UBE2E1

Summary

UBE2E1 (ubiquitin conjugating enzyme E2 E1, HGNC:12477) is a protein-coding gene on chromosome 3p24.2, encoding Ubiquitin-conjugating enzyme E2 E1 (P51965). Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins.

The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation. Ubiquitination involves at least three classes of enzymes: ubiquitin-activating enzymes, or E1s, ubiquitin-conjugating enzymes, or E2s, and ubiquitin-protein ligases, or E3s. This gene encodes a member of the E2 ubiquitin-conjugating enzyme family. Three alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.

Source: NCBI Gene 7324 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 16 total
• Druggable target: yes
• MANE Select transcript: NM_003341

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12477
Approved symbol	UBE2E1
Name	ubiquitin conjugating enzyme E2 E1
Location	3p24.2
Locus type	gene with protein product
Status	Approved
Aliases	UbcH6
Ensembl gene	ENSG00000170142
Ensembl biotype	protein_coding
OMIM	602916
Entrez	7324

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 8 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000306627, ENST00000346855, ENST00000424381, ENST00000442670, ENST00000452012, ENST00000467766, ENST00000475680, ENST00000481622, ENST00000484048, ENST00000493707, ENST00000495141, ENST00000856464, ENST00000913090

RefSeq mRNA: 3 — MANE Select: NM_003341 NM_001202476, NM_003341, NM_182666

CCDS: CCDS2638, CCDS2639, CCDS56244

Canonical transcript exons

ENST00000306627 — 6 exons

Exon	Start	End
ENSE00001152768	23805955	23806088
ENSE00003581987	23807237	23807421
ENSE00003599439	23889112	23889259
ENSE00003700269	23811460	23811510
ENSE00003701917	23887567	23887699
ENSE00003893929	23890509	23891640

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 98.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 109.1638 / max 435.9345, expressed in 1826 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
35709	84.5500	1825
35710	12.4250	1786
35708	6.7417	1689
35717	2.4944	661
35713	1.2072	771
35712	0.9159	582
202704	0.3803	146
35711	0.2368	83
35716	0.1700	73
35715	0.0426	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	98.92	gold quality
oral cavity	UBERON:0000167	98.64	gold quality
ventricular zone	UBERON:0003053	98.62	gold quality
embryo	UBERON:0000922	98.59	gold quality
upper arm skin	UBERON:0004263	98.55	gold quality
superficial temporal artery	UBERON:0001614	98.51	gold quality
bronchial epithelial cell	CL:0002328	98.43	gold quality
mucosa of paranasal sinus	UBERON:0005030	98.41	gold quality
pons	UBERON:0000988	98.37	gold quality
lower lobe of lung	UBERON:0008949	98.33	gold quality
palpebral conjunctiva	UBERON:0001812	98.30	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.28	gold quality
esophagus squamous epithelium	UBERON:0006920	98.25	gold quality
epithelium of esophagus	UBERON:0001976	98.24	gold quality
pharyngeal mucosa	UBERON:0000355	98.23	gold quality
penis	UBERON:0000989	98.23	gold quality
epithelium of bronchus	UBERON:0002031	98.23	gold quality
mammary duct	UBERON:0001765	98.21	gold quality
bronchus	UBERON:0002185	98.21	gold quality
ganglionic eminence	UBERON:0004023	98.16	gold quality
mammalian vulva	UBERON:0000997	98.15	gold quality
calcaneal tendon	UBERON:0003701	98.14	gold quality
germinal epithelium of ovary	UBERON:0001304	98.13	gold quality
visceral pleura	UBERON:0002401	98.09	gold quality
gingiva	UBERON:0001828	98.08	gold quality
parietal pleura	UBERON:0002400	98.05	gold quality
seminal vesicle	UBERON:0000998	98.04	gold quality
diaphragm	UBERON:0001103	98.04	gold quality
gingival epithelium	UBERON:0001949	98.03	gold quality
epithelium of mammary gland	UBERON:0003244	98.02	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-6819	yes	264.17
E-ANND-3	yes	5.65
E-CURD-112	no	2.54

