UCHL1

Summary

UCHL1 (ubiquitin C-terminal hydrolase L1, HGNC:12513) is a protein-coding gene on chromosome 4p13, encoding Ubiquitin carboxyl-terminal hydrolase isozyme L1 (P09936). Deubiquitinase that plays a role in the regulation of several processes such as maintenance of synaptic function, cardiac function, inflammatory response or osteoclastogenesis.

The protein encoded by this gene belongs to the peptidase C12 family. This enzyme is a thiol protease that hydrolyzes a peptide bond at the C-terminal glycine of ubiquitin. This gene is specifically expressed in the neurons and in cells of the diffuse neuroendocrine system. Mutations in this gene may be associated with Parkinson disease.

Source: NCBI Gene 7345 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary spastic paraplegia (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 237 total — 12 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 85
• Druggable target: yes
• MANE Select transcript: NM_004181

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12513
Approved symbol	UCHL1
Name	ubiquitin C-terminal hydrolase L1
Location	4p13
Locus type	gene with protein product
Status	Approved
Aliases	PGP9.5, Uch-L1, UCHL-1
Ensembl gene	ENSG00000154277
Ensembl biotype	protein_coding
OMIM	191342
Entrez	7345

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 12 protein_coding, 4 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000284440, ENST00000381760, ENST00000472501, ENST00000503431, ENST00000504818, ENST00000505232, ENST00000508768, ENST00000510566, ENST00000512419, ENST00000512788, ENST00000514764, ENST00000514924, ENST00000875269, ENST00000875270, ENST00000926175, ENST00000926176, ENST00000961377, ENST00000961378, ENST00000961379

RefSeq mRNA: 1 — MANE Select: NM_004181 NM_004181

CCDS: CCDS3462

Canonical transcript exons

ENST00000284440 — 9 exons

Exon	Start	End
ENSE00001014976	41256928	41257009
ENSE00001700600	41257115	41257126
ENSE00003492110	41263225	41263291
ENSE00003551797	41261715	41261800
ENSE00003569503	41260647	41260797
ENSE00003584567	41264103	41264161
ENSE00003591655	41261876	41261923
ENSE00003615749	41267987	41268455
ENSE00003788913	41257609	41257737

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 99.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 248.2111 / max 2861.0143, expressed in 1423 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47450	246.0768	1418
47458	0.6979	392
47451	0.4594	194
47452	0.4048	243
47457	0.3906	222
47459	0.1816	76

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pons	UBERON:0000988	99.88	gold quality
right frontal lobe	UBERON:0002810	99.84	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.82	gold quality
dorsal root ganglion	UBERON:0000044	99.81	gold quality
prefrontal cortex	UBERON:0000451	99.81	gold quality
cortical plate	UBERON:0005343	99.79	gold quality
substantia nigra pars compacta	UBERON:0001965	99.73	gold quality
superior vestibular nucleus	UBERON:0007227	99.73	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.72	gold quality
hypothalamus	UBERON:0001898	99.70	gold quality
frontal cortex	UBERON:0001870	99.68	gold quality
nucleus accumbens	UBERON:0001882	99.68	gold quality
adenohypophysis	UBERON:0002196	99.63	gold quality
Brodmann (1909) area 10	UBERON:0013541	99.63	gold quality
amygdala	UBERON:0001876	99.62	gold quality
frontal pole	UBERON:0002795	99.61	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.60	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.60	gold quality
pituitary gland	UBERON:0000007	99.59	gold quality
neocortex	UBERON:0001950	99.56	gold quality
orbitofrontal cortex	UBERON:0004167	99.56	gold quality
cingulate cortex	UBERON:0003027	99.55	gold quality
ganglionic eminence	UBERON:0004023	99.55	gold quality
caudate nucleus	UBERON:0001873	99.54	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.54	gold quality
anterior cingulate cortex	UBERON:0009835	99.54	gold quality
cerebral cortex	UBERON:0000956	99.51	gold quality
forebrain	UBERON:0001890	99.48	gold quality
telencephalon	UBERON:0001893	99.46	gold quality
Ammon’s horn	UBERON:0001954	99.45	gold quality

Single-cell (SCXA)

Detected in 23 experiment(s), a significant marker in 18.

Experiment	Marker?	Max mean expression
E-HCAD-25	yes	6832.17
E-MTAB-11121	yes	1474.13
E-HCAD-5	yes	1218.04
E-HCAD-31	yes	1081.12
E-MTAB-9388	yes	1076.40
E-GEOD-81547	yes	1013.04
E-HCAD-10	yes	714.20
E-MTAB-10662	yes	522.89
E-GEOD-83139	yes	466.48
E-GEOD-98556	yes	216.45
E-HCAD-35	yes	50.49
E-GEOD-81608	yes	20.74
E-MTAB-5061	yes	19.82
E-ENAD-27	yes	14.30
E-CURD-114	yes	12.60

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CREB1, CTNNBL1, HNF4A, MYBL2, NFKB, RELA, REST, SPI1, TP53, YY1

miRNA regulators (miRDB)

44 targeting UCHL1, 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-4455	100.00	65.48	1587
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-6757-3P	99.63	66.88	1089
HSA-MIR-6126	99.62	68.09	996
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-497-3P	99.61	69.71	1990
HSA-MIR-1224-5P	99.48	65.59	803
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-7702	99.06	65.95	698
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-214-3P	98.71	68.12	2128
HSA-MIR-761	98.71	68.07	2051
HSA-MIR-6728-3P	98.63	67.63	1534
HSA-MIR-9500	98.62	66.54	1845
HSA-MIR-4463	98.56	66.05	1071

Literature-anchored findings (GeneRIF, showing 40)

• PGP9.5 colocalizes with JAB1 and p27(Kip1)in the nucleus (PMID:12082530)
• 2D fingerprinting & mass spectrometry reveal specific targets of protein oxidation in Alzheimer’s disease brain, including ubiquitin carboxy-terminal hydrolase L-1, suggesting involvement of oxidatively modified proteins in neurodegeneration. (PMID:12160938)
• exhibits a second, dimerization-dependent, ubiquityl ligase activity; a polymorphic variant of UCH-L1 that is associated with decreased Parkinson’s disease risk has reduced ligase activity but comparable hydrolase activity as the wild-type enzyme (PMID:12408865)
• Alterations in alpha-helical content and hydrolase activity of parkinsonism-associated ubiquitin carboxyl-terminal hydrolase L1 variants. (PMID:12705903)
• The identification of pathogenic mutations in the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) has elucidated the ubiquitin proteasome system (UPS) and its potential role as a causal pathway in Parkinson’s disease (PD). (PMID:12784265)
• ubiquitin carboxyl-terminal hydrolase L1 is oxidatively modified and downregulated in idiopathic Parkinson’s and Alzheimer’s diseases (PMID:14722078)
• A statistically significant inverse genetic association of the UCHL1 S18Y variant has been found confirming UCHL1 as a susceptibility gene for Parkinson’s disease. (PMID:15048890)
• Data show that impairment of UCH-L1 ubiquitin hydrolase activity may be an important contributor to neurodegeneration associated with accumulation of ubiquitinated proteins and inflammation. (PMID:15194490)
• study expands the immunophenotype of granular cell tumor (S100, CD68, protein gene product 9.5, and inhibin-alpha) regardless of location and supports a neural origin (PMID:15214825)
• Important issues regarding UCHL-1 and its role in Parkinson disease remain inconclusive, especially regarding the pathogenicity of the mendelian I93M mutation (PMID:15221445)
• UCH-L1 accumulation is likely to play a pathological role in inclusion formation in Parkinson’s disease (PMID:15228595)
• The relative amount of nerve fibers in rat prostate, detected by PGP 9.5, does not change during postnatal development (PMID:15716245)
• Analyses confirmed a significant inverse association of the UCHL1 S18Y polymorphism with PD overall (OR=0.18, 95% CI=0.05-0.64, p=0.002, recessive model) and in several strata. (PMID:15882803)
• Excess UCH-L1 influenced the distribution of proliferating cell nuclear antigen and suggests a specific role for UCH-L1 in the processes of mitotic proliferation and differentiation of spermatogonial stem cells during spermatogenesis. (PMID:16177983)
• multiple functional balance is closely linked to the intermolecular interactions between the UCH-L1 monomer and the final dimeric configuration (PMID:16316632)
• functional relevance of S18Y polymorphism of UCHL1 in 946 Caucasian Huntington’s disease patients; allelic variation on locus S18Y is responsible for 1.1% of the variance in the HD age-at-onset, & the rare Y allele is associated with younger-aged cases (PMID:16369839)
• These results suggest that UCH-L1 spatially mediates and enhances neurogenesis in the embryonic brain by regulating progenitor cell morphology. (PMID:16371654)
• Together, these observations show reduced UCHL-1 expression as a contributory factor in the abnormal protein aggregation in DLB, and points UCHL-1 as a putative therapeutic target in the treatment of DLB. (PMID:16380264)
• Down-regulation of UCH-L1 is associated with Uterine Cervical Neoplasms (PMID:16402389)
• the three-dimensional structure of human UCH-L1 at 2.4-A resolution by x-ray crystallography was determined. (PMID:16537382)
• allele and YY genotype of S18Y in the UCH-L1 gene may have a protective effect against sporadic AD in female subjects, probably due to altering the function of UCH-L1 and the interactions among different risk factors. (PMID:16626667)
• Silencing of the UCHL1 gene is associated with colorectal and ovarian cancers (PMID:16642472)
• Exposure to chronic hyperglycemia following 90% partial pancreatectomy leads to reduced Uch-L1 expression (PMID:16644676)
• UCH-L1 deficiency and impairment of the ubiquitin-dependent protein degradation pathway can contribute to the increased cell death observed in many lysosomal storage disorders. (PMID:16888648)
• UCHL1 is involved in the degradation of unwanted, misfolded, or damaged proteins and is overexpressed in >50% of lung cancers, its overexpression in chronic smokers may represent an early event in the transformation from normal epithelium to malignancy. (PMID:17108109)
• Ubiquitin side chains critical for establishing the Michaelis complex and enabling catalysis were identified, and features of this complex that differ between UCH-L1 and a homologue, UCH-L3 are revealed. (PMID:17144664)
• UCHL1 expression seems to be associated with the metastatic phenotype of renal cell carcinoma (PMID:17200335)
• The tyrosine variant was significantly inversely associated with PD (P=0.049) and with a low age of onset (50 years) (P=0.017) in the case-control material, supporting the hypothesis of a protective function. (PMID:17287139)
• UCH-L1 is not expressed specifically in dopamine neurons. The abundant expression of UCH-L1 in peripheral neurons may be of relevance for the spectrum of symptoms in different forms of Parkinson’s. (PMID:17599367)
• UCHL1 may partially attenuate vascular remodeling through inhibition of NF-kappaB activity. (PMID:17690318)
• Mutations of the UCH-L1 gene and alterations of its proteins’ activity have been found to associate with several neurodegenerative disorders: Parkinson’s, Huntington’s and Alzheimer’s diseases [review] (PMID:17925890)
• The finding that PGP 9.5 and ChA are expressed by PC-3 and DU145 cells suggests that these cells may have been derived from metastatic adenocarcinomas which had undergone neuroendocrine differentiation or expression occurred as a result of cell culture. (PMID:17929277)
• Abberant promoter methylation is the primary mechanism of transcriptional silencing of the UCHL1 gene and methylation of UCHL1 gene promoter increases in the progression of colorectal neoplasms. (PMID:17994469)
• UCHL1 S18Y is not a major susceptibility factor for PD in white populations although we cannot exclude the possibility that the S18Y variant exerts weak effects on risk, particularly in early-onset disease. (PMID:18093156)
• The carbonyl modification of UCH-L1 and subsequent abnormal interactions of carbonyl-modified UCH-L1 with multiple proteins, including tubulin, constitute one of the causes of sporadic Parkinson’s disease. (PMID:18250096)
• Mice that lack of UCH-L1 in neurons decrease in their ubiquitin-proteasome system function and enhanced sensitivity to oxidative stress. (PMID:18411255)
• UCH-L1 expression seems to be associated with the metastatic potential of HRCC SN12C cell clones. (PMID:18494032)
• methylation of the UCHL1 gene is associated with a poor prognosis in patients with renal cell carcinoma (PMID:18499164)
• PGP9.5 is a tumor suppressor gene that is inactivated by promoter methylation or gene deletion in several types of human cancers. (PMID:18512240)
• The C allele in exon 3 of UCH-L1 gene might be one of the risk factors for Parkinson’s disease in Shanghai Han Nationality, but the polymorphisms of C/T in exon 4 showed no association with the onset of PD. (PMID:18543214)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	uchl1	ENSDARG00000026871
mus_musculus	Uchl1	ENSMUSG00000029223
rattus_norvegicus	Uchl1	ENSRNOG00000002343
drosophila_melanogaster	Uch	FBGN0010288
caenorhabditis_elegans		WBGENE00006721
caenorhabditis_elegans		WBGENE00006722
caenorhabditis_elegans		WBGENE00006723

Paralogs (3): UCHL5 (ENSG00000116750), UCHL3 (ENSG00000118939), BAP1 (ENSG00000163930)

Protein

Protein identifiers

Ubiquitin carboxyl-terminal hydrolase isozyme L1 — P09936 (reviewed: P09936)

Alternative names: Neuron cytoplasmic protein 9.5, PGP 9.5, Ubiquitin thioesterase L1

All UniProt accessions (7): P09936, D6R956, D6R974, D6RE83, D6RF53, D6RJD9, V9HW74

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinase that plays a role in the regulation of several processes such as maintenance of synaptic function, cardiac function, inflammatory response or osteoclastogenesis. Abrogates the ubiquitination of multiple proteins including WWTR1/TAZ, EGFR, HIF1A and beta-site amyloid precursor protein cleaving enzyme 1/BACE1. In addition, recognizes and hydrolyzes a peptide bond at the C-terminal glycine of ubiquitin to maintain a stable pool of monoubiquitin that is a key requirement for the ubiquitin-proteasome and the autophagy-lysosome pathways. Regulates amyloid precursor protein/APP processing by promoting BACE1 degradation resulting in decreased amyloid beta production. Plays a role in the immune response by regulating the ability of MHC I molecules to reach cross-presentation compartments competent for generating Ag-MHC I complexes. Mediates the ‘Lys-48’-linked deubiquitination of the transcriptional coactivator WWTR1/TAZ leading to its stabilization and inhibition of osteoclastogenesis. Deubiquitinates and stabilizes epidermal growth factor receptor EGFR to prevent its degradation and to activate its downstream mediators. Modulates oxidative activity in skeletal muscle by regulating key mitochondrial oxidative proteins. Enhances the activity of hypoxia-inducible factor 1-alpha/HIF1A by abrogateing its VHL E3 ligase-mediated ubiquitination and consequently inhibiting its degradation.

Subunit / interactions. Monomer. Homodimer. Interacts with SNCA. Interacts with COPS5.

Subcellular location. Cytoplasm. Endoplasmic reticulum membrane.

Tissue specificity. Found in neuronal cell bodies and processes throughout the neocortex (at protein level). Expressed in neurons and cells of the diffuse neuroendocrine system and their tumors. Weakly expressed in ovary. Down-regulated in brains from Parkinson disease and Alzheimer disease patients.

Post-translational modifications. O-glycosylated.

Disease relevance. Parkinson disease 5 (PARK5) [MIM:613643] A complex neurodegenerative disorder with manifestations ranging from typical Parkinson disease to dementia with Lewy bodies. Clinical features include parkinsonian symptoms (resting tremor, rigidity, postural instability and bradykinesia), dementia, diffuse Lewy body pathology, autonomic dysfunction, hallucinations and paranoia. Disease susceptibility is associated with variants affecting the gene represented in this entry. Spastic paraplegia 79A, autosomal dominant, with ataxia (SPG79A) [MIM:620221] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG79A is a slowly progressive form characterized by late-onset spastic ataxia, neuropathy, and often optic atrophy. The disease is caused by variants affecting the gene represented in this entry. Spastic paraplegia 79B, autosomal recessive (SPG79B) [MIM:615491] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG79B is characterized by childhood onset blindness, cerebellar ataxia, nystagmus, dorsal column dysfunction, and spasticity with upper motor neuron dysfunction. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Oxidation of Met-1, Met-6, Met-12, Met-124 and Met-179 to methionine sulfoxide, and oxidation of Cys-220 to cysteine sulfonic acid have been observed in brains from Alzheimer disease (AD) and Parkinson disease (PD) patients. In AD, UCHL1 was found to be associated with neurofibrillary tangles. In contrast to UCHL3, does not hydrolyze a peptide bond at the C-terminal glycine of NEDD8.

Similarity. Belongs to the peptidase C12 family.

Isoforms (3)

UniProt ID	Names	Canonical?
P09936-1	1	yes
P09936-2	2
P09936-3	3

RefSeq proteins (1): NP_004172* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001578	Peptidase_C12_UCH	Domain
IPR036959	Peptidase_C12_UCH_sf	Homologous_superfamily
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR057254	UCH_AS	Conserved_site

Pfam: PF01088

Enzyme classification (BRENDA):

• EC 3.4.19.12 — ubiquitinyl hydrolase 1 (BRENDA: 30 organisms, 328 substrates, 173 inhibitors, 70 Km, 58 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
UBIQUITIN-7-AMIDO-4-METHYLCOUMARIN	—	7
DABCYL-FKKKGGGDVKE-EDANS	0.0142–0.0616	6
UBIQUITIN 7-AMIDO-4-METHYLCOUMARIN	—	5
UBIQUITIN ETHYL ESTER	0.0006–0.03	5
DABCYL-FRLKGGAPIKGV-EDANS	0.0048–0.0217	3
UBIQUITIN-W-G75A	0.0001–0.0004	2
UBIQUITIN-W-G76A	0.0011–0.002	2
UBIQUITIN-W-H68A	0.0005	2
UBIQUITIN-W-I44A	0.0003–0.0004	2
UBIQUITIN-W-K11A	0.0011–0.0023	2
UBIQUITIN-W-K48A	0.0003–0.0007	2
UBIQUITIN-W-K63A	0.0004–0.0008	2
UBIQUITIN-W-K6A	0.0009–0.0014	2
UBIQUITIN-W-L71A	0.008–0.0198	2
UBIQUITIN-W-L73A	0.0058–0.0104	2

UniProt features (61 total): sequence variant 10, helix 10, strand 9, site 8, mutagenesis site 7, modified residue 4, turn 3, splice variant 2, region of interest 2, active site 2, chain 1, propeptide 1, lipid moiety-binding region 1, domain 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
8EDE	X-RAY DIFFRACTION	1.8
8XI7	X-RAY DIFFRACTION	1.95
9O4M	X-RAY DIFFRACTION	2
8DY8	X-RAY DIFFRACTION	2.1
4JKJ	X-RAY DIFFRACTION	2.15
8PW1	X-RAY DIFFRACTION	2.2
7ZM0	X-RAY DIFFRACTION	2.24
4DM9	X-RAY DIFFRACTION	2.35
2ETL	X-RAY DIFFRACTION	2.4
3IFW	X-RAY DIFFRACTION	2.4
3IRT	X-RAY DIFFRACTION	2.8
3KVF	X-RAY DIFFRACTION	2.8
3KW5	X-RAY DIFFRACTION	2.83
2LEN	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P09936-F1	93.58	0.79

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 (10): 84 (transition state stabilizer); 124 (susceptible to oxidation); 176 (important for enzyme activity); 179 (susceptible to oxidation); 220 (susceptible to oxidation); 90 (nucleophile); 161 (proton donor); 1 (susceptible to oxidation); 6 (susceptible to oxidation); 12 (susceptible to oxidation)

Post-translational modifications (5): 1, 125, 220, 1, 1

Mutagenesis-validated functional residues (7):

Position	Phenotype
73	no effect on enzymatic parameters.
90	abolishes enzymatic activity.
97	2-fold increase in affinity for ubiquitin ethyl ester, slight reduction in enzymatic activity.
161	10000-fold decrease in enzymatic activity; no change in affinity for ubiquitin ethyl ester.
161	abolishes enzymatic activity.
176	6-fold decrease in affinity for ubiquitin ethyl ester; 97.5% decrease in enzymatic activity.
204	almost complete loss of activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5689603	UCH proteinases

MSigDB gene sets: 498 (showing top): TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, E2F_Q4_01, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, GOBP_AXO_DENDRITIC_TRANSPORT, GOBP_BEHAVIOR, BASSO_B_LYMPHOCYTE_NETWORK, GOBP_ADULT_BEHAVIOR, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_DN, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_NEUROGENESIS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, TGACCTY_ERR1_Q2, GOBP_ORGANELLE_TRANSPORT_ALONG_MICROTUBULE

GO Biological Process (18): male germ cell proliferation (GO:0002176), response to ischemia (GO:0002931), axon target recognition (GO:0007412), adult walking behavior (GO:0007628), regulation of macroautophagy (GO:0016241), protein deubiquitination (GO:0016579), axonal transport of mitochondrion (GO:0019896), protein catabolic process (GO:0030163), eating behavior (GO:0042755), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), negative regulation of MAPK cascade (GO:0043409), positive regulation of glycolytic process (GO:0045821), neuromuscular process (GO:0050905), muscle cell development (GO:0055001), cellular response to xenobiotic stimulus (GO:0071466), proteolysis (GO:0006508), ubiquitin-dependent protein catabolic process (GO:0006511), axonogenesis (GO:0007409)

GO Molecular Function (12): cysteine-type endopeptidase activity (GO:0004197), cysteine-type deubiquitinase activity (GO:0004843), omega peptidase activity (GO:0008242), signaling receptor inhibitor activity (GO:0030547), ubiquitin protein ligase binding (GO:0031625), alpha-2A adrenergic receptor binding (GO:0031694), ribosome binding (GO:0043022), ubiquitin binding (GO:0043130), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787)

GO Cellular Component (11): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), neuronal cell body (GO:0043025), neuron projection terminus (GO:0044306), axon cytoplasm (GO:1904115), endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), membrane (GO:0016020), axon (GO:0030424)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Deubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
protein metabolic process	2
cysteine-type peptidase activity	2
peptidase activity	2
cytoplasm	2
neuron projection	2
germ cell proliferation	1
response to stress	1
cell communication	1
axonogenesis	1
adult locomotory behavior	1
walking behavior	1
regulation of autophagy	1
macroautophagy	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
mitochondrion transport along microtubule	1
axonal transport	1
axon cytoplasm	1
macromolecule catabolic process	1
feeding behavior	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
MAPK cascade	1
regulation of MAPK cascade	1
negative regulation of intracellular signal transduction	1
glycolytic process	1
regulation of glycolytic process	1
positive regulation of purine nucleotide catabolic process	1
positive regulation of carbohydrate metabolic process	1
positive regulation of ATP metabolic process	1
nervous system process	1
muscle cell differentiation	1
cell development	1
response to xenobiotic stimulus	1
cellular response to chemical stimulus	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1

Protein interactions and networks

STRING

3486 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UCHL1	SNCA	P37840	940
UCHL1	PRKN	O60260	914
UCHL1	HSPA8	P11142	848
UCHL1	PARK7	Q99497	823
UCHL1	ZUP1	Q96AP4	815
UCHL1	USP14	P54578	811
UCHL1	ENO2	P09104	801
UCHL1	GIGYF2	Q6Y7W6	791
UCHL1	PINK1	Q9BXM7	789
UCHL1	LRRK2	Q5S007	785
UCHL1	FBXO7	Q9Y3I1	776
UCHL1	NAALADL1	Q9UQQ1	765
UCHL1	CDKN2A	P42771	734
UCHL1	HSP90AA1	P07900	725
UCHL1	HTRA2	O43464	721

IntAct

218 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
APP	UCHL1	psi-mi:“MI:0915”(physical association)	0.700
UCHL1	APP	psi-mi:“MI:0915”(physical association)	0.700
TRAF6	UCHL1	psi-mi:“MI:0915”(physical association)	0.680
UCHL1	ATG5	psi-mi:“MI:0915”(physical association)	0.680
UCHL1	IKBKE	psi-mi:“MI:0915”(physical association)	0.680
UCHL1	EIF1B	psi-mi:“MI:0915”(physical association)	0.680
UCHL1	NEDD8	psi-mi:“MI:0915”(physical association)	0.670
UCHL1	CBX1	psi-mi:“MI:0915”(physical association)	0.670
UCHL1	USP21	psi-mi:“MI:0915”(physical association)	0.670
UCHL1		psi-mi:“MI:0407”(direct interaction)	0.650
UCHL1		psi-mi:“MI:0570”(protein cleavage)	0.650

BioGRID (386): UCHL1 (Affinity Capture-MS), PLA2G2A (Biochemical Activity), UCHL1 (Reconstituted Complex), PARK2 (Affinity Capture-Western), UCHL1 (Affinity Capture-Western), UCHL1 (Biochemical Activity), UCHL1 (Affinity Capture-MS), UCHL1 (Reconstituted Complex), UCHL1 (Affinity Capture-MS), UCHL1 (Two-hybrid), UCHL1 (Affinity Capture-Western), UBC (Biochemical Activity), UCHL1 (Affinity Capture-MS), UCHL1 (Affinity Capture-MS), UCHL1 (Affinity Capture-MS)

ESM2 similar proteins: A0FKG7, A0JN39, A5PK00, D2SW95, O04482, O35815, O60763, P09936, P11029, P11497, P23356, P23514, P23727, P26450, P27986, P41541, P50103, P53618, P54252, Q00981, Q06AT3, Q13085, Q28559, Q2TBG8, Q5M939, Q5R4J9, Q5R685, Q5R922, Q5SWU9, Q5ZIA5, Q60HC8, Q63787, Q6P0H6, Q6SEG5, Q80UM3, Q86VN1, Q8GYA6, Q8K2H2, Q8RWF0, Q9BXJ9

Diamond homologs: A1L2G3, A2VDM8, B0W2R4, B3MIV9, B3NPV7, B4GAM2, B4HST0, B4JW98, B4KT51, B4LQ24, B4P6P6, B4QHH0, C4A0D9, D3ZHS6, O04482, P09936, Q00981, Q06AT3, Q09444, Q17N72, Q291J4, Q52L14, Q54N38, Q5F3N6, Q66JB6, Q7K5N4, Q92560, Q99PU7, Q9FFF2, Q9R0P9, Q9UUB6, Q9WUP7, Q9XSJ0, Q9Y5K5, P50103, Q60HC8, Q9GM50, Q8IIJ6, O01391, P15374

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
UCHL1	“up-regulates quantity”	UBC	cleavage

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
Signaling by PTK6	5	36.2×	4e-05
Signaling by Non-Receptor Tyrosine Kinases	5	36.2×	4e-05
Telomere Extension By Telomerase	5	30.4×	9e-05
G1 Phase	5	26.2×	1e-04
Cyclin E associated events during G1/S transition	5	19.0×	4e-04
Cyclin A:Cdk2-associated events at S phase entry	5	17.7×	5e-04
G1/S Transition	5	15.5×	8e-04
Cyclin D associated events in G1	5	15.5×	8e-04

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of cell cycle	5	15.6×	7e-03
negative regulation of epithelial cell proliferation	5	15.6×	7e-03
protein import into nucleus	6	9.3×	7e-03
regulation of cell cycle	8	6.4×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	8
Uncertain significance	81
Likely benign	87
Benign	25

Top pathogenic / likely-pathogenic (20)

Variant ID	HGVS	Classification
1447591	NM_004181.5(UCHL1):c.30del (p.Glu11fs)	Pathogenic
1699069	NM_004181.5(UCHL1):c.250C>T (p.Gln84Ter)	Pathogenic
2443800	NM_004181.5(UCHL1):c.73C>T (p.Gln25Ter)	Pathogenic
2443801	NM_004181.5(UCHL1):c.95_98dup (p.Leu34fs)	Pathogenic
2578416	NM_004181.5(UCHL1):c.260_261dup (p.Asn88fs)	Pathogenic
3068443	NM_004181.5(UCHL1):c.366_367del (p.Lys123fs)	Pathogenic
3650800	NM_004181.5(UCHL1):c.418C>T (p.Gln140Ter)	Pathogenic
3697686	NM_004181.5(UCHL1):c.346C>T (p.Gln116Ter)	Pathogenic
375650	NM_004181.5(UCHL1):c.647C>A (p.Ala216Asp)	Pathogenic
3767302	NM_004181.5(UCHL1):c.30dup (p.Glu11fs)	Pathogenic
4528900	NM_004181.5(UCHL1):c.360_361dup (p.Thr121fs)	Pathogenic
88635	NM_004181.5(UCHL1):c.20A>C (p.Glu7Ala)	Pathogenic
1445694	NM_004181.5(UCHL1):c.460-2A>G	Likely pathogenic
3338080	NM_004181.5(UCHL1):c.629_631del (p.Gly210del)	Likely pathogenic
3345701	NM_004181.5(UCHL1):c.24del (p.Asn9fs)	Likely pathogenic
3776083	NM_004181.5(UCHL1):c.583A>T (p.Lys195Ter)	Likely pathogenic
3780777	NM_004181.5(UCHL1):c.325+1G>A	Likely pathogenic
3898760	NM_004181.5(UCHL1):c.44_45+2del	Likely pathogenic
493394	NM_004181.5(UCHL1):c.385_388dup (p.Ala130fs)	Likely pathogenic
522605	NM_004181.5(UCHL1):c.459+2T>C	Likely pathogenic

SpliceAI

1078 predictions. Top by Δscore:

Variant	Effect	Δscore
4:41257127:G:GG	donor_gain	1.0000
4:41260639:A:AG	acceptor_gain	1.0000
4:41260645:A:AG	acceptor_gain	1.0000
4:41260645:AGCAT:A	acceptor_gain	1.0000
4:41260646:G:GA	acceptor_gain	1.0000
4:41260646:GC:G	acceptor_gain	1.0000
4:41260646:GCA:G	acceptor_gain	1.0000
4:41260646:GCAT:G	acceptor_gain	1.0000
4:41260646:GCATG:G	acceptor_gain	1.0000
4:41260798:G:GA	donor_loss	1.0000
4:41260799:T:A	donor_loss	1.0000
4:41261712:A:AG	acceptor_gain	1.0000
4:41261712:AAGAG:A	acceptor_gain	1.0000
4:41261713:A:G	acceptor_gain	1.0000
4:41261714:G:GG	acceptor_gain	1.0000
4:41261992:G:GT	donor_gain	1.0000
4:41262047:A:T	donor_gain	1.0000
4:41263221:TTAGG:T	acceptor_loss	1.0000
4:41263224:G:GA	acceptor_loss	1.0000
4:41263224:GGTA:G	acceptor_gain	1.0000
4:41263289:TTGGT:T	donor_loss	1.0000
4:41263292:G:GA	donor_loss	1.0000
4:41263293:T:A	donor_loss	1.0000
4:41264172:G:GT	donor_gain	1.0000
4:41264173:A:T	donor_gain	1.0000
4:41264210:C:G	donor_gain	1.0000
4:41257011:T:G	donor_loss	0.9900
4:41257733:CCCAG:C	donor_loss	0.9900
4:41257734:CCAG:C	donor_loss	0.9900
4:41257735:CAGGT:C	donor_loss	0.9900

AlphaMissense

1467 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:41268041:T:C	F214L	0.999
4:41268043:C:A	F214L	0.999
4:41268043:C:G	F214L	0.999
4:41263246:C:G	H161D	0.998
4:41260724:G:C	Q84H	0.997
4:41260724:G:T	Q84H	0.997
4:41260713:T:C	F81L	0.996
4:41260715:C:A	F81L	0.996
4:41260715:C:G	F81L	0.996
4:41260741:G:A	C90Y	0.996
4:41260744:G:A	G91D	0.996
4:41260753:G:A	G94E	0.996
4:41263248:T:A	H161Q	0.996
4:41263248:T:G	H161Q	0.996
4:41264106:G:A	G177E	0.996
4:41268011:T:C	F204L	0.996
4:41268013:C:A	F204L	0.996
4:41268013:C:G	F204L	0.996
4:41257720:T:C	F53L	0.995
4:41257722:T:A	F53L	0.995
4:41257722:T:G	F53L	0.995
4:41263249:T:C	F162L	0.995
4:41263251:T:A	F162L	0.995
4:41263251:T:G	F162L	0.995
4:41263291:G:C	D176H	0.995
4:41260761:C:G	H97D	0.994
4:41260764:G:C	A98P	0.994
4:41263246:C:A	H161N	0.994
4:41263289:T:C	L175P	0.993
4:41264103:A:T	D176V	0.993

dbSNP variants (sampled 300 via entrez): RS1000356470 (4:41263415 C>G), RS10004654 (4:41263076 T>C), RS1000478164 (4:41257441 G>A,C), RS1000559278 (4:41256749 G>A,C), RS10005744 (4:41264786 A>G), RS1000654787 (4:41261052 G>A), RS1000723042 (4:41267463 G>C,T), RS1000815265 (4:41258745 C>A,T), RS1001162445 (4:41255187 A>G), RS1001509081 (4:41255497 C>T), RS1001812836 (4:41260271 T>A,G), RS1001994690 (4:41265333 C>A,T), RS1002328766 (4:41266939 G>A), RS1002450703 (4:41260563 C>T), RS1002926989 (4:41265583 G>T)

Disease associations

OMIM: gene MIM:191342 | disease phenotypes: MIM:615491, MIM:613643, MIM:620221

GenCC curated gene-disease

Disease	Classification	Inheritance
early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome	Strong	Autosomal recessive
spastic paraplegia 79A, autosomal dominant, with ataxia	Strong	Autosomal dominant
Parkinson disease 5, autosomal dominant, susceptibility to	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
hereditary spastic paraplegia	Moderate	AR
hereditary spastic paraplegia	Definitive	AD

Mondo (4): early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome (MONDO:0014209), Parkinson disease 5, autosomal dominant, susceptibility to (MONDO:0013340), spastic paraplegia 79A, autosomal dominant, with ataxia (MONDO:0859363), optic nerve disorder (MONDO:0002135)

Orphanet (2): Early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome (Orphanet:352654), Young-onset Parkinson disease (Orphanet:2828)

HPO phenotypes

85 total (30 of 85 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000529	Progressive visual loss
HP:0000545	Myopia
HP:0000551	Color vision defect
HP:0000572	Visual loss
HP:0000597	Ophthalmoparesis
HP:0000640	Gaze-evoked nystagmus
HP:0000648	Optic atrophy
HP:0000649	Abnormality of visual evoked potentials
HP:0000651	Diplopia
HP:0000713	Agitation
HP:0000716	Depression
HP:0000726	Dementia
HP:0000727	Frontal lobe dementia
HP:0000736	Short attention span
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0000768	Pectus carinatum
HP:0001152	Saccadic smooth pursuit interruptions
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001258	Spastic paraplegia
HP:0001260	Dysarthria
HP:0001272	Cerebellar atrophy
HP:0001310	Dysmetria
HP:0001332	Dystonia
HP:0001337	Tremor

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000477_57	Cognitive performance	9.000000e-06
GCST009391_302	Metabolite levels	4.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0003926	neuropsychological test
EFO:0010429	triacylglycerol 56:2 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009901	Optic Nerve Diseases	C10.292.700; C11.640

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6159 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — C12: Ubiquitin C-terminal hydrolase

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

Ligand	Action	Affinity	Parameter
LDN-91946	Inhibition	5.64	pKi

Binding affinities (BindingDB)

11 measured of 15 human assays (16 total across all organisms); most potent 11 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2S)-2-[4-(1H-pyrazol-4-yl)-2,3-dihydroindole-1-carbonyl]pyrrolidine-1-carbonitrile	IC50	550 nM	US-10669234: Cyanopyrrolidines as dub inhibitors for the treatment of cancer
(2S)-2-[4-(5-methyl-1H-pyrazol-4-yl)-2,3-dihydroindole-1-carbonyl]pyrrolidine-1-carbonitrile	IC50	550 nM	US-10669234: Cyanopyrrolidines as dub inhibitors for the treatment of cancer
tert-butyl (2S)-2-[4-(5-cyano-1H-pyrazol-4-yl)-2,3-dihydroindole-1-carbonyl]pyrrolidine-1-carboxylate	IC50	550 nM	US-10669234: Cyanopyrrolidines as dub inhibitors for the treatment of cancer
1-[(2S)-1-cyanopyrrolidine-2-carbonyl]-N-methyl-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2,3-dihydroindole-6-carboxamide	IC50	550 nM	US-10669234: Cyanopyrrolidines as dub inhibitors for the treatment of cancer
(2S)-2-[4-[5-(trifluoromethyl)-1H-pyrazol-4-yl]-2,3-dihydropyrrolo[3,2-c]pyridine-1-carbonyl]pyrrolidine-1-carbonitrile	IC50	550 nM	US-10669234: Cyanopyrrolidines as dub inhibitors for the treatment of cancer
5-Chloro-1-[(2,5-dichlorophenyl)methyl]-1H-indole-2,3-dione 3-(O-acetyloxime)	IC50	2500 nM
tert-butyl (2S)-2-[6-(1H-imidazol-2-yl)-4-phenyl-2,3-dihydroindole-1-carbonyl]pyrrolidine-1-carboxylate	IC50	5500 nM	US-10669234: Cyanopyrrolidines as dub inhibitors for the treatment of cancer
tert-butyl (2S)-2-[4-phenyl-6-(1H-1,2,4-triazol-5-yl)-2,3-dihydroindole-1-carbonyl]pyrrolidine-1-carboxylate	IC50	5500 nM	US-10669234: Cyanopyrrolidines as dub inhibitors for the treatment of cancer
(2S)-2-[6-(5-methyl-1H-1,2,4-triazol-3-yl)-4-phenyl-2,3-dihydroindole-1-carbonyl]pyrrolidine-1-carbonitrile	IC50	5500 nM	US-10669234: Cyanopyrrolidines as dub inhibitors for the treatment of cancer
Acetyl Isogambogic Acid	IC50	11100 nM
Mangiferin	IC50	56600 nM

ChEMBL bioactivities

213 potent at pChembl≥5 of 274 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.30	IC50	50	nM	CHEMBL5589657
6.97	Kd	106.1	nM	CHEMBL5653589
6.97	ED50	106.1	nM	CHEMBL5653589
6.64	IC50	230	nM	8RK64
6.64	IC50	230	nM	CHEMBL5191704
6.40	Ki	400	nM	CHEMBL3407553
6.26	IC50	550	nM	CHEMBL5169766
6.26	IC50	550	nM	CHEMBL5911248
6.26	IC50	550	nM	CHEMBL5849835
6.26	IC50	550	nM	CHEMBL6052414
6.26	IC50	550	nM	CHEMBL5810685
6.26	IC50	550	nM	CHEMBL5969062
6.26	IC50	550	nM	CHEMBL5861974
6.26	IC50	550	nM	CHEMBL5892743
6.26	IC50	550	nM	CHEMBL5910482
6.26	IC50	550	nM	CHEMBL5956399
6.26	IC50	550	nM	CHEMBL5808821
6.26	IC50	550	nM	CHEMBL5925527
6.26	IC50	550	nM	CHEMBL5861286
6.26	IC50	550	nM	CHEMBL5891981
6.26	IC50	550	nM	CHEMBL5772195
6.26	IC50	550	nM	CHEMBL5912328
6.26	IC50	550	nM	CHEMBL5899249
6.26	IC50	550	nM	CHEMBL6047438
6.26	IC50	550	nM	CHEMBL5987946
6.26	IC50	550	nM	CHEMBL6002948
6.26	IC50	550	nM	CHEMBL5763097
6.26	IC50	550	nM	CHEMBL5770951
6.26	IC50	550	nM	CHEMBL5986802
6.26	IC50	550	nM	CHEMBL5942977
6.26	IC50	550	nM	CHEMBL6004041
6.26	IC50	550	nM	CHEMBL5881405
6.26	IC50	550	nM	CHEMBL5828190
6.26	IC50	550	nM	CHEMBL4791650
6.26	IC50	550	nM	CHEMBL6041153
6.24	IC50	580	nM	CHEMBL5169766
6.22	IC50	600	nM	CHEMBL5192316
6.17	IC50	670	nM	CHEMBL5175498
6.17	IC50	670	nM	CHEMBL5565231
6.13	Ki	740	nM	CHEMBL540117
6.09	IC50	810	nM	CHEMBL1241672
6.08	IC50	830	nM	CHEMBL5192316
6.06	IC50	880	nM	CHEMBL1241673
6.04	Ki	910	nM	CHEMBL553923
6.03	IC50	940	nM	CHEMBL1241765
5.92	Ki	1200	nM	CHEMBL536998
5.85	Ki	1400	nM	CHEMBL536764
5.82	Ki	1500	nM	CHEMBL537224
5.70	Ki	2000	nM	CHEMBL537225
5.64	Ki	2300	nM	CHEMBL1190585

PubChem BioAssay actives

39 with measured affinity, of 139 total; 32 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
(3S)-1-cyano-N-[1-[4-(pent-4-ynylcarbamoyl)phenyl]imidazol-4-yl]pyrrolidine-3-carboxamide	2112710: Inhibition of 6His-tagged human UCHL1 using Ub-Rh110Gly as fluorogenic substrate preincubated for 1 hr followed by substrate addition by plate reader analysis	ic50	0.0500	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149721: Binding affinity to human UCHL1 incubated for 45 mins by Kinobead based pull down assay	kd	0.1061	uM
1-cyano-N-(5-morpholin-4-yl-1,3-thiazol-2-yl)pyrrolidine-3-carboxamide	1871606: Inhibition of UCHL1 (unknown origin) using Ub-Rho-morpholine as substrate preincubated for 30 mins followed by substrate addition by fluorescence based assay	ic50	0.2300	uM
(3S)-N-[5-(2-azidoacetyl)-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridin-2-yl]-1-cyanopyrrolidine-3-carboxamide	1852163: Inhibition of UCHL1 (unknown origin) using Ub-AMC as substrate preincubated with enzyme for 1 hr followed by substrate addition and measured for 1 hr by fluorescence based analysis	ic50	0.2300	uM
[(Z)-[5-chloro-1-[(2,5-dichlorophenyl)methyl]-2-oxoindol-3-ylidene]amino] acetate	1558717: Competitive inhibition of UCHL1 in human H1299 cells using Ub-AMC substrate	ki	0.4000	uM
(3S)-1-cyano-N-(5-phenyl-1,3-thiazol-2-yl)pyrrolidine-3-carboxamide	1853539: Inhibition of FLAG-tagged UCHL1 (unknown origin) expressed in CAL-51 cells using HA-Ub-VME as substrate incubated for 30 mins by HTRF assay	ic50	0.5500	uM
(3S)-1-cyano-N-[5-(4-ethynylphenyl)-1,3-thiazol-2-yl]pyrrolidine-3-carboxamide	1853533: Inhibition of GST-tagged recombinant UCHL1 (unknown origin) using Ub-Lys-TAMRA as substrate incubated for 30 mins by fluorescence polarization assay	ic50	0.6000	uM
(2S)-2-[4-[5-(trifluoromethyl)-1H-pyrazol-4-yl]-2,3-dihydroindole-1-carbonyl]pyrrolidine-1-carbonitrile	2080113: Inhibition of recombinant wild type UCH-L1 (unknown origin) by fluorescence based analysis	ic50	0.6700	uM
2-[4-[5-(trifluoromethyl)-1H-pyrazol-4-yl]indole-1-carbonyl]pyrrolidine-1-carbonitrile	1871607: Inhibition of UCHL1 (unknown origin) using Ub-Rho as substrate preincubated for 30 mins followed by substrate addition	ic50	0.6700	uM
3-amino-2-(naphthalene-2-carbonyl)-6-oxo-7H-thieno[2,3-b]pyridine-5-carboxylic acid;hydrochloride	307538: Inhibition of UCHL1	ki	0.7400	uM
[(E)-[5-bromo-1-[(3,4-dichlorophenyl)methyl]-2-oxoindol-3-ylidene]amino] acetate	2080111: Inhibition of UCH-L1 (unknown origin) expressed in Escherichia coli BL21 (DE3)	ic50	0.8100	uM
[(E)-[5-bromo-1-[(2,5-dichlorophenyl)methyl]-2-oxoindol-3-ylidene]amino] acetate	506806: Inhibition of UCHL1 in human H1299 cells	ic50	0.8800	uM
3-amino-2-(4-methylbenzoyl)-6-oxo-7H-thieno[2,3-b]pyridine-5-carboxylic acid;hydrochloride	307538: Inhibition of UCHL1	ki	0.9100	uM
[(E)-[1-[(3,4-dichlorophenyl)methyl]-5-iodo-2-oxoindol-3-ylidene]amino] acetate	2080111: Inhibition of UCH-L1 (unknown origin) expressed in Escherichia coli BL21 (DE3)	ic50	0.9400	uM
(3S)-1-cyano-N-[1-[4-(1,3-dimethylindazol-6-yl)phenyl]imidazol-4-yl]pyrrolidine-3-carboxamide	2112710: Inhibition of 6His-tagged human UCHL1 using Ub-Rh110Gly as fluorogenic substrate preincubated for 1 hr followed by substrate addition by plate reader analysis	ic50	1.0000	uM
3-amino-2-(4-chlorobenzoyl)-6-oxo-7H-thieno[2,3-b]pyridine-5-carboxylic acid;hydrochloride	307538: Inhibition of UCHL1	ki	1.2000	uM
3-amino-2-(4-tert-butylbenzoyl)-6-oxo-7H-thieno[2,3-b]pyridine-5-carboxylic acid;hydrochloride	307538: Inhibition of UCHL1	ki	1.4000	uM
3-amino-2-(naphthalene-1-carbonyl)-6-oxo-7H-thieno[2,3-b]pyridine-5-carboxylic acid;hydrochloride	307538: Inhibition of UCHL1	ki	1.5000	uM
3-amino-2-(cyclohexanecarbonyl)-6-oxo-7H-thieno[2,3-b]pyridine-5-carboxylic acid;hydrochloride	307538: Inhibition of UCHL1	ki	2.0000	uM
3-amino-2-benzoyl-6-oxo-7H-thieno[2,3-b]pyridine-5-carboxylic acid	506808: Inhibition of UCHL1	ki	2.3000	uM
3-amino-2-benzoyl-6-oxo-7H-thieno[2,3-b]pyridine-5-carboxylic acid;hydrochloride	307538: Inhibition of UCHL1	ki	2.8000	uM
(E)-3-(6-bromo-2-pyridinyl)-2-cyano-N-[(1S)-1-phenylbutyl]prop-2-enamide	761491: Inhibition of UCH-L1 in human Z138 cells after 1 hr by immunoblotting analysis	ic50	3.0000	uM
3-amino-6-oxo-2-[4-(trifluoromethyl)benzoyl]-7H-thieno[2,3-b]pyridine-5-carboxylic acid;hydrochloride	307538: Inhibition of UCHL1	ki	3.6000	uM
N-[[4-(1-adamantylcarbamoyl)phenyl]methyl]-2-cyanopyrimidine-5-carboxamide	2112710: Inhibition of 6His-tagged human UCHL1 using Ub-Rh110Gly as fluorogenic substrate preincubated for 1 hr followed by substrate addition by plate reader analysis	ic50	4.2000	uM
3-amino-2-(2-methoxybenzoyl)-6-oxo-7H-thieno[2,3-b]pyridine-5-carboxylic acid;hydrochloride	307538: Inhibition of UCHL1	ki	5.3000	uM
(E)-4-[(2S,17S)-12-acetyloxy-8,21,21-trimethyl-5-(3-methylbut-2-enyl)-8-(4-methylpent-3-enyl)-14,18-dioxo-3,7,20-trioxahexacyclo[15.4.1.02,15.02,19.04,13.06,11]docosa-4,6(11),9,12,15-pentaen-19-yl]-2-methylbut-2-enoic acid	1794863: Fluorometric Ub-AMC Hydrolysis Assay from Article 10.1021/acschembio.7b00543: “Cell Lysate-Based AlphaLISA Deubiquitinase Assay Platform for Identification of Small Molecule Inhibitors.”	ic50	5.4000	uM
2-[4-[1-but-3-ynyl-3-(trifluoromethyl)pyrazol-4-yl]indole-1-carbonyl]pyrrolidine-1-carbonitrile	1871607: Inhibition of UCHL1 (unknown origin) using Ub-Rho as substrate preincubated for 30 mins followed by substrate addition	ic50	6.4000	uM
(2R,4aS,6aR,6aS,14aS,14bR)-10-hydroxy-2,4a,6a,6a,9,14a-hexamethyl-11-oxo-1,3,4,5,6,13,14,14b-octahydropicene-2-carboxylic acid	1794863: Fluorometric Ub-AMC Hydrolysis Assay from Article 10.1021/acschembio.7b00543: “Cell Lysate-Based AlphaLISA Deubiquitinase Assay Platform for Identification of Small Molecule Inhibitors.”	ic50	6.8000	uM
methyl (4S)-6-fluoro-4-[[(2S)-2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butyl]amino]propanoyl]amino]-5-oxohexanoate	2080114: Inhibition of His-tagged UCH-L1 (unknown origin) expressed in Escherichia coli BL21 (DE3) by fluorescence based analysis	ic50	7.7000	uM
methyl (4S)-4-[[(2S)-2-[[(2S)-2-[(4-ethynylphenyl)methoxycarbonylamino]-3-methylbutanoyl]amino]propanoyl]amino]-6-fluoro-5-oxohexanoate	2080114: Inhibition of His-tagged UCH-L1 (unknown origin) expressed in Escherichia coli BL21 (DE3) by fluorescence based analysis	ic50	7.7000	uM
1,3,6,7-tetrahydroxy-2-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyxanthen-9-one	1794863: Fluorometric Ub-AMC Hydrolysis Assay from Article 10.1021/acschembio.7b00543: “Cell Lysate-Based AlphaLISA Deubiquitinase Assay Platform for Identification of Small Molecule Inhibitors.”	ic50	8.9000	uM
3-amino-2-(2-methylbenzoyl)-6-oxo-7H-thieno[2,3-b]pyridine-5-carboxylic acid;hydrochloride	307538: Inhibition of UCHL1	ki	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	6
sodium arsenite	increases abundance, increases expression, decreases methylation, affects cotreatment	5
Cadmium Chloride	decreases expression, increases abundance, increases expression, decreases reaction, affects expression (+1 more)	5
methylmercuric chloride	increases expression, affects cotreatment	4
Decitabine	decreases reaction, increases abundance, increases expression, affects cotreatment, affects expression (+2 more)	4
Arsenic	affects cotreatment, increases abundance, increases expression	3
Tobacco Smoke Pollution	affects expression, increases expression	3
trichostatin A	affects cotreatment, affects expression, affects methylation, decreases expression, decreases reaction (+1 more)	2
mercuric bromide	affects cotreatment, increases expression	2
Acetaminophen	decreases expression, increases expression	2
Air Pollutants	decreases expression, increases expression, increases abundance	2
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Copper	affects cotreatment, increases abundance, increases expression	2
Doxorubicin	affects expression	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Smoke	decreases expression, increases expression	2
Cyclosporine	increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
tungsten carbide	affects cotreatment, increases expression	1
daidzein	affects cotreatment, decreases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	decreases expression	1
sodium arsenate	increases abundance, increases expression	1
polysaccharide-K	increases expression	1
arsenite	increases methylation, decreases expression	1
tobacco tar	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1

ChEMBL screening assays

66 unique, capped per target: 66 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1243699	Binding	Inhibition of UCHL1 in human H1299 cells	Mechanisms, biology and inhibitors of deubiquitinating enzymes. — Nat Chem Biol

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3KQ	Abcam HEK293T UCHL1 KO	Transformed cell line	Female
CVCL_D1UU	Abcam U-87MG UCHL1 KO	Cancer cell line	Male
CVCL_TW11	HAP1 UCHL1 (-) 1	Cancer cell line	Male
CVCL_TW12	HAP1 UCHL1 (-) 2	Cancer cell line	Male
CVCL_TW13	HAP1 UCHL1 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02382627	Not specified	TERMINATED	Choroidal Thickness in Optic Neuropathy