UGDH

Summary

UGDH (UDP-glucose 6-dehydrogenase, HGNC:12525) is a protein-coding gene on chromosome 4p14, encoding UDP-glucose 6-dehydrogenase (O60701). Catalyzes the formation of UDP-alpha-D-glucuronate, a constituent of complex glycosaminoglycans.

The protein encoded by this gene converts UDP-glucose to UDP-glucuronate and thereby participates in the biosynthesis of glycosaminoglycans such as hyaluronan, chondroitin sulfate, and heparan sulfate. These glycosylated compounds are common components of the extracellular matrix and likely play roles in signal transduction, cell migration, and cancer growth and metastasis. The expression of this gene is up-regulated by transforming growth factor beta and down-regulated by hypoxia. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 7358 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental and epileptic encephalopathy, 84 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 124 total — 2 pathogenic, 19 likely-pathogenic
• Phenotypes (HPO): 32
• Druggable target: yes
• MANE Select transcript: NM_003359

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12525
Approved symbol	UGDH
Name	UDP-glucose 6-dehydrogenase
Location	4p14
Locus type	gene with protein product
Status	Approved
Aliases	GDH, UDPGDH, UDP-GlcDH, UGD
Ensembl gene	ENSG00000109814
Ensembl biotype	protein_coding
OMIM	603370
Entrez	7358

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 25 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000316423, ENST00000501493, ENST00000503779, ENST00000505698, ENST00000506179, ENST00000507089, ENST00000509391, ENST00000510490, ENST00000510881, ENST00000514106, ENST00000515021, ENST00000515398, ENST00000907836, ENST00000907837, ENST00000907838, ENST00000907839, ENST00000907840, ENST00000907841, ENST00000907842, ENST00000907843, ENST00000907844, ENST00000907845, ENST00000911343, ENST00000911344, ENST00000911345, ENST00000959852, ENST00000959853, ENST00000959854

RefSeq mRNA: 3 — MANE Select: NM_003359 NM_001184700, NM_001184701, NM_003359

CCDS: CCDS3455, CCDS54757, CCDS54758

Canonical transcript exons

ENST00000316423 — 12 exons

Exon	Start	End
ENSE00000711736	39503875	39503985
ENSE00000711741	39504417	39504508
ENSE00000711745	39505237	39505370
ENSE00000826496	39505618	39505748
ENSE00000826497	39508566	39508660
ENSE00000826498	39509760	39509907
ENSE00000826499	39510353	39510550
ENSE00001420804	39498755	39500253
ENSE00002075999	39527283	39527439
ENSE00003464255	39510661	39510861
ENSE00003477877	39521351	39521519
ENSE00003502570	39514083	39514184

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 98.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 59.7985 / max 999.9408, expressed in 1777 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
51853	53.6358	1688
51848	1.7908	762
51854	1.4362	944
51852	1.3901	822
51855	1.2723	824
51850	0.2443	125
51847	0.0290	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
colonic mucosa	UBERON:0000317	98.67	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.66	gold quality
islet of Langerhans	UBERON:0000006	98.46	gold quality
mucosa of transverse colon	UBERON:0004991	97.68	gold quality
vena cava	UBERON:0004087	96.91	gold quality
rectum	UBERON:0001052	96.72	gold quality
ileal mucosa	UBERON:0000331	96.26	gold quality
decidua	UBERON:0002450	95.77	gold quality
bronchial epithelial cell	CL:0002328	95.68	gold quality
liver	UBERON:0002107	95.58	gold quality
stromal cell of endometrium	CL:0002255	95.56	gold quality
right lobe of liver	UBERON:0001114	95.16	gold quality
colonic epithelium	UBERON:0000397	94.89	gold quality
calcaneal tendon	UBERON:0003701	94.52	gold quality
epithelium of bronchus	UBERON:0002031	94.35	gold quality
layer of synovial tissue	UBERON:0007616	94.26	gold quality
jejunal mucosa	UBERON:0000399	94.21	gold quality
pancreas	UBERON:0001264	94.19	gold quality
cartilage tissue	UBERON:0002418	94.19	gold quality
bronchus	UBERON:0002185	94.05	gold quality
transverse colon	UBERON:0001157	94.01	gold quality
germinal epithelium of ovary	UBERON:0001304	94.01	gold quality
choroid plexus epithelium	UBERON:0003911	93.93	gold quality
gingival epithelium	UBERON:0001949	93.78	gold quality
synovial joint	UBERON:0002217	93.46	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.45	gold quality
endometrium	UBERON:0001295	93.44	gold quality
gingiva	UBERON:0001828	93.35	gold quality
ventricular zone	UBERON:0003053	92.99	gold quality
gall bladder	UBERON:0002110	92.93	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-15	yes	1857.60
E-GEOD-81608	yes	528.13
E-MTAB-6653	yes	420.17
E-MTAB-5061	yes	18.29
E-GEOD-83139	no	2.98
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KLF2, PPARA, RXRA, SP1, SPI1, ZBTB7B

miRNA regulators (miRDB)

109 targeting UGDH, 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-3613-3P	100.00	76.36	7965
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 38)

• UGDH core promoter has a role in up- and down-regulation of UGDH after TGF-beta stimulation and in hypoxic conditions (PMID:12682078)
• role of Cys-276 as a catalytic residue; Lys-279 is likely to have a role in positioning active site residues and in maintaining the hexameric quaternary structure (PMID:15044486)
• Gly-13 plays an important role for efficient binding of NAD(+) to human UDP-glucose dehydrogenase (PMID:15247292)
• C276 plays an important role for efficient binding of UDP-glucose to hUGDH (PMID:15898741)
• Our results indicate that the region from nucleotide position -486 to -632 relative to the start of the small transcript contains positive regulatory elements that contribute to gene expression. (PMID:16002992)
• report the presence of an inhibitory cis-element in the distal region of the UGDH promoter that interacts with putative transcriptional repressors for the negative regulation of the UGDH gene (PMID:16495656)
• UGDH was purified and crystallized, and diffraction data proposes that the biological unit of UGDH is a tetramer. (PMID:17073734)
• Alteration of lysine 220 to alanine, histidine, or arginine significantly impaired enzyme function. (PMID:17209547)
• Results suggest that UGDH Ala222 and Ser233 play an important role in maintaining the hexameric structure and the reduced binding affinities for substrates are attributable to its altered subunit communication. (PMID:17927902)
• This demonstrates that the UGDH transcript and protein quantities, the enzyme activity, and glycosaminoglycan contents increase in LMP2A overexpressed human embryonic kidney 293 (HEK293) cells. (PMID:18717819)
• perturbation caused by the mutation of a residue at a considerably distant location from the oligomeric interfaces is preferentially distributed throughout specific sites, especially the large flexible regions in the UGDH structure (PMID:19358821)
• Results support the UGDH content in prostatic acini as a novel candidate biomarker that may complement the development of a multi-biomarker panel for detecting PC within the tumor adjacent field on a histologically normal biopsy specimen. (PMID:19676054)
• UGDH can regulate cell motility through the production of glycosaminoglycans (PMID:20691680)
• Structure and mechanism of human UDP-glucose 6-dehydrogenase. (PMID:21502315)
• high UGDH levels may underlie susceptibility of the orbit to localized overproduction of hyaluronan in Graves disease. (PMID:21576248)
• An atypical allosteric mechanism in human UDP-alpha-D-glucose 6-dehydrogenase (UGDH) based on an easily acquired and identifiable structural attribute: packing defects in the protein core. (PMID:21595445)
• A structurally detailed model of UDP-alpha-D-glucose 6-dehydrogenase (UGDH) demonstrates hinge-bending motion that represents allosteric feedback inhibition and substrate-product exchange during the catalytic cycle. (PMID:21961565)
• An alternate crystal structure of human UGDH (hUGDH) in complex with UDP-glucose at 2.8 A resolution, is reported. (PMID:21984906)
• Structural and kinetic evidence that catalytic reaction of human UDP-glucose 6-dehydrogenase involves covalent thiohemiacetal and thioester enzyme intermediates. (PMID:22123821)
• both missense mutations significantly reducing the ability of UGDH to provide precursors for cardiac cushion formation, which is essential to subsequent valve formation. (PMID:22815472)
• Mammalian UGDH displays hysteresis (observed as a lag in progress curves), indicating that the enzyme undergoes a slow transition from an inactive to an active state. Human UGDH is sensitive to product inhibition during the lag. (PMID:23363239)
• Kinetic analysis of wild-type UGDH and hexamer T325A showed that upon increasing enzyme concentration, which favors the hexameric species, activity was decreased and exhibited cooperativity. Cooperative kinetics was not observed in obligate dimer T325D. (PMID:24145036)
• UGDH protein level in osteoarthritis cartilage was much lower than in control cartilage. (PMID:25465897)
• UGDH displays hysteresis because of a slow isomerization from an inactive state (E*) to an active state (E). We show that the structure of E* constrains UGDH in a conformation that favors feedback inhibition at physiological pH. (PMID:25478983)
• study has identified several new proteins like RHOC, DLG5, UGDH, TMOD3 in addition to known chemoresistance associated proteins in non-small cell lung carcinoma. (PMID:26898345)
• Data indicate that the A136M substitution in UDP-glucose dehydrogenase (hUGDH) stabilizes the hexamer. (PMID:27966912)
• Data show that KLF4 upregulates UGDH expression in a mCpG-dependent manner, and UGDH is required for KLF4-induced cell migration of glioblastoma (GBM) in vitro. UGDH knockdown decreases GAG abundance in GBM cells, as well as cell proliferation and migration in vitro. In intracranial xenografts, reduced UGDH inhibits tumor growth and migration, accompanied by a decrease in the expression of extracellular matrix proteins. (PMID:29479058)
• the unfolded state of the ID-tail rectifies the dynamics and structure of UGDH to favour inhibitor binding; because this entropic rectifier does not have any sequence or structural constraints, it is an easily acquired adaptation; this model implies that evolution selects for disordered segments to tune the energy landscape of proteins, which may explain the persistence of intrinsic disorder in the proteome (PMID:30420606)
• The crystal structures of UGDH(A104L) show that the allosteric switch still adopts the E and E* states, albeit with a more rigid protein core. However, the progress curves of UGDH(A104L) do not show hysteresis, which suggests that the E* and E states are now in rapid equilibrium. (PMID:30457329)
• These data indicate that UGDH expression and localization are an early sero-diagnostic marker in addition to a poor prognostic indicator in lung AC patients. (PMID:30787260)
• UDP-glucose 6-dehydrogenase regulates hyaluronic acid production and promotes breast cancer progression. (PMID:31308490)
• This study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. (PMID:32001716)
• Integration of Sugar Metabolism and Proteoglycan Synthesis by UDP-glucose Dehydrogenase. (PMID:32749901)
• UDP-glucose 6-dehydrogenase knockout impairs migration and decreases in vivo metastatic ability of breast cancer cells. (PMID:32768525)
• Targeting UDP-glucose dehydrogenase inhibits ovarian cancer growth and metastasis. (PMID:32893977)
• UDP-glucose 6-dehydrogenase lessens sorafenib sensitivity via modulating unfolded protein response. (PMID:35617808)
• Phenotypic and genetic characteristics of 24 cases of early infantile epileptic encephalopathy in East China, including a rare case of biallelic UGDH mutations. (PMID:37593999)
• UGDH promotes tumor-initiating cells and a fibroinflammatory tumor microenvironment in ovarian cancer. (PMID:37858159)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ugdh	ENSDARG00000019838
mus_musculus	Ugdh	ENSMUSG00000029201
rattus_norvegicus	Ugdh	ENSRNOG00000002643
drosophila_melanogaster	sgl	FBGN0261445
caenorhabditis_elegans		WBGENE00005022

Protein

Protein identifiers

UDP-glucose 6-dehydrogenase — O60701 (reviewed: O60701)

All UniProt accessions (7): O60701, D6RHF4, E7ER83, E7ER95, E7ETF4, E7EV97, E9PBD2

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the formation of UDP-alpha-D-glucuronate, a constituent of complex glycosaminoglycans. Required for the biosynthesis of chondroitin sulfate and heparan sulfate. Required for embryonic development via its role in the biosynthesis of glycosaminoglycans. Required for proper brain and neuronal development.

Subunit / interactions. Homohexamer.

Tissue specificity. Detected in heart, placenta, liver, pancreas, spleen, thymus, prostate, ovary, small intestine and colon. Widely expressed.

Disease relevance. Developmental and epileptic encephalopathy 84 (DEE84) [MIM:618792] A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE84 is an autosomal recessive form characterized by onset of refractory seizures in the first months of life. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. UDP-alpha-D-xylose (UDX) acts as a feedback inhibitor. It binds at the same site as the substrate, but functions as allosteric inhibitor by triggering a conformation change that disrupts the active hexameric ring structure and gives rise to an inactive, horseshoe-shaped hexamer.

Domain organisation. The protein goes through several conformation states during the reaction cycle, giving rise to hysteresis. In the initial state, the ligand-free protein is in an inactive conformation (E*). Substrate binding triggers a change to the active conformation (E). UDP-xylose binding triggers the transition to a distinct, inhibited conformation. The presence of an intrinsically disordered C-terminus promotes a more dynamic protein structure and favors a conformation with high affinity for UPD-xylose. The allosteric switch region moves by about 5 Angstroms when UDP-xylose is bound, and occupies part of the UDP-glucose binding site. At the same time it promotes domain movements that disrupt the active hexameric ring structure and lead to the formation of a horseshoe-shaped, inactive hexamer.

Pathway. Nucleotide-sugar biosynthesis; UDP-alpha-D-glucuronate biosynthesis; UDP-alpha-D-glucuronate from UDP-alpha-D-glucose: step 1/1.

Similarity. Belongs to the UDP-glucose/GDP-mannose dehydrogenase family.

Isoforms (3)

UniProt ID	Names	Canonical?
O60701-1	1	yes
O60701-2	2
O60701-3	3

RefSeq proteins (3): NP_001171629, NP_001171630, NP_003350* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001732	UDP-Glc/GDP-Man_DH_N	Domain
IPR008927	6-PGluconate_DH-like_C_sf	Homologous_superfamily
IPR014026	UDP-Glc/GDP-Man_DH_dimer	Domain
IPR014027	UDP-Glc/GDP-Man_DH_C	Domain
IPR017476	UDP-Glc/GDP-Man	Family
IPR028356	UDPglc_DH_euk	Family
IPR036220	UDP-Glc/GDP-Man_DH_C_sf	Homologous_superfamily
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily

Pfam: PF00984, PF03720, PF03721

Enzyme classification (BRENDA):

• EC 1.1.1.22 — UDP-glucose 6-dehydrogenase (BRENDA: 44 organisms, 83 substrates, 53 inhibitors, 124 Km, 48 kcat entries)

Substrate kinetics (BRENDA)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
NAD+	0.006–6.3	53
UDP-GLUCOSE	0.0092–1.5	24
UDP-ALPHA-D-GLUCOSE	0.0073–2.21	22
UDPGLUCOSE	0.015–8.4	12
UDP	0.017–0.98	4
5-AZIDO-UDP-GLUCOSE	0.0562	1
ALDEHYDE INTERMEDIATE	0.058	1

Catalyzed reactions (Rhea), 1 shown:

• UDP-alpha-D-glucose + 2 NAD(+) + H2O = UDP-alpha-D-glucuronate + 2 NADH + 3 H(+) (RHEA:23596)

UniProt features (112 total): sequence variant 23, strand 21, helix 20, binding site 14, mutagenesis site 13, turn 7, region of interest 4, active site 3, modified residue 2, splice variant 2, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
5VR8	X-RAY DIFFRACTION	2
2Q3E	X-RAY DIFFRACTION	2
5TJH	X-RAY DIFFRACTION	2.05
9DGZ	ELECTRON MICROSCOPY	2.06
4EDF	X-RAY DIFFRACTION	2.08
2QG4	X-RAY DIFFRACTION	2.1
6C58	X-RAY DIFFRACTION	2.2
3KHU	X-RAY DIFFRACTION	2.3
3TF5	X-RAY DIFFRACTION	2.3
6C5A	X-RAY DIFFRACTION	2.3
9DH0	ELECTRON MICROSCOPY	2.38
3ITK	X-RAY DIFFRACTION	2.4
3PTZ	X-RAY DIFFRACTION	2.5
6C4J	X-RAY DIFFRACTION	2.53
5W4X	X-RAY DIFFRACTION	2.65
6C4K	X-RAY DIFFRACTION	2.65
4RJT	X-RAY DIFFRACTION	2.7
3TDK	X-RAY DIFFRACTION	2.8
6C5Z	X-RAY DIFFRACTION	2.95
3PRJ	X-RAY DIFFRACTION	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60701-F1	93.89	0.92

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 (3): 161 (proton donor/acceptor); 220 (proton donor/acceptor); 276 (nucleophile)

Ligand- & substrate-binding residues (14): 41; 89–93; 130–132; 161–165; 165; 220–224; 260; 267–273; 276–279; 338–339; 346; 442 …

Post-translational modifications (2): 107, 476

Mutagenesis-validated functional residues (13):

Position	Phenotype
94	loss of hexamer formation. causes formation of stable dimers. strongly reduced affinity for nad and udp-glucose, and str
104	impairs protein folding. decreases affinity for udp-glucose. no effect on inhibition by udp-xylose. no effect on hystere
104	no significant effect on catalytic activity and on affinity for nad and udp-glucose. decreases affinity for the inhibito
131	reduced affinity for udp-glucose, and reduced catalytic efficiency.
132	nearly abolishes enzyme activity. stabilizes the enzyme in a low-activity hexameric conformation.
136	stabilizes the active conformation of the hexamer. decreases affinity for udp-xylose, but not for udp-glucose. disrupts
161	abolishes hydrolysis of the covalent intermediate between substrate and the catalytic cysteine residue.
220	loss of enzyme activity.
276	loss of enzyme activity.
280	loss of enzyme activity.
323–325	loss of hexamer formation. causes formation of stable dimers. strongly decreased specific activity at ph 8.4.
465–494	no effect on the intrinsically disordered nature of the c-terminus. no effect on affinity for the inhibitor udp-xylose.
465–494	strongly decreases affinity for the inhibitor udp-xylose.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-173599	Formation of the active cofactor, UDP-glucuronate

MSigDB gene sets: 351 (showing top): MODULE_93, MODULE_52, REACTOME_BIOLOGICAL_OXIDATIONS, GOZGIT_ESR1_TARGETS_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_NEUROGENESIS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_GASTRULATION_WITH_MOUTH_FORMING_SECOND, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_AMINOGLYCAN_BIOSYNTHETIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS

GO Biological Process (8): gastrulation with mouth forming second (GO:0001702), glycosaminoglycan biosynthetic process (GO:0006024), UDP-glucuronate biosynthetic process (GO:0006065), heparan sulfate proteoglycan biosynthetic process (GO:0015012), protein hexamerization (GO:0034214), neuron development (GO:0048666), chondroitin sulfate proteoglycan biosynthetic process (GO:0050650), polysaccharide biosynthetic process (GO:0000271)

GO Molecular Function (7): UDP-glucose 6-dehydrogenase activity (GO:0003979), identical protein binding (GO:0042802), NAD binding (GO:0051287), catalytic activity (GO:0003824), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor (GO:0016616), oxidoreductase activity, acting on the CH-CH group of donors, NAD or NADP as acceptor (GO:0016628)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Glucuronidation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
proteoglycan biosynthetic process	2
protein O-linked glycosylation via xylose	2
cellular anatomical structure	2
gastrulation	1
aminoglycan biosynthetic process	1
glycosaminoglycan metabolic process	1
nucleotide-sugar biosynthetic process	1
carboxylic acid biosynthetic process	1
UDP-glucuronate metabolic process	1
heparan sulfate proteoglycan metabolic process	1
protein complex oligomerization	1
neuron differentiation	1
cell development	1
chondroitin sulfate proteoglycan metabolic process	1
polysaccharide metabolic process	1
macromolecule biosynthetic process	1
carbohydrate biosynthetic process	1
oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	1
protein binding	1
adenyl nucleotide binding	1
molecular_function	1
catalytic activity	1
oxidoreductase activity, acting on CH-OH group of donors	1
oxidoreductase activity, acting on the CH-CH group of donors	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
extracellular vesicle	1

Protein interactions and networks

STRING

2417 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UGDH	UXS1	Q8NBZ7	775
UGDH	GALE	Q14376	773
UGDH	UGP2	Q16851	760
UGDH	UGT1A6	P19224	676
UGDH	UGT1A8	Q9HAW9	668
UGDH	UGT1A7	Q9HAW7	667
UGDH	UGT1A1	P22309	661
UGDH	HAS2	Q92819	660
UGDH	UGT1A4	P22310	660
UGDH	UGT1A10	Q9HAW8	660
UGDH	HAS3	O00219	619
UGDH	MIOX	Q9UGB7	615
UGDH	TGDS	O95455	595
UGDH	HAS1	Q92839	593
UGDH	GPI	P06744	593

IntAct

82 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
UGDH	UGDH	psi-mi:“MI:0915”(physical association)	0.590
UGDH	UGDH	psi-mi:“MI:0407”(direct interaction)	0.590
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530
TMEM9	ESYT2	psi-mi:“MI:0914”(association)	0.530
GGH	UGDH	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
	UGDH	psi-mi:“MI:0945”(oxidoreductase activity electron transfer reaction)	0.440
SIRT3		psi-mi:“MI:0915”(physical association)	0.400
UGDH	TNPO1	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
UGDH		psi-mi:“MI:0915”(physical association)	0.370
UGDH	RAD51	psi-mi:“MI:0915”(physical association)	0.370
UGDH	UGT1A1	psi-mi:“MI:0915”(physical association)	0.370
LRRK2		psi-mi:“MI:0914”(association)	0.350
DKKL1	VWA8	psi-mi:“MI:0914”(association)	0.350
GGH	TGOLN2	psi-mi:“MI:0914”(association)	0.350
FAS	PEX1	psi-mi:“MI:0914”(association)	0.350

BioGRID (138): UGDH (Two-hybrid), UGDH (Affinity Capture-MS), UGDH (Affinity Capture-MS), UGDH (Affinity Capture-MS), UGDH (Affinity Capture-MS), TRAPPC4 (Co-fractionation), UGDH (Co-fractionation), UGDH (Co-fractionation), UGDH (Affinity Capture-MS), UGDH (Affinity Capture-MS), UGDH (Affinity Capture-MS), UGDH (Affinity Capture-MS), UGDH (Affinity Capture-MS), UGDH (Affinity Capture-MS), UGDH (Affinity Capture-MS)

ESM2 similar proteins: A0A0U3AB61, A2BX55, A4FY94, A6USK4, A6UU98, A6VK13, A7HM89, A8F6M1, A9BHC5, B3CLT4, B3CN84, B6YRQ9, B8I769, C0R2N7, O02373, O05973, O60701, P12378, P27829, P50504, P58591, P67066, P67067, Q11YY8, Q19905, Q1MPZ8, Q1RKF8, Q2GCV3, Q2GHD8, Q30TL4, Q31AF6, Q3YRE3, Q45410, Q4UK39, Q5F3T9, Q5FG00, Q5GTK9, Q5HAK8, Q5R7B3, Q68VX0

Diamond homologs: A0A0U3AB61, B7F958, D4GYH5, O02373, O05973, O32271, O34862, O54068, O60701, O70199, O70475, O86422, P12378, P96718, Q19905, Q1RKF8, Q2QS13, Q2QS14, Q4UK39, Q58454, Q5F3T9, Q5R7B3, Q68VX0, Q75GS4, Q92GB1, Q96558, Q9AUV6, Q9FM01, Q9FZE1, Q9LF33, Q9LIA8, O07299, O33952, P11759, P51585, P59793, Q04872, Q47329, Q7DBF9, Q887P8

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 79 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.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of miRNA transcription	5	20.8×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	19
Uncertain significance	54
Likely benign	11
Benign	1

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
3330806	NM_003359.4(UGDH):c.1270del (p.Asp424fs)	Pathogenic
810658	NM_003359.4(UGDH):c.193C>T (p.Arg65Ter)	Pathogenic
3376216	NM_003359.4(UGDH):c.528_531del (p.Asp176fs)	Likely pathogenic
4072030	NM_003359.4(UGDH):c.1084G>A (p.Ala362Thr)	Likely pathogenic
4072031	NM_003359.4(UGDH):c.742G>C (p.Val248Leu)	Likely pathogenic
810641	NM_003359.4(UGDH):c.1346A>G (p.His449Arg)	Likely pathogenic
810642	NM_003359.4(UGDH):c.1328G>A (p.Arg443His)	Likely pathogenic
810643	NM_003359.4(UGDH):c.1324C>T (p.Arg442Trp)	Likely pathogenic
810644	NM_003359.4(UGDH):c.1228G>T (p.Ala410Ser)	Likely pathogenic
810645	NM_003359.4(UGDH):c.1177C>T (p.Arg393Trp)	Likely pathogenic
810647	NM_003359.4(UGDH):c.1068T>G (p.Tyr356Ter)	Likely pathogenic
810648	NM_003359.4(UGDH):c.916A>G (p.Met306Val)	Likely pathogenic
810649	NM_003359.4(UGDH):c.907G>A (p.Val303Ile)	Likely pathogenic
810650	NM_003359.4(UGDH):c.811G>C (p.Gly271Arg)	Likely pathogenic
810651	NM_003359.4(UGDH):c.764T>C (p.Ile255Thr)	Likely pathogenic
810652	NM_003359.4(UGDH):c.651G>C (p.Glu217Asp)	Likely pathogenic
810653	NM_003359.4(UGDH):c.523C>G (p.Pro175Ala)	Likely pathogenic
810654	NM_003359.4(UGDH):c.463C>T (p.Gln155Ter)	Likely pathogenic
810655	NM_003359.4(UGDH):c.374T>C (p.Ile125Thr)	Likely pathogenic
810660	NM_003359.4(UGDH):c.125T>C (p.Ile42Thr)	Likely pathogenic
810661	NM_003359.4(UGDH):c.70G>A (p.Ala24Thr)	Likely pathogenic

SpliceAI

1484 predictions. Top by Δscore:

Variant	Effect	Δscore
4:39503870:ATTAC:A	donor_loss	1.0000
4:39503871:TTAC:T	donor_loss	1.0000
4:39503872:TA:T	donor_loss	1.0000
4:39503981:AATTC:A	acceptor_gain	1.0000
4:39503982:ATTC:A	acceptor_gain	1.0000
4:39503983:TTC:T	acceptor_gain	1.0000
4:39503984:TC:T	acceptor_gain	1.0000
4:39503984:TCCT:T	acceptor_loss	1.0000
4:39503985:CC:C	acceptor_gain	1.0000
4:39503986:C:CC	acceptor_gain	1.0000
4:39503986:CTGT:C	acceptor_loss	1.0000
4:39503995:C:CT	acceptor_gain	1.0000
4:39504412:CTTA:C	donor_loss	1.0000
4:39504414:TAC:T	donor_loss	1.0000
4:39504415:A:C	donor_loss	1.0000
4:39504416:C:CT	donor_loss	1.0000
4:39504504:GGACA:G	acceptor_gain	1.0000
4:39504505:GACA:G	acceptor_gain	1.0000
4:39504506:ACA:A	acceptor_gain	1.0000
4:39504507:CA:C	acceptor_gain	1.0000
4:39504507:CAC:C	acceptor_gain	1.0000
4:39504508:ACT:A	acceptor_loss	1.0000
4:39504509:C:CA	acceptor_loss	1.0000
4:39504509:C:CC	acceptor_gain	1.0000
4:39504511:G:C	acceptor_gain	1.0000
4:39504511:G:GC	acceptor_gain	1.0000
4:39504515:C:CT	acceptor_gain	1.0000
4:39504516:A:T	acceptor_gain	1.0000
4:39504517:A:AC	acceptor_gain	1.0000
4:39504517:A:C	acceptor_gain	1.0000

AlphaMissense

3263 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:39504431:A:G	W417R	1.000
4:39504431:A:T	W417R	1.000
4:39504452:C:G	A410P	1.000
4:39505624:T:C	D344G	1.000
4:39505625:C:G	D344H	1.000
4:39505638:T:A	K339N	1.000
4:39505638:T:G	K339N	1.000
4:39505639:T:A	K339I	1.000
4:39505640:T:C	K339E	1.000
4:39505641:G:C	F338L	1.000
4:39505641:G:T	F338L	1.000
4:39505643:A:G	F338L	1.000
4:39505651:C:T	G335E	1.000
4:39505652:C:G	G335R	1.000
4:39505652:C:T	G335R	1.000
4:39508633:T:G	D280A	1.000
4:39508651:C:T	G274E	1.000
4:39508654:C:T	G273D	1.000
4:39508656:A:C	F272L	1.000
4:39508656:A:T	F272L	1.000
4:39508658:A:G	F272L	1.000
4:39508660:C:T	G271E	1.000
4:39509848:A:C	C241W	1.000
4:39509872:G:C	S233R	1.000
4:39509872:G:T	S233R	1.000
4:39509874:T:G	S233R	1.000
4:39509875:G:C	S232R	1.000
4:39509875:G:T	S232R	1.000
4:39509877:T:G	S232R	1.000
4:39510356:T:A	K220N	1.000

dbSNP variants (sampled 300 via entrez): RS1000084236 (4:39502551 A>G), RS10001159 (4:39519608 G>A,C), RS10004662 (4:39504233 A>C,G), RS1000521950 (4:39528058 C>T), RS1000567123 (4:39498547 A>C), RS1000586805 (4:39521024 C>G,T), RS1000621202 (4:39498876 G>A,T), RS10007626 (4:39513796 C>A,G), RS10007732 (4:39513917 C>G,T), RS1000809898 (4:39503557 T>C), RS1000870669 (4:39527814 C>G,T), RS1000950593 (4:39507562 C>T), RS1001028045 (4:39517839 C>T), RS10010387 (4:39505320 T>C), RS1001059929 (4:39500671 T>C)

Disease associations

OMIM: gene MIM:603370 | disease phenotypes: MIM:618792

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 84	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital heart disease	Disputed	AD

Mondo (2): developmental and epileptic encephalopathy, 84 (MONDO:0032918), infantile spasms (MONDO:0018097)

Orphanet (2): West syndrome (Orphanet:3451), Infantile epileptic spasms syndrome (Orphanet:697160)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000179	Thick lower lip vermilion
HP:0000252	Microcephaly
HP:0000286	Epicanthus
HP:0000307	Pointed chin
HP:0000319	Smooth philtrum
HP:0000490	Deeply set eye
HP:0000508	Ptosis
HP:0000581	Blepharophimosis
HP:0000664	Synophrys
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001284	Areflexia
HP:0001290	Generalized hypotonia
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001357	Plagiocephaly
HP:0002072	Chorea
HP:0002119	Ventriculomegaly
HP:0002179	Opisthotonus
HP:0002188	Delayed CNS myelination
HP:0002521	Hypsarrhythmia
HP:0003487	Babinski sign
HP:0008936	Axial hypotonia
HP:0009748	Large earlobe
HP:0010851	EEG with burst suppression
HP:0011097	Epileptic spasm
HP:0011344	Severe global developmental delay
HP:0011471	Gastrostomy tube feeding in infancy
HP:0012745	Short palpebral fissure

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST012083_2	Response to tofacitinib treatment in psoriasis (herpes zoster)	4.000000e-06
GCST012085_2	Response to tofacitinib treatment in psoriasis (herpes zoster)(time to event)	2.000000e-08
GCST90014033_29	Haemorrhoidal disease	6.000000e-09

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067024 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, affects cotreatment, decreases expression	6
sodium arsenite	affects expression, decreases expression, increases expression	4
cobaltous chloride	decreases expression, affects cotreatment, increases expression	3
Benzo(a)pyrene	affects expression, increases methylation, affects cotreatment, increases expression	3
Estradiol	affects cotreatment, decreases expression, increases expression	3
Tobacco Smoke Pollution	affects expression, increases expression	3
Genistein	decreases expression, increases reaction, increases expression	3
Particulate Matter	decreases expression, increases abundance, increases expression	3
bisphenol A	affects expression, decreases expression	2
perfluorooctanoic acid	decreases expression, increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
Arsenic Trioxide	decreases expression, increases expression	2
Acetaminophen	decreases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Cisplatin	increases expression	2
Rotenone	decreases expression, increases expression	2
Tunicamycin	increases expression	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
hydroxyethyl methacrylate	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects cotreatment, decreases expression	1
lead acetate	increases expression	1
methylselenic acid	affects expression	1
piperine	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
beta-lapachone	increases expression	1
sulforaphane	increases expression	1
butyraldehyde	decreases expression	1
zinc chromate	increases abundance, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652767	Binding	Binding affinity to human UGDH incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8XX	Ubigene HCT 116 UGDH KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01413711	PHASE4	WITHDRAWN	An Open-Label, Single and Multiple Oral Dose Pharmacokinetic Study of Vigabatrin in Infants With Infantile Spasms
NCT02092883	PHASE4	COMPLETED	Evaluation of Neuroinflammation in Children With Infantile Spasms
NCT01575639	PHASE3	COMPLETED	Prednisolone in Infantile Spasms- High Dose Versus Usual Dose
NCT01828437	PHASE3	COMPLETED	Addition of Pyridoxine to Prednisolone in Infantile Spasms
NCT02299115	PHASE3	WITHDRAWN	Prednisolone Versus Vigabatrin in the First-line Treatment of Infantile Spasms
NCT02953548	PHASE3	COMPLETED	Trial of Cannabidiol (CBD; GWP42003-P) for Infantile Spasms (GWPCARE7)
NCT02954887	PHASE3	COMPLETED	Phase 3 Trial of Cannabidiol (CBD; GWP42003-P) for Infantile Spasms: Open-label Extension Phase (GWPCARE7)
NCT00441896	PHASE2	COMPLETED	A Randomized, Controlled Trial of Ganaxolone in Patients With Infantile Spasms
NCT00442104	PHASE2	TERMINATED	Open-label Extension to Protocol 1042-0500
NCT02829827	PHASE2	TERMINATED	A Phase 2 Study of Radiprodil in Subjects With Drug-resistant Infantile Spasms (IS)
NCT03976076	PHASE2	TERMINATED	A Study of Orally Administered JBPOS0101 in Refractory Infantile Spasms Patients
NCT06819670	PHASE2	RECRUITING	A Study to Prevent Infantile Spasms Relapse
NCT01006811	PHASE2/PHASE3	COMPLETED	Use of the Modified Atkins Diet in Infantile Spasms
NCT01549288	PHASE2/PHASE3	WITHDRAWN	Trial of the Modified Atkins Diet in Infantile Spasms Refractory to Hormonal Therapy
NCT05279118	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Ketogenic Diet vs ACTH for the Treatment of Children With West Syndrome
NCT06201897	PHASE2/PHASE3	RECRUITING	Cortical Excitability in West Syndrome Using Transcranial Magnetic Stimulation
NCT00001325	Not specified	COMPLETED	Metabolic Abnormalities in Children With Epilepsy
NCT00552045	Not specified	COMPLETED	Epilepsy Phenome/Genome Project
NCT00968136	Not specified	COMPLETED	Short-term Ketogenic Diet as Compared With Conventional Long-term Trial in Refractory Infantile Spasms: A Randomized, Controlled Study
NCT01073579	Not specified	COMPLETED	Sabril Patient Registry
NCT01367964	Not specified	UNKNOWN	Prevention of West Syndrome With Low-dose Adrenocorticotropin Hormone (ACTH)
NCT01723787	Not specified	COMPLETED	Genetic Studies in Patients and Families With Infantile Spasms
NCT02220114	Not specified	COMPLETED	Acceptability Study of a New Paediatric Form of Vigabatrin in Infants and Children With Infantile Spasms or Pharmacoresistant Partial Epilepsy
NCT02885389	Not specified	COMPLETED	Molecular Genetics in Infantile Spasms
NCT04302116	Not specified	RECRUITING	Vigabatrin With High Dose Prednisolone Combination Therapy vs Vigabatrin Alone for Infantile Spasm
NCT05126914	Not specified	RECRUITING	Multicentre Real-life Follow-up Study of Rare Epileptic Syndromes in Children and Adolescents
NCT06315829	Not specified	COMPLETED	Artificial Intelligence-based Video Analysis to Detect Infantile Spasms