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

73 targeting UBE2E1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-548AV-5P	99.60	70.84	2107

Literature-anchored findings (GeneRIF, showing 13)

• isolated ISG15-modified and unmodified UbcH6 proteins, and analyzed their abilities to form thioester intermediates with ubiquitin (PMID:16428300)
• UbcH6 and ataxin-1 are E2-substrate cognate pairs in the ubiquitin-proteasome system. (PMID:18439907)
• UbcH6 modulates the transcriptional repression activity of ataxin-1 by modulating the degradation of ataxin-1. (PMID:18519031)
• E1 ligase of the proteasome is inhibitd by ziram and has a role in preventing dopaminergic cell damage (PMID:18818210)
• Ro52 has both cytoplasmic and nuclear substrates, and mediates ubiquitination through UBE2D1 in the cytoplasm and through UBE2E1 in the nucleus. (PMID:18845142)
• Smallangle X-ray scattering experiments show that the Lys63 tetra-Ub chain is dynamic in solution, adopting an ensemble of conformations that are more compact than the extended form in the crystal. (PMID:19664638)
• USP7 is critical in maintaining the steady state levels of UbE2E1 in cells. (PMID:23603909)
• Auto-ubiquitination of Ube2E1 is intramolecular.RNF4 enhances Ube2E1 self-ubiquitination. (PMID:25960396)
• UBE2E1 expression was adversely correlated with AML survival; UBE2E1 expression was negatively correlated with patients’ response to induction chemotherapy (PMID:27855695)
• study reveals that UbE2E1 is an in vivo E2 for the PRC1 ligase complex and thus plays an important role in the regulation of H2A Lys-119 monoubiquitination (PMID:28073915)
• IPO11 provides protection in another way, the researchers found. The transport receptor also shuttles UBE2E1, an enzyme necessary for PTEN ubiquitination, into the nucleus. Thanks to IPO11, normal cells keep all of their UBE2E1 in the nucleus, allowing PTEN to continue functioning in the cytoplasm. In cells lacking IPO11, UBE2E1 remains in the cytoplasm and promotes the destruction of PTEN. (PMID:28258103)
• OTUB1 depletion dramatically destabilizes the E2-conjugating enzyme UBE2E1 in both mouse and human OTUB1 knockout cell lines. (PMID:30282802)
• found that critical UBE2E1 residues involved in the capture of the TRIM21 substrate lysine are conserved in ubiquitin-conjugating E2s, whereas residues critical for SUMOylation are not conserved (PMID:31160341)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ube2e1	ENSMUSG00000021774
rattus_norvegicus	Ube2e1	ENSRNOG00000008794

Paralogs (12): UBE2D1 (ENSG00000072401), UBE2D4 (ENSG00000078967), UBE2D3 (ENSG00000109332), UBE2D2 (ENSG00000131508), UBE2Q2 (ENSG00000140367), UBE2L6 (ENSG00000156587), UBE2Q1 (ENSG00000160714), UBE2E3 (ENSG00000170035), UBE2E2 (ENSG00000182247), UBE2L3 (ENSG00000185651), UBE2QL1 (ENSG00000215218), UBE2L5 (ENSG00000236444)

Protein

Protein identifiers

Ubiquitin-conjugating enzyme E2 E1 — P51965 (reviewed: P51965)

Alternative names: (E3-independent) E2 ubiquitin-conjugating enzyme E1, E2 ubiquitin-conjugating enzyme E1, UbcH6, Ubiquitin carrier protein E1, Ubiquitin-protein ligase E1

All UniProt accessions (4): P51965, B7Z306, C9J2P0, H7C061

UniProt curated annotations — full annotation on UniProt →

Function. Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. Catalyzes the covalent attachment of ISG15 to other proteins. Mediates the selective degradation of short-lived and abnormal proteins. In vitro also catalyzes ‘Lys-48’-linked polyubiquitination. Catalyzes monoubiquitination of other proteins in both an E3-dependent and E3-independent manner.

Subunit / interactions. Interacts with RNF14.

Subcellular location. Nucleus.

Post-translational modifications. ISGylation suppresses ubiquitin E2 enzyme activity. Autoubiquitinated in vitro.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the ubiquitin-conjugating enzyme family.

Isoforms (3)

UniProt ID	Names	Canonical?
P51965-1	1	yes
P51965-2	2
P51965-3	3

RefSeq proteins (3): NP_001189405, NP_003332, NP_872607 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000608	UBC	Domain
IPR016135	UBQ-conjugating_enzyme/RWD	Homologous_superfamily
IPR023313	UBQ-conjugating_AS	Active_site

Pfam: PF00179

Enzyme classification (BRENDA):

• EC 2.3.2.23 — E2 ubiquitin-conjugating enzyme (BRENDA: 20 organisms, 93 substrates, 28 inhibitors, 12 Km, 8 kcat entries)
• EC 2.3.2.24 — (E3-independent) E2 ubiquitin-conjugating enzyme (BRENDA: 5 organisms, 56 substrates, 7 inhibitors, 6 Km, 6 kcat entries)
• EC 2.3.2.25 — N-terminal E2 ubiquitin-conjugating enzyme (BRENDA: 2 organisms, 22 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[UBIQUITIN-CARRIER-PROTEIN UBC2B]-L-CYSTEINE	0.0001	5
[UBE2W]-S-UBIQUITINYL-L-CYSTEINE	0.2203–0.3014	2
[HISTONE H2A]-L-LYSINE	0.0008–0.0028	2
[HISTONE H2B]-L-LYSINE	0.0015–0.012	2
S-UBIQUITINYL-[E1 UBIQUITIN-ACTIVATING ENZYME]-L	1	1
[UBIQUITIN CARRIER PROTEIN UBC4]-L-CYSTEINE	0.0019	1
[CYTOCHROME C]-L-LYSINE	0.125	1
[HISTONE H3]-L-LYSINE	0.0013	1

UniProt features (30 total): helix 7, strand 4, turn 3, compositionally biased region 3, splice variant 2, mutagenesis site 2, initiator methionine 1, chain 1, sequence variant 1, sequence conflict 1, domain 1, region of interest 1, active site 1, modified residue 1, cross-link 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
5LBN	X-RAY DIFFRACTION	1.42
3BZH	X-RAY DIFFRACTION	1.6
1XR9	X-RAY DIFFRACTION	1.79
4JJQ	X-RAY DIFFRACTION	1.95
8IYA	X-RAY DIFFRACTION	2.43
6FGA	X-RAY DIFFRACTION	2.82

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51965-F1	87.13	0.78

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 (1): 131 (glycyl thioester intermediate)

Post-translational modifications (2): 2, 136

Mutagenesis-validated functional residues (2):

Position	Phenotype
108	inhibits tdp43 ubiquitination. no effect on setdb1 ubiquitination.
131	loss of catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

21 pathways

ID	Pathway
R-HSA-1169408	ISG15 antiviral mechanism
R-HSA-141430	Inactivation of APC/C via direct inhibition of the APC/C complex
R-HSA-174048	APC/C:Cdc20 mediated degradation of Cyclin B
R-HSA-174084	Autodegradation of Cdh1 by Cdh1:APC/C
R-HSA-174154	APC/C:Cdc20 mediated degradation of Securin
R-HSA-174178	APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1
R-HSA-174184	Cdc20:Phospho-APC/C mediated degradation of Cyclin A
R-HSA-176407	Conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphase
R-HSA-176408	Regulation of APC/C activators between G1/S and early anaphase
R-HSA-176409	APC/C:Cdc20 mediated degradation of mitotic proteins
R-HSA-176412	Phosphorylation of the APC/C
R-HSA-179409	APC-Cdc20 mediated degradation of Nek2A
R-HSA-2467813	Separation of Sister Chromatids
R-HSA-2559582	Senescence-Associated Secretory Phenotype (SASP)
R-HSA-68867	Assembly of the pre-replicative complex
R-HSA-69017	CDK-mediated phosphorylation and removal of Cdc6
R-HSA-8853884	Transcriptional Regulation by VENTX
R-HSA-8866652	Synthesis of active ubiquitin: roles of E1 and E2 enzymes
R-HSA-8866654	E3 ubiquitin ligases ubiquitinate target proteins
R-HSA-9687136	Aberrant regulation of mitotic exit in cancer due to RB1 defects
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 209 (showing top): REACTOME_DNA_REPLICATION, REACTOME_APC_C_CDH1_MEDIATED_DEGRADATION_OF_CDC20_AND_OTHER_APC_C_CDH1_TARGETED_PROTEINS_IN_LATE_MITOSIS_EARLY_G1, REACTOME_APC_C_CDC20_MEDIATED_DEGRADATION_OF_CYCLIN_B, REACTOME_CONVERSION_FROM_APC_C_CDC20_TO_APC_C_CDH1_IN_LATE_ANAPHASE, REACTOME_PHOSPHORYLATION_OF_THE_APC_C, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, REACTOME_APC_CDC20_MEDIATED_DEGRADATION_OF_NEK2A, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MORF_RAD21, MORF_HDAC2, MODULE_16

GO Biological Process (8): protein polyubiquitination (GO:0000209), ubiquitin-dependent protein catabolic process (GO:0006511), protein monoubiquitination (GO:0006513), protein ubiquitination (GO:0016567), ISG15-protein conjugation (GO:0032020), positive regulation of transcription by RNA polymerase II (GO:0045944), protein K48-linked ubiquitination (GO:0070936), negative regulation of gene expression (GO:0010629)

GO Molecular Function (7): ubiquitin-protein transferase activity (GO:0004842), ATP binding (GO:0005524), ISG15 transferase activity (GO:0042296), ubiquitin conjugating enzyme activity (GO:0061631), nucleotide binding (GO:0000166), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (4): ubiquitin ligase complex (GO:0000151), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
APC/C-mediated degradation of cell cycle proteins	4
APC/C:Cdc20 mediated degradation of mitotic proteins	2
APC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpoint	2
Activation of APC/C and APC/C:Cdc20 mediated degradation of mitotic proteins	2
Protein ubiquitination	2
Antimicrobial mechanism of IFN-stimulated genes	1
Inhibition of the proteolytic activity of APC/C required for the onset of anaphase by mitotic spindle checkpoint components	1
Mitotic Anaphase	1
Cellular Senescence	1
DNA Replication Pre-Initiation	1
Switching of origins to a post-replicative state	1
Generic Transcription Pathway	1
Aberrant regulation of mitotic cell cycle due to RB1 defects	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein ubiquitination	3
protein modification by small protein conjugation	2
ubiquitin-like protein transferase activity	2
cellular anatomical structure	2
modification-dependent protein catabolic process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
protein polyubiquitination	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein conjugating enzyme activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
intracellular protein-containing complex	1
transferase complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1

Protein interactions and networks

STRING

2736 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UBE2E1	RNF167	Q9H6Y7	828
UBE2E1	RNF20	Q5VTR2	807
UBE2E1	NEDD4L	Q96PU5	719
UBE2E1	MARCHF5	Q9NX47	695
UBE2E1	RNF40	O75150	667
UBE2E1	UBA1	P22314	656
UBE2E1	UBE3A	P78355	638
UBE2E1	G3V2F7	G3V2F7	637
UBE2E1	ARIH1	Q9Y4X5	630
UBE2E1	MARCHF9	Q86YJ5	614
UBE2E1	UBE2E3	Q969T4	605
UBE2E1	ATXN1	P54253	587
UBE2E1	UBE2V2	Q15819	575
UBE2E1	RNF2	Q99496	571
UBE2E1	MCMBP	Q9BTE3	566

IntAct

105 interactions, top by confidence:

A	B	Type	Score
RNF25	UBE2E1	psi-mi:“MI:0915”(physical association)	0.750
RNF25	UBE2E1	psi-mi:“MI:0914”(association)	0.750
UBE2E1	OTUB1	psi-mi:“MI:0915”(physical association)	0.660
OTUB1	UBE2E1	psi-mi:“MI:0914”(association)	0.660
UBE2E1	ZNRF1	psi-mi:“MI:0915”(physical association)	0.650
ZNRF1	UBE2E1	psi-mi:“MI:0915”(physical association)	0.650
ZNRF1	UBE2E1	psi-mi:“MI:0220”(ubiquitination reaction)	0.650
POU5F1	WWP2	psi-mi:“MI:0220”(ubiquitination reaction)	0.650
ospG	UBE2E1	psi-mi:“MI:0914”(association)	0.560
UBE2E1	ospG	psi-mi:“MI:0915”(physical association)	0.560
RNF111	UBE2E1	psi-mi:“MI:0915”(physical association)	0.550
UBE2E1	RNF167	psi-mi:“MI:0915”(physical association)	0.550
RNF5	UBE2E1	psi-mi:“MI:0915”(physical association)	0.550
UBE2E1	RNF111	psi-mi:“MI:0915”(physical association)	0.550
TRIB2	POTEF	psi-mi:“MI:0914”(association)	0.530
TRIB1	UBE2E1	psi-mi:“MI:0914”(association)	0.530
UBE2E1	RNF11	psi-mi:“MI:0915”(physical association)	0.530
RNF11	UBE2E1	psi-mi:“MI:0220”(ubiquitination reaction)	0.530
RNF25	IVL	psi-mi:“MI:0914”(association)	0.530
DET1	UBE2E1	psi-mi:“MI:0914”(association)	0.530
TRIB2	UBE2E1	psi-mi:“MI:0914”(association)	0.530
PAF1	UBE2E1	psi-mi:“MI:0407”(direct interaction)	0.520
ospG	UBE2L6	psi-mi:“MI:0914”(association)	0.500
TP53	UBA1	psi-mi:“MI:0220”(ubiquitination reaction)	0.440
UBE2E1	TRAF6	psi-mi:“MI:0220”(ubiquitination reaction)	0.440
XIAP	UBE2E1	psi-mi:“MI:0220”(ubiquitination reaction)	0.440
NHLRC1	UBA1	psi-mi:“MI:0915”(physical association)	0.400
RNF20	UBE2E1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (311): UBE2E1 (Reconstituted Complex), UBE2E1 (Reconstituted Complex), SLX5 (Biochemical Activity), SLX8 (Biochemical Activity), UBE2E1 (Reconstituted Complex), UBE2E1 (Reconstituted Complex), UBE2E1 (Reconstituted Complex), UBE2E1 (Reconstituted Complex), RNF26 (Two-hybrid), UBE2E1 (Reconstituted Complex), UBE2E1 (Reconstituted Complex), UBE2E1 (Reconstituted Complex), UBE2E1 (Reconstituted Complex), UBE2E1 (Reconstituted Complex), UBE2E1 (Biochemical Activity)

ESM2 similar proteins: A3KN22, O74549, P0C8G3, P21734, P25869, P27949, P49427, P51965, P52482, P52491, P61081, P61082, P62253, P62254, P62255, Q08BH7, Q1RMW1, Q29503, Q3UWQ3, Q42540, Q42541, Q54TI6, Q55EY8, Q5M8Y2, Q5U203, Q5ZKX6, Q6C9W0, Q6CSW8, Q6DCZ9, Q6FVQ8, Q6IRC7, Q6NY82, Q6P8D9, Q6ZWZ2, Q712K3, Q75AF2, Q7ZY08, Q8CFI2, Q91W82, Q95017

Diamond homologs: A0A1B0GUS4, A5PJC4, A5PKP9, D3ZDK2, O13685, O14933, O74196, O74810, P0C8G3, P0C8G4, P0C8G5, P15731, P15732, P21734, P25867, P25869, P27949, P35128, P35129, P35131, P35132, P35133, P35134, P35135, P43102, P46595, P49427, P51668, P51965, P52482, P52483, P52485, P52487, P52490, P52492, P61077, P61078, P61079, P61080, P61088

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
“Ub:E1 (UBA1 substrate)”	“up-regulates activity”	UBE2E1	ubiquitination
“Ub:E1 (UBA6 substrate)”	“up-regulates activity”	UBE2E1	ubiquitination
UBE2E1	“up-regulates activity”	RNF167	binding
UBE2E1	“up-regulates activity”	ZSWIM2	binding
UBE2E1	“up-regulates activity”	MPG	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 97 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
E3 ubiquitin ligases ubiquitinate target proteins	5	15.4×	1e-03
Antigen processing: Ubiquitination & Proteasome degradation	23	13.6×	3e-18
Class I MHC mediated antigen processing & presentation	12	13.3×	9e-09
PKR-mediated signaling	5	11.2×	4e-03
Adaptive Immune System	12	5.7×	9e-05

GO biological processes:

GO term	Partners	Fold	FDR
protein autoubiquitination	12	31.6×	5e-13
protein K63-linked ubiquitination	9	27.1×	6e-09
protein polyubiquitination	19	24.6×	3e-19
ubiquitin-dependent protein catabolic process	27	22.5×	1e-26
positive regulation of protein ubiquitination	8	19.2×	1e-06
protein K48-linked ubiquitination	8	15.2×	6e-06
protein ubiquitination	31	14.4×	2e-25
positive regulation of proteasomal ubiquitin-dependent protein catabolic process	6	14.2×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	4
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1855 predictions. Top by Δscore:

Variant	Effect	Δscore
3:23806084:GAGAG:G	donor_gain	1.0000
3:23806085:AGAGG:A	donor_loss	1.0000
3:23806086:GAG:G	donor_gain	1.0000
3:23806087:AGGT:A	donor_loss	1.0000
3:23806090:T:G	donor_loss	1.0000
3:23811444:A:AG	acceptor_gain	1.0000
3:23811445:T:G	acceptor_gain	1.0000
3:23811508:CAGGT:C	donor_loss	1.0000
3:23811511:GT:G	donor_loss	1.0000
3:23889106:TTTTA:T	acceptor_loss	1.0000
3:23889107:TTTAG:T	acceptor_loss	1.0000
3:23889108:TTAGG:T	acceptor_loss	1.0000
3:23889109:TAGG:T	acceptor_loss	1.0000
3:23806089:G:GG	donor_gain	0.9900
3:23807417:AAGAG:A	donor_loss	0.9900
3:23807419:GAGG:G	donor_loss	0.9900
3:23807420:AG:A	donor_loss	0.9900
3:23807421:GGTA:G	donor_loss	0.9900
3:23807422:GT:G	donor_loss	0.9900
3:23807423:T:G	donor_loss	0.9900
3:23811456:CCA:C	acceptor_loss	0.9900
3:23811458:A:AG	acceptor_gain	0.9900
3:23811458:AG:A	acceptor_loss	0.9900
3:23811459:G:GG	acceptor_gain	0.9900
3:23811459:G:T	acceptor_loss	0.9900
3:23811459:GA:G	acceptor_gain	0.9900
3:23811507:GCAG:G	donor_gain	0.9900
3:23811511:G:GG	donor_gain	0.9900
3:23887565:A:AG	acceptor_gain	0.9900
3:23887565:AGT:A	acceptor_gain	0.9900

AlphaMissense

1273 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:23811460:A:C	R51S	1.000
3:23811460:A:T	R51S	1.000
3:23811470:G:A	E55K	1.000
3:23811474:T:C	L56P	1.000
3:23811506:T:C	C67R	1.000
3:23887569:C:A	A69D	1.000
3:23887598:T:A	W79R	1.000
3:23887598:T:C	W79R	1.000
3:23887599:G:C	W79S	1.000
3:23887600:G:C	W79C	1.000
3:23887600:G:T	W79C	1.000
3:23887611:T:A	I83N	1.000
3:23887616:G:A	G85R	1.000
3:23887616:G:C	G85R	1.000
3:23887616:G:T	G85W	1.000
3:23887617:G:A	G85E	1.000
3:23887644:G:A	G94D	1.000
3:23887649:T:C	F96L	1.000
3:23887650:T:C	F96S	1.000
3:23887651:C:A	F96L	1.000
3:23887651:C:G	F96L	1.000
3:23887656:T:A	L98H	1.000
3:23887656:T:C	L98P	1.000
3:23887679:T:C	Y106H	1.000
3:23887680:A:G	Y106C	1.000
3:23887682:C:T	P107S	1.000
3:23887683:C:A	P107H	1.000
3:23887694:C:A	P111T	1.000
3:23887694:C:T	P111S	1.000
3:23887695:C:A	P111Q	1.000

dbSNP variants (sampled 300 via entrez): RS1000060375 (3:23887039 T>TA), RS1000060469 (3:23865727 T>C,G), RS1000107442 (3:23819201 T>C), RS1000142358 (3:23872288 A>T), RS1000173893 (3:23872487 A>G), RS1000182651 (3:23832355 G>T), RS1000198553 (3:23871736 G>A), RS1000272125 (3:23871257 G>T), RS1000336186 (3:23817830 G>A), RS1000344680 (3:23879733 T>C), RS1000374992 (3:23838714 C>T), RS1000431729 (3:23865451 C>G), RS1000459583 (3:23891120 T>C), RS1000475749 (3:23870411 C>T), RS1000492469 (3:23877545 G>A,C)

Disease associations

OMIM: gene MIM:602916 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002481_10	Acne (severe)	1.000000e-06
GCST007044_10	Extremely high intelligence	3.000000e-11
GCST009391_153	Metabolite levels	3.000000e-06
GCST011358_14	Academic attainment (English)	7.000000e-06
GCST011358_2	Academic attainment (English)	2.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0010486	glucuronate measurement
EFO:0011015	educational attainment

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105876 (SINGLE PROTEIN)

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

Binding affinities (BindingDB)

27 measured of 119 human assays (119 total across all organisms); most potent 27 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-phenylpyrazolo[1,5-a]pyrimidin-7-	IC50	55 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7-	IC50	55 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(rac)-[(1R,2R,3S,4R)-4-{[2-(2,4-dichlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-	IC50	55 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(rac)-((1R,2R,3S,4R)-4-(2-(3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)pyrazolo[1,5-	IC50	55 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-	IC50	55 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(rac)-((1R,2R,3S,4R)-2,3-Dihydroxy-4-((2-(3-phenoxyphenyl)pyrazolo[1,5-	IC50	55 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(2-(trifluoromethyl)pyridin-4-	IC50	55 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(rac)-((1R,2R,3S,4R)-2,3-Dihydroxy-4-((2-(5-(trifluoromethyl)thiophen-2-	IC50	55 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(6-(trifluoromethyl)pyridin-2-	IC50	55 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(2-phenoxyphenyl)pyrazolo[1,5-	IC50	55 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(rac)-((1R,2R,3S,4R)-4-(2-(3-benzylpenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-2,3-	IC50	55 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(rac)-((1R,2R,3S,4R)-4-(2-(3-benzoylphenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)-	IC50	55 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(rac)-[(1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(1H-indol-5-yl)pyrazolo[1,5-a]pyrimidin-7-	IC50	55 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(2-(trifluoromethylthio)phenyl)pyrazolo[1,5-	IC50	55 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(rac)-((1R,2R,3S,4R)-2,3-dihydroxy-4-(2-(4-(trifluoromethylthio)phenyl)pyrazolo[1,5-	IC50	55 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(rac)-((1R,2R,3S,4R)-4-(2-(6-chlorobenzo[b]thiophen-2-yl)pyrazolo[1,5-a]pyrimidin-	IC50	55 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(rac)-((1R,2R,3S,4R)-4-(2-(5-ethylbenzo[b]thiophen-2-yl)pyrazolo[1,5-a]pyrimidin-7-	IC50	55 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(s.e.)-((1R,2R,3S,4R)-4-(2-(2,4-dichloronaphthalen-1-yl)pyrazolo[1,5-a]pyrimidin-7-	IC50	55 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(rac)-{(1R,2R,3S,4R)-2,3-dihydroxy-4-[(5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-	IC50	550 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(rac)-{(1R,2R,3S,4R)-4-[(5-chloro-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)amino]-2,3-	IC50	550 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(rac)-((1R,2R,3S,4R)-4-(2-(4-bromophenyl)-5-chloropyrazolo[1,5-a]pyrimidin-7-	IC50	550 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(rac)-((1R,2R,3S,4R)-4-{[5-chloro-2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-	IC50	550 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(rac)-((1R,2R,3S,4R)-4-(5-chloro-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidin-7-	IC50	550 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(rac)-[(1R,2R,3S,4R)-4-{[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]-pyrimidin-7-	IC50	550 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(rac)-{(1R,2R,3S,4R)-2,3-dihydroxy-4-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-	IC50	550 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(s.e.)-{(1R,2R,3S,4R)-4-[(3,6-dichloro-2-{3-	IC50	550 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme
(s.e.)-{(1R,2R,3S,4R)-4-[(6-chloro-2-{3-[(trifluoromethyl)sulfanyl]phenyl}pyrazolo[1,	IC50	550 nM	US-9796725: Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme

ChEMBL bioactivities

27 potent at pChembl≥5 of 27 total, top 27 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.26	IC50	55	nM	CHEMBL5759269
7.26	IC50	55	nM	CHEMBL5864078
7.26	IC50	55	nM	CHEMBL5780833
7.26	IC50	55	nM	CHEMBL5887314
7.26	IC50	55	nM	CHEMBL5768102
7.26	IC50	55	nM	CHEMBL6003529
7.26	IC50	55	nM	CHEMBL5803994
7.26	IC50	55	nM	CHEMBL5954380
7.26	IC50	55	nM	CHEMBL5918592
7.26	IC50	55	nM	CHEMBL5958476
7.26	IC50	55	nM	CHEMBL5940945
7.26	IC50	55	nM	CHEMBL5747752
7.26	IC50	55	nM	CHEMBL5971124
7.26	IC50	55	nM	CHEMBL5832385
7.26	IC50	55	nM	CHEMBL5828810
7.26	IC50	55	nM	CHEMBL5997651
7.26	IC50	55	nM	CHEMBL6065415
7.26	IC50	55	nM	CHEMBL6053122
6.26	IC50	550	nM	CHEMBL5793677
6.26	IC50	550	nM	CHEMBL5743820
6.26	IC50	550	nM	CHEMBL5866556
6.26	IC50	550	nM	CHEMBL5799754
6.26	IC50	550	nM	CHEMBL6054356
6.26	IC50	550	nM	CHEMBL5762899
6.26	IC50	550	nM	CHEMBL5929395
6.26	IC50	550	nM	CHEMBL5960054
6.26	IC50	550	nM	CHEMBL5769060

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	4
trichostatin A	affects cotreatment, decreases expression	3
Acetaminophen	decreases expression, increases expression	2
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
kojic acid	decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
1,6-hexamethylene diisocyanate	increases methylation	1
2,2’,3’,4,4’,5-hexachlorobiphenyl	affects expression	1
celastrol	decreases expression	1
nickel acetate	increases expression	1
PCB 180	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	affects cotreatment, increases methylation	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	decreases expression	1
Cannabidiol	increases expression	1
Carbamazepine	affects expression	1
Doxorubicin	decreases expression	1
Iron	decreases expression	1
Methylcholanthrene	affects binding, increases reaction	1
Nickel	increases expression	1
Polychlorinated Biphenyls	affects expression	1
Silicon Dioxide	increases expression	1
Thiram	decreases expression	1
Vitamin D	affects expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4020065	Binding	Inhibition of recombinant human E1 charging with ubiquitin at 20 to 100 uM after 10 mins in presence of ATP by coomassie staining based SDS PAGE analysis	Mind the Metal: A Fragment Library-Derived Zinc Impurity Binds the E2 Ubiquitin-Conjugating Enzyme Ube2T and Induces Structural Rearrangements. — J Med Chem

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3KJ	Abcam HEK293T UBE2E1 KO	Transformed cell line	Female
CVCL_TV62	HAP1 UBE2E1 (-) 1	Cancer cell line	Male
CVCL_TV63	HAP1 UBE2E1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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