PDHB

Summary

PDHB (pyruvate dehydrogenase E1 subunit beta, HGNC:8808) is a protein-coding gene on chromosome 3p14.3, encoding Pyruvate dehydrogenase E1 component subunit beta, mitochondrial (P11177). Together with PDHA1 forms the heterotetrameric E1 subunit of the pyruvate dehydrogenase (PDH) complex.

The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and carbon dioxide, and provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle. The PDH complex is composed of multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and lipoamide dehydrogenase (E3). The E1 enzyme is a heterotetramer of two alpha and two beta subunits. This gene encodes the E1 beta subunit. Mutations in this gene are associated with pyruvate dehydrogenase E1-beta deficiency. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 5162 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pyruvate dehydrogenase E1-beta deficiency (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 12
• Clinical variants (ClinVar): 397 total — 17 pathogenic, 20 likely-pathogenic
• Phenotypes (HPO): 28
• Druggable target: yes
• MANE Select transcript: NM_000925

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8808
Approved symbol	PDHB
Name	pyruvate dehydrogenase E1 subunit beta
Location	3p14.3
Locus type	gene with protein product
Status	Approved
Aliases	PDHE1B, E1beta
Ensembl gene	ENSG00000168291
Ensembl biotype	protein_coding
OMIM	179060
Entrez	5162

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 13 protein_coding, 5 retained_intron, 1 nonsense_mediated_decay

ENST00000302746, ENST00000383714, ENST00000461692, ENST00000469364, ENST00000469827, ENST00000474765, ENST00000479945, ENST00000480626, ENST00000482894, ENST00000485460, ENST00000909150, ENST00000909152, ENST00000909153, ENST00000909154, ENST00000909155, ENST00000909156, ENST00000909157, ENST00000962538, ENST00000962539

RefSeq mRNA: 3 — MANE Select: NM_000925 NM_000925, NM_001173468, NM_001315536

CCDS: CCDS2890, CCDS54602, CCDS82795

Canonical transcript exons

ENST00000302746 — 10 exons

Exon	Start	End
ENSE00001835890	58427630	58428179
ENSE00001931564	58433768	58433832
ENSE00003484528	58430657	58430942
ENSE00003520071	58430128	58430238
ENSE00003562164	58428473	58428614
ENSE00003574534	58429708	58429799
ENSE00003579089	58431731	58431793
ENSE00003670871	58431877	58431984
ENSE00003672873	58431593	58431628
ENSE00003690105	58433631	58433684

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 99.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 73.8955 / max 1218.7888, expressed in 1826 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42689	73.8955	1826

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.46	gold quality
heart right ventricle	UBERON:0002080	99.32	gold quality
biceps brachii	UBERON:0001507	98.85	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.71	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.70	gold quality
left ventricle myocardium	UBERON:0006566	98.69	gold quality
body of tongue	UBERON:0011876	98.61	gold quality
deltoid	UBERON:0001476	98.60	gold quality
myocardium	UBERON:0002349	98.52	gold quality
choroid plexus epithelium	UBERON:0003911	98.47	gold quality
vastus lateralis	UBERON:0001379	98.41	gold quality
tibialis anterior	UBERON:0001385	98.40	gold quality
quadriceps femoris	UBERON:0001377	98.36	gold quality
cardiac ventricle	UBERON:0002082	98.23	gold quality
adrenal tissue	UBERON:0018303	98.21	gold quality
heart left ventricle	UBERON:0002084	98.20	gold quality
triceps brachii	UBERON:0001509	98.13	gold quality
skeletal muscle tissue	UBERON:0001134	98.00	gold quality
muscle organ	UBERON:0001630	97.94	gold quality
skeletal muscle organ	UBERON:0014892	97.94	gold quality
gastrocnemius	UBERON:0001388	97.84	gold quality
muscle tissue	UBERON:0002385	97.83	gold quality
muscle of leg	UBERON:0001383	97.82	gold quality
heart	UBERON:0000948	97.79	gold quality
gluteal muscle	UBERON:0002000	97.77	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.77	gold quality
diaphragm	UBERON:0001103	97.74	gold quality
apex of heart	UBERON:0002098	97.74	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	97.73	gold quality
cardiac muscle of right atrium	UBERON:0003379	97.69	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

38 targeting PDHB, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-3606-3P	99.11	69.84	3254
HSA-MIR-194-5P	99.01	69.65	1465
HSA-MIR-942-3P	98.81	69.04	876
HSA-MIR-6893-3P	97.79	64.91	1238

Literature-anchored findings (GeneRIF, showing 10)

• Data indicate that PDH deficiency in our patient involves a post-translational modification in which EGFR-PTK-mediated tyrosine phosphorylation of the E1beta protein leads to enhanced ubiquitination followed by proteasome-mediated degradation. (PMID:17923481)
• clinical findings are similar to those of PDHA1 deficiency, except that ataxia was more frequent in PDHA1 cases and consanguinity was found only in PDHB families. (PMID:18164639)
• Species specificity in the interaction between hE1beta and hE2 in pyruvate dehydrogenase complex. (PMID:18206651)
• Sequencing of PDHB reveals a homozygous point mutation (c.302T>C), causing a predicted amino acid change in patient 1. Patient 2 is compound heterozygote for mutations c.301A>G (p.M101V) and c.313G>A (p.R105Q). (PMID:19924563)
• PHD3 depletion did not affect the expression of the PDH-E1alpha, E1beta, and E2 subunits, or the phosphorylation status of E1alpha, but destabilized the PDH complex (PDC), resulting in less functional PDC. (PMID:25088999)
• Data indicate that (pro)renin receptor ATP6PA2 interacts with the E1 beta subunit of pyruvate dehydrogenase and controlling its protein stability (PMID:25720494)
• PDHB was downregulated in nasopharyngeal carcinoma cells. Forced expression of PDHB in NPC cells inhibited cell growth and migration, while knocking down the expression of PDHB promoted the growth, migration, and tumorigenesis of NPC cells. PDHB inhibited ERK signaling and cell growth driven by RasV12. (PMID:26857147)
• Building on evidence that PDH activity depends on the stability of a multi-protein PDH complex, the authors found that the PDH-E1beta subunit of the PDH complