha-beta T cell homeostasis (GO:0160165), regulation of G1/S transition of mitotic cell cycle (GO:2000045), ubiquitin-dependent protein catabolic process (GO:0006511)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (11): proteasome complex (GO:0000502), P-body (GO:0000932), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), proteasome core complex (GO:0005839), synaptic vesicle (GO:0008021), proteasome core complex, alpha-subunit complex (GO:0019773), proteasome storage granule (GO:0034515), extracellular exosome (GO:0070062)

Reactome top-level categories

18 top-level categories:

Category	Pathways
Antigen processing-Cross presentation	2
APC/C-mediated degradation of cell cycle proteins	2
Host Interactions of HIV factors	2
Downstream signaling events of B Cell Receptor (BCR)	1
Cellular response to hypoxia	1
Regulation of APC/C activators between G1/S and early anaphase	1
APC/C:Cdc20 mediated degradation of mitotic proteins	1
APC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpoint	1
Cyclin E associated events during G1/S transition	1
Cyclin A:Cdk2-associated events at S phase entry	1
Signaling by WNT	1
TCR signaling	1
Regulation of Apoptosis	1
Mitotic Anaphase	1
Fc epsilon receptor (FCERI) signaling	1
Stabilization of p53	1
Metabolism of polyamines	1
Transport of small molecules	1

GO top-level categories

58 GO namespaces:

Category	Terms
proteasomal protein catabolic process	3
intracellular protein-containing complex	3
cellular anatomical structure	3
positive regulation of cytokine production	2
cytoplasm	2
biological_process	1
DNA metabolic process	1
DNA damage response	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cellular response to stress	1
response to stress	1
developmental process involved in reproduction	1
male gamete generation	1
protein catabolic process	1
cilium-dependent cell motility	1
cilium movement involved in cell motility	1
sperm motility	1
type II interferon production	1
regulation of type II interferon production	1
interleukin-2 production	1
regulation of interleukin-2 production	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
positive regulation of tumor necrosis factor superfamily cytokine production	1
response to cytokine	1
innate immune response	1
ubiquitin-dependent protein catabolic process	1
CD8-positive, alpha-beta T cell activation	1
alpha-beta T cell differentiation	1
T cell differentiation in thymus	1
T cell selection	1
alpha-beta T cell activation involved in immune response	1
T cell differentiation involved in immune response	1
T-helper 1 type immune response	1
T-helper cell differentiation	1
regulatory T cell differentiation	1
negative regulation of T cell differentiation	1
regulation of regulatory T cell differentiation	1
cell cycle	1
sexual reproduction	1
reproductive process	1
meiotic nuclear division	1
regulation of protein catabolic process	1
binding	1
endopeptidase complex	1
cytoplasmic ribonucleoprotein granule	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
proteasome complex	1
catalytic complex	1
exocytic vesicle	1
presynapse	1
proteasome core complex	1
intracellular membraneless organelle	1
extracellular vesicle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 12 of 38 annotations. The rest are phylogenetic / computational / electronic (IEA).

12 experimentally-supported GO terms:

GO term	NS	Evidence
proteasomal protein catabolic process	BP	direct assay
proteasome-mediated ubiquitin-dependent protein catabolic process	BP	direct assay
regulation of proteasomal protein catabolic process	BP	direct assay
response to oxidative stress	BP	direct assay
cytoplasm	CC	direct assay
cytosol	CC	direct assay
extracellular exosome	CC	high-throughput assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
proteasome complex	CC	direct assay
proteasome core complex	CC	direct assay
proteasome core complex, alpha-subunit complex	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 3,312 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PSMA4	CHRNA5	P30532	939
PSMA4	CHRNA3	P32297	932
PSMA4	CHRNB4	P30926	930
PSMA4	POMP	Q9Y244	856
PSMA4	PSMB1	P20618	842
PSMA4	PSMB9	P28065	747
PSMA4	PSMB3	P31147	741
PSMA4	PSMB6	P28072	709
PSMA4	PSMB2	P31145	700
PSMA4	PSMB4	P28070	697
PSMA4	PSMC2	P35998	684
PSMA4	PSMB7	Q99436	662
PSMA4	PSMC3	P17980	661
PSMA4	HYKK	A2RU49	655
PSMA4	PSMG1	O95456	636

IntAct

Human interaction partners of PSMA4 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

23 partners by confidence:

Partner	Interaction type	MIscore	Records
PSMA1	physical association	0.920	1
PSMA2	physical association	0.910	5
PSMA7	physical association	0.880	10
PSMB7	association	0.790	1
PSMA5	physical association	0.740	1
POMP	physical association	0.680	1
ATXN1	physical association	0.670	6
HTT	physical association	0.670	3
PSMA6	physical association	0.670	2
HIF1A	association	0.580	4
PSMA3	physical association	0.570	4
IKZF1	physical association	0.560	6
CARD9	physical association	0.560	3
GOLGA2	physical association	0.560	3
REL	physical association	0.560	3
TFIP11	physical association	0.560	3
TRIM38	physical association	0.560	3
PSME4	association	0.530	1
PSMG2	association	0.530	1
NFKBIA	physical association	0.400	1
PSMD1	association	0.350	1
UBB	association	0.350	1
TRAF6	physical association	0.000	1

BioGRID (876 interactions; top human partners by supporting records in a sample of 600 records): PSMA2 (Co-fractionation; 12 records), PSMA1 (Affinity Capture-MS; 10 records), PSMA7 (Co-fractionation; 9 records), PSMB1 (Co-fractionation; 7 records), PSMB2 (Co-fractionation; 7 records), PSMB4 (Affinity Capture-MS; 7 records), PSMB7 (Affinity Capture-MS; 7 records), PSMC5 (Co-fractionation; 7 records), PSMA5 (Co-fractionation; 6 records), PSMB3 (Co-fractionation; 6 records), PSMC1 (Co-fractionation; 6 records), PSMD14 (Co-fractionation; 6 records), PSMA3 (Co-fractionation; 5 records), PSMD2 (Co-fractionation; 5 records), PSMD4 (Co-fractionation; 5 records)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
PSMA4	“form complex”	“26S Proteasome”	binding

Protein complexes (CORUM) (5)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

5 complexes by size:

Complex	Subunits	Members
★ PA700-20S-PA28 complex	36	PSMA5, PSMD4, PSMD6, PSMD9, PSME1, PSME2, PSMD11, PSMB1, PSMB4, PSMC1, PSMA3, PSMB5, PSMD10, PSMA7, PSMC5, PSMD14, PSMD7, PSMA6, PSMB6, PSMD12, PSMD3, PSMD1, PSMA4, PSMB7, PSMC3, PSMC4, PSMC6, PSMD8, PSMB3, PSMC2, PSMD13, PSMA1, PSMA2, PSMB2, PSMD2, PSMD5
★ 26S proteasome	22	PSMA2, PSMA7, PSMB3, PSMA5, PSMA6, PSMB4, PSMB7, PSMC1, PSMC2, PSMC5, PSMC6, PSMA3, PSMB2, PSMB5, PSMC3, PSMC4, PSMD13, PSMD4, PSMA1, PSMA4, PSMB1, PSMB6
★ PA28-20S proteasome	16	PSMA6, PSMB5, PSMA2, PSMA7, PSMB2, PSMB4, PSME1, PSMA3, PSMB1, PSMB3, PSMB6, PSME2, PSMA1, PSMA5, PSMB7, PSMA4
★ PA28gamma-20S proteasome	15	PSMB5, PSMA5, PSMB1, PSMB4, PSME3, PSMA1, PSMA4, PSMA7, PSMB2, PSMA2, PSMA3, PSMB6, PSMB7, PSMA6, PSMB3
★ 20S proteasome	14	PSMA5, PSMA6, PSMB1, PSMB6, PSMA2, PSMA7, PSMB2, PSMB3, PSMB4, PSMB5, PSMB7, PSMA1, PSMA3, PSMA4

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 23 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
Antigen processing: Ub, ATP-independent proteasomal degradation	7	181.7×	1e-14
Regulation of activated PAK-2p34 by proteasome mediated degradation	9	114.0×	6e-16
Vpu mediated degradation of CD4	9	108.7×	7e-16
Autodegradation of the E3 ubiquitin ligase COP1	9	108.7×	7e-16
Ubiquitin-dependent degradation of Cyclin D	9	108.7×	7e-16
Vif-mediated degradation of APOBEC3G	9	103.8×	9e-16
Proteasome assembly	11	102.0×	1e-18
AUF1 (hnRNP D0) binds and destabilizes mRNA	9	101.6×	9e-16

GO biological processes:

GO term	Partners	Fold	FDR
proteasome-mediated ubiquitin-dependent protein catabolic process	9	20.4×	6e-08
positive regulation of canonical NF-kappaB signal transduction	5	15.8×	1e-03

Disease & clinical

Genetic variants

Variant evidence for PSMA4: 24 ClinVar records (0 pathogenic / likely pathogenic); 1 PharmGKB clinical annotation; 28 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	11
Likely benign	1
Benign	1

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 44 predictions of 552):

Position(s)	Effect	Δscore	Sites
15:78542220–78542221	donor_loss	1.0000	5
15:78544867–78544868	acceptor_loss	1.0000	6
15:78544958–78544959	donor_loss	1.0000	4
15:78545626	acceptor_gain	1.0000
15:78545631–78545632	acceptor_gain	1.0000	2
15:78545632–78545633	acceptor_loss	1.0000	5
15:78545765–78545766	donor_loss	1.0000	4
15:78546573–78546574	acceptor_loss	1.0000	6
15:78546699–78546700	donor_loss	1.0000	5
15:78541903–78541904	acceptor_loss	0.9900	6

AlphaMissense

1,055 missense substitutions predicted likely pathogenic (of 1,709 scored), across 219 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M25	9	0.884	0.988
D82	8	1.000	1.000
D6	8	0.999	1.000
F12	8	0.997	1.000
D140	8	0.991	0.998
D151	8	0.989	0.998
S153	8	0.985	1.000
N155	8	0.982	1.000
D202	8	0.978	0.998
F130	8	0.975	1.000
D116	8	0.948	0.994
D57	8	0.937	0.981
H30	8	0.890	0.988
E22	7	0.998	1.000
W159	7	0.998	1.000
Q20	7	0.991	1.000
E26	7	0.991	0.998
Q119	7	0.984	0.999
W139	7	0.984	0.995
Q123	7	0.983	0.997

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

6 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (validation)	unfavorable	5.3e-05
Lung Adenocarcinoma (TCGA)	unfavorable	8.55e-05
Pancreatic Adenocarcinoma (TCGA)	unfavorable	0.00048
Head and Neck Squamous Cell Carcinoma (TCGA)	unfavorable	0.000752
Lung Squamous Cell Carcinoma (TCGA)	favorable	0.00081
Kidney Renal Papillary Cell Carcinoma (TCGA)	unfavorable	0.000988

Disease associations

OMIM: gene MIM:176846 | disease phenotypes:

GWAS associations

28 associations:

Study	Trait	p-value
GCST012020_134	Serum metabolite levels	7e-66
GCST000170_1	Lung cancer	5e-20
GCST000172_1	Lung cancer	3e-18
GCST002539_37	Schizophrenia	2e-13
GCST006803_49	Schizophrenia	3e-12
GCST003262_1037	Post bronchodilator FEV1	5e-11
GCST004946_68	Schizophrenia	2e-10
GCST007637_9	Diffusing capacity of carbon monoxide	3e-10
GCST004521_99	Autism spectrum disorder or schizophrenia	5e-10
GCST002798_1	Pulmonary artery enlargement and chronic obstructive pulmonary disease	7e-10
GCST011702_7	Smoking cessation	9e-10
GCST003262_1075	Post bronchodilator FEV1	1e-9
GCST003775_1	Lung cancer	1e-9
GCST011020_8	Intracranial aneurysm	1e-9
GCST003262_1096	Post bronchodilator FEV1	3e-9
GCST003262_277	Post bronchodilator FEV1	4e-9
GCST000233_1	Lung cancer	1e-8
GCST003262_431	Post bronchodilator FEV1	1e-8
GCST004521_197	Autism spectrum disorder or schizophrenia	2e-8
GCST003264_900	Post bronchodilator FEV1/FVC ratio	3e-8
GCST011021_13	Intracranial aneurysm	3e-8
GCST001476_19	Response to tocilizumab in rheumatoid arthritis	4e-8
GCST004521_68	Autism spectrum disorder or schizophrenia	5e-8
GCST003264_508	Post bronchodilator FEV1/FVC ratio	3e-7
GCST003264_858	Post bronchodilator FEV1/FVC ratio	3e-7
GCST003264_1319	Post bronchodilator FEV1/FVC ratio	5e-7
GCST003262_227	Post bronchodilator FEV1	6e-7
GCST003264_669	Post bronchodilator FEV1/FVC ratio	2e-6

EFO canonical traits (from GWAS)

5 canonical traits:

EFO ID	Trait name
EFO:0006347	pulmonary artery enlargement
EFO:0004314	forced expiratory volume
EFO:0004713	FEV/FVC ratio
EFO:0009369	diffusing capacity of the lung for carbon monoxide
EFO:0004319	smoking cessation

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2364701 (PROTEIN COMPLEX), CHEMBL3831201 (PROTEIN COMPLEX GROUP), CHEMBL6066933 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 44,921 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

6 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL325041	BORTEZOMIB	4	13,415
CHEMBL451887	CARFILZOMIB	4	13,156
CHEMBL2141296	IXAZOMIB	3	6,376
CHEMBL371405	MARIZOMIB	3	7,520
CHEMBL1232461	MOLIBRESIB	2	1,601
CHEMBL2103884	OPROZOMIB	2	2,853

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

1 annotations by evidence level (1 strongest → 4):

Variant	Association	Level	Drugs	Phenotypes
rs57064725	Metabolism/PK	3	cotinine	Tobacco Use Disorder

PharmGKB variants

1 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs57064725	PSMA4	3	0.00	1	cotinine

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

1 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs57064725	cotinine	Metabolism/PK	Allele A is associated with increased concentrations of cotinine in people with Tobacco Use Disorder as compared to allele C.	PMID:26833182

Binding affinities (BindingDB)

149 measured of 188 human assays (190 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Cinnabaramide G	IC50	0.6 nM
CHEMBL4102324	IC50	0.92 nM
CINNABARAMIDE A	IC50	1 nM
MARIZOMIB	IC50	1.3 nM
CHEMBL4460323	IC50	1.5 nM
Alpha-ketocarbonyl derivative	IC50	2 nM
(R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-6-carboxamido)propanamido)butylboronic acid	IC50	2.4 nM
CHEMBL4517600	IC50	2.4 nM
CHEMBL4587036	IC50	2.5 nM
CHEMBL4444107	IC50	3.4 nM
CHEMBL5197285	IC50	3.4 nM
CHEMBL4541038	IC50	3.6 nM
CHEMBL4547405	IC50	3.9 nM
CHEMBL5171225	IC50	4 nM
CHEMBL4581126	IC50	4.3 nM
CHEMBL4542373	IC50	4.6 nM
CHEMBL4558648	IC50	4.6 nM
CHEMBL4467618	IC50	4.8 nM
CHEMBL5186240	IC50	5.2 nM
Alpha-ketocarbonyl derivative	IC50	6 nM
Cinnabaramide F	IC50	6 nM
CHEMBL4447701	IC50	6.4 nM
CHEMBL4435814	IC50	6.4 nM
CHEMBL4436430	IC50	6.5 nM
CHEMBL432281	IC50	7 nM
CHEMBL5202627	IC50	7 nM
CHEMBL5208573	IC50	7.2 nM
CHEMBL4559271	IC50	7.7 nM
CHEMBL5172645	IC50	8.1 nM
CHEMBL5179570	IC50	8.4 nM
CHEMBL5209077	IC50	8.6 nM
CHEMBL5173459	IC50	8.9 nM
CHEMBL5188065	IC50	9.3 nM
CHEMBL5196378	IC50	9.3 nM
CHEMBL4572638	IC50	9.4 nM
CHEMBL5201055	IC50	9.4 nM
CHEMBL4441018	IC50	9.5 nM
Cinnabaramide C	IC50	12 nM
TP-103	IC50	14 nM
CHEMBL4578081	IC50	14 nM
MLN2238	IC50	15 nM
CHEMBL4443333	IC50	15 nM
CHEMBL4864661	IC50	16 nM
CHEMBL4875208	IC50	16 nM
CHEMBL4557130	IC50	17 nM
CHEMBL27225	IC50	18 nM
TP-108	IC50	18 nM
CHEMBL2114122	IC50	20 nM
TP-109	IC50	20 nM
CHEMBL5173758	IC50	20 nM

ChEMBL bioactivities

315 potent at pChembl≥5 of 341 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.22	IC50	0.6	nM	CINNABARAMIDE G
9.22	Ki	0.6	nM	CHEMBL5624541
9.22	Ki	0.6	nM	BORTEZOMIB
9.04	IC50	0.92	nM	CHEMBL4102324
9.00	IC50	1	nM	CINNABARAMIDE A
8.89	IC50	1.3	nM	MARIZOMIB
8.82	IC50	1.5	nM	CHEMBL4460323
8.70	IC50	2	nM	CHEMBL307387
8.66	IC50	2.2	nM	CHEMBL5419917
8.62	IC50	2.4	nM	CHEMBL4517600
8.62	IC50	2.4	nM	BORTEZOMIB
8.62	IC50	2.4	nM	CHEMBL5413513
8.60	IC50	2.5	nM	CHEMBL4587036
8.59	IC50	2.56	nM	BORTEZOMIB
8.57	IC50	2.7	nM	CHEMBL3237863
8.57	IC50	2.7	nM	CHEMBL5394365
8.52	IC50	3	nM	BORTEZOMIB
8.47	IC50	3.4	nM	CHEMBL4444107
8.47	IC50	3.4	nM	CHEMBL6143686
8.46	IC50	3.43	nM	CHEMBL5197285
8.44	IC50	3.6	nM	CHEMBL4541038
8.41	IC50	3.9	nM	CHEMBL3237862
8.41	IC50	3.9	nM	CHEMBL4547405
8.40	IC50	4	nM	CHEMBL5406440
8.39	IC50	4.1	nM	CHEMBL3237864
8.39	IC50	4.1	nM	CHEMBL3237867
8.39	IC50	4.03	nM	CHEMBL5171225
8.37	IC50	4.28	nM	CHEMBL4581126
8.34	IC50	4.6	nM	CHEMBL4542373
8.34	IC50	4.6	nM	CHEMBL4558648
8.32	IC50	4.8	nM	CHEMBL3237873
8.32	IC50	4.8	nM	CHEMBL4467618
8.30	IC50	5	nM	CHEMBL5398681
8.29	IC50	5.1	nM	CHEMBL3237865
8.29	IC50	5.15	nM	CHEMBL5186240
8.28	IC50	5.2	nM	CHEMBL5429323
8.28	IC50	5.2	nM	CHEMBL5431451
8.25	IC50	5.6	nM	CHEMBL5423645
8.24	IC50	5.7	nM	CHEMBL3237866
8.24	IC50	5.7	nM	CHEMBL3237860
8.23	IC50	5.9	nM	CHEMBL3237868
8.22	IC50	6	nM	CINNABARAMIDE F
8.22	IC50	6	nM	CHEMBL5412037
8.22	IC50	6	nM	CHEMBL74336
8.20	IC50	6.3	nM	CHEMBL5440712
8.19	IC50	6.4	nM	CHEMBL4447701
8.19	IC50	6.4	nM	CHEMBL4435814
8.19	IC50	6.5	nM	CHEMBL4436430
8.19	IC50	6.5	nM	IXAZOMIB
8.16	IC50	6.91	nM	BORTEZOMIB

PubChem BioAssay actives

314 with measured affinity, of 1003 total; 50 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
methyl (2R)-2-acetamido-3-[(2R,3S,4R)-2-[(S)-[(1S)-cyclohex-2-en-1-yl]-hydroxymethyl]-4-hexyl-3-hydroxy-3-methyl-5-oxopyrrolidine-2-carbonyl]sulfanylpropanoate	277357: Inhibition of human 20S proteasome	ic50	0.0006	uM
[(1R)-1-[[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]-(pyrazine-2-carbonyl)amino]-3-methylbutyl]boronic acid	2131634: Binding affinity to 20s proteosome (unknown origin) assessed as inhibition constant	ki	0.0006	uM
Bortezomib	2205591: Inhibition of 20S proteasome (unknown origin)	ki	0.0006	uM
1-N-[(2S)-1-[[(2S)-1-[(2-chlorophenyl)methylamino]-1-oxo-4-phenylbutan-2-yl]amino]-4-(2,2-dimethylpropylamino)-1,4-dioxobutan-2-yl]-4-N-(1,3-thiazol-2-yl)piperidine-1,4-dicarboxamide	1903224: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-Leu Leu-Val-Tyr-AMC as substrate preincubated for 15 mins followed by substrate addition measured by fluorescence assay	ic50	0.0009	uM
(1R,4R,5S)-1-[(S)-[(1S)-cyclohex-2-en-1-yl]-hydroxymethyl]-4-hexyl-5-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione	277357: Inhibition of human 20S proteasome	ic50	0.0010	uM
(1R,4R,5S)-4-(2-chloroethyl)-1-[(S)-[(1S)-cyclohex-2-en-1-yl]-hydroxymethyl]-5-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione	1853759: Inhibition of 20S proteasome (unknown origin) by fluorescence based assay	ic50	0.0013	uM
1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]-4-N-(1,3-thiazol-2-yl)piperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0015	uM
N-[5-[[amino(nitramido)methylidene]amino]-1-[(4-methyl-1-oxopentan-2-yl)amino]-1-oxopentan-2-yl]-2-cyclopentyl-10-(1,3-dioxoisoindol-2-yl)decanamide	3028: Compound was evaluated for inhibitory activity against 20S proteasome from human liver and brain	ic50	0.0020	uM
4-[(1R)-1-[[2-[[2,5-bis(trifluoromethyl)benzoyl]amino]-3-cyclopropylpropanoyl]amino]-3-methylbutyl]-2-methyl-3,5,10-trioxa-4-boratricyclo[5.2.1.02,6]decane-8-carboxylic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0022	uM
4-N-(4-benzoylphenyl)-1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]piperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0024	uM
4-[(1R)-1-[[2-[[2,5-bis(trifluoromethyl)benzoyl]amino]-2-cyclopentylacetyl]amino]-3-methylbutyl]-2-methyl-3,5,10-trioxa-4-boratricyclo[5.2.1.02,6]decane-8-carboxylic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0024	uM
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]-5-carbamimidamidopentanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-N-[(2S)-5-carbamimidamido-1-[[(2S)-5-carbamimidamido-1-[[(2S)-5-carbamimidamido-1-[[2-[[2-[[2-[[(2S)-4-methyl-1-[[(2S)-4-methyl-1-[[(2S)-4-methyl-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-2-oxoethyl]amino]-2-oxoethyl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]pentanediamide	1559513: Inhibition of human 20S proteasome using Suc-LLVY-AMC as substrate measured every 5 mins for 120 mins by fluorescence based assay	ic50	0.0025	uM
4-[(1R)-1-[[2-[[2,5-bis(trifluoromethyl)benzoyl]amino]-2-cyclopropylacetyl]amino]-3-methylbutyl]-2-methyl-3,5,10-trioxa-4-boratricyclo[5.2.1.02,6]decane-8-carboxylic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0027	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0027	uM
4-N-(4-fluorophenyl)-1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]piperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0034	uM
1-N-[(2S)-4-(2,2-dimethylpropylamino)-1,4-dioxo-1-[[(2S)-1-oxo-4-phenyl-1-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]amino]butan-2-yl]amino]butan-2-yl]-4-N-methyl-4-N-(1,3-thiazol-2-yl)piperidine-1,4-dicarboxamide	1903224: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-Leu Leu-Val-Tyr-AMC as substrate preincubated for 15 mins followed by substrate addition measured by fluorescence assay	ic50	0.0034	uM
4-methyl-N-[(2R)-1-[[(2R)-4-methyl-1-[(2S)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]-4-phenylbutanoyl]amino]pentanamide	2236585: Activation of 26s proteosome (unknown origin)	ic50	0.0034	uM
1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]-4-N-pyridin-3-ylpiperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0036	uM
4-N-(1,3-benzothiazol-2-yl)-1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]piperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0039	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[3-phenylmethoxy-2-(phenylmethoxymethyl)propyl]butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0039	uM
[(1R)-1-[[2-[(2,5-dibromobenzoyl)amino]acetyl]amino]-3-methylbutyl]boronic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0040	uM
1-N-[(2S)-4-(2,2-dimethylpropylamino)-1,4-dioxo-1-[[(2S)-1-oxo-4-phenyl-1-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]amino]butan-2-yl]amino]butan-2-yl]-4-N-pyridin-3-ylpiperidine-1,4-dicarboxamide	1903224: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-Leu Leu-Val-Tyr-AMC as substrate preincubated for 15 mins followed by substrate addition measured by fluorescence assay	ic50	0.0040	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[5-phenylmethoxy-4-(phenylmethoxymethyl)pentyl]butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0041	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[5-phenylmethoxy-4-(phenylmethoxymethyl)pentyl]pentanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0041	uM
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]-5-carbamimidamidopentanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-N-[(2S)-5-carbamimidamido-1-[[(2S)-5-carbamimidamido-1-[[(2S)-5-carbamimidamido-1-[[2-[[2-[[2-[[(2S)-3-(4-hydroxyphenyl)-1-[[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-2-oxoethyl]amino]-2-oxoethyl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]pentanediamide	1559513: Inhibition of human 20S proteasome using Suc-LLVY-AMC as substrate measured every 5 mins for 120 mins by fluorescence based assay	ic50	0.0043	uM
1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]-4-N-(1,3,4-thiadiazol-2-yl)piperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0046	uM
4-N-(4-chlorophenyl)-1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]piperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0046	uM
4-N-(4-methoxyphenyl)-1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]piperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0048	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-(4-phenylmethoxybutyl)butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0048	uM
[(1R)-1-[[2-[[2,5-bis(trifluoromethyl)benzoyl]amino]-3-cyclopropylpropanoyl]amino]-3-methylbutyl]boronic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0050	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[3-phenylmethoxy-2-(phenylmethoxymethyl)propyl]pentanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0051	uM
(2S)-N’-(2,2-dimethylpropyl)-2-[[4-[methyl(pyridine-3-carbonyl)amino]piperidine-1-carbonyl]amino]-N-[(2S)-1-oxo-4-phenyl-1-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]amino]butan-2-yl]butanediamide	1903224: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-Leu Leu-Val-Tyr-AMC as substrate preincubated for 15 mins followed by substrate addition measured by fluorescence assay	ic50	0.0052	uM
4-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-2-methyl-3,5,10-trioxa-4-boratricyclo[5.2.1.02,6]decane-8-carboxylic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0052	uM
[(1R)-1-[[2-[[2,5-bis(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-methylbutyl]boronic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0052	uM
[(1R)-1-[[2-[[2,5-bis(trifluoromethyl)benzoyl]amino]-2-cyclopropylacetyl]amino]-3-methylbutyl]boronic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0056	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]pentanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0057	uM
benzyl N-[(2S)-1-[[(2R)-1-[(1R,2S)-2-[[(2R,3S)-3-[(2S)-butan-2-yl]-4-oxooxetane-2-carbonyl]amino]cyclopropyl]-4-phenylbutan-2-yl]amino]-1-oxopropan-2-yl]carbamate	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0057	uM
(2S)-2-[(2,5-dichlorobenzoyl)amino]-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0059	uM
(2R)-2-acetamido-3-[(2R,3S,4R)-2-[(S)-[(1S)-cyclohex-2-en-1-yl]-hydroxymethyl]-4-hexyl-3-hydroxy-3-methyl-5-oxopyrrolidine-2-carbonyl]sulfanylpropanoic acid	277357: Inhibition of human 20S proteasome	ic50	0.0060	uM
[(1R)-1-[[2-[[2,5-bis(trifluoromethyl)benzoyl]amino]-2-cyclopentylacetyl]amino]-3-methylbutyl]boronic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0060	uM
N-[5-[[amino(nitramido)methylidene]amino]-1-[(4-methyl-1-oxopentan-2-yl)amino]-1-oxopentan-2-yl]-10-cyano-2-cyclopentyldecanamide	3028: Compound was evaluated for inhibitory activity against 20S proteasome from human liver and brain	ic50	0.0060	uM
4-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-3,5,10-trioxa-4-boratricyclo[5.2.1.02,6]decane-8-carboxylic acid	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0063	uM
1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]-4-N-(1,2-oxazol-3-yl)piperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0064	uM
(2S)-2-[[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-4-methyl-N-[(2S)-1-[[(2S)-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]pentanamide	1559513: Inhibition of human 20S proteasome using Suc-LLVY-AMC as substrate measured every 5 mins for 120 mins by fluorescence based assay	ic50	0.0064	uM
1-N-[(2S)-4-methyl-1-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopentan-2-yl]-4-N-pyrazin-2-ylpiperidine-1,4-dicarboxamide	1624025: Inhibition of human 20S proteasome preincubated for 15 mins followed by substrate addition	ic50	0.0065	uM
Ixazomib	2033891: Inhibition of human 20S proteasome chymotrypsin-like activity using Suc-Leu-Leu-Val-Tyr-AMC as fluorogenic peptide pre-incubated for 10 mins with compound followed by substrate addition for 60 mins by spectrofluorimetric analysis	ic50	0.0065	uM
4-N-(4-chlorophenyl)-1-N-[(2S)-4-(2,2-dimethylpropylamino)-1,4-dioxo-1-[[(2S)-1-oxo-4-phenyl-1-[[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]amino]butan-2-yl]amino]butan-2-yl]-4-N-methylpiperidine-1,4-dicarboxamide	1903224: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-Leu Leu-Val-Tyr-AMC as substrate preincubated for 15 mins followed by substrate addition measured by fluorescence assay	ic50	0.0069	uM
(2S)-N-[(2S,3R,4R)-3-hydroxy-5-[[(2S)-1-[(2-hydroxy-4-methoxyphenyl)methylamino]-3-methyl-1-oxobutan-2-yl]amino]-5-oxo-1-phenyl-4-[(3,4,5-trimethoxyphenyl)methylamino]pentan-2-yl]-3,3-dimethyl-2-[(2-naphthalen-1-ylacetyl)amino]butanamide	3027: Tested in vitro for inhibition of chymotrypsin like activity of purified human 20S proteasome	ic50	0.0070	uM
Carfilzomib	1770085: Inhibition of human 20S proteasome chymotrypsin-like activity in human RPMI-8226 cells using Suc-LLVY-AMC as fluorogenic substrate incubated for 3 hrs by fluorescence assay	ic50	0.0070	uM
(2S)-2-[[(2S)-3-(4-hydroxyphenyl)-2-[(2-naphthalen-1-ylacetyl)amino]propanoyl]amino]-N-[1-(4-hydroxyphenyl)-3-oxopropan-2-yl]-3-methylbutanamide	248827: Inhibitory concentration to inhibit chymotrypsin-like activity of 20S proteasome prepared from human leukemia HL-60 cells was determined	ic50	0.0070	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Arsenic	decreases expression, increases abundance, affects cotreatment, increases expression	3
Particulate Matter	decreases expression, increases abundance, affects expression	3
bisphenol A	decreases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
uranyl acetate	affects expression	1
arsenite	affects binding, increases reaction	1
nickel sulfate	decreases expression	1
epigallocatechin gallate	increases expression	1
arsenic trichloride	decreases expression, increases abundance	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases expression	1
CD 437	decreases expression	1
K 7174	decreases expression	1
poly(propyleneimine)	increases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	decreases expression	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
picoxystrobin	increases expression	1
bisphenol AF	increases expression	1
Air Pollutants, Occupational	decreases expression	1
Vehicle Emissions	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Doxorubicin	increases metabolic processing	1
Environmental Pollutants	affects expression	1

ChEMBL screening assays

175 unique, capped per target: 166 binding, 6 admet, 3 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3222879	Binding	Inhibition of human 20S proteasome using Suc-LLVY-AMC as substrate preincubated for 30 mins followed by substrate addition measured after 90 mins by fluorescence assay	Oxathiazole-2-one derivative of bortezomib: Synthesis, stability and proteasome inhibition activity — *Medchemcomm*
CHEMBL4736581	ADMET	Inhibition of human 20S proteasome stably expressed in HEK293 cells at 5 to 50 uM using succinyl-LLVY-AMC as substrate preincubated for 30 mins followed by substrate addition and measured at 3 mins interval for 30 mins by fluorescence assay	A covalent p97/VCP ATPase inhibitor can overcome resistance to CB-5083 and NMS-873 in colorectal cancer cells. — *Eur J Med Chem*
CHEMBL834792	Functional	Inhibitory concentration to inhibit trypsin-like activity of 20S proteasome from human leukemia HL-60 cells was determined	Structure-based design of derivatives of tyropeptin A as the potent and selective inhibitors of mammalian 20S proteasome. — *Bioorg Med Chem Lett*

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for PSMA4 across ~30M SureChEMBL compounds — explore on Sugi Predict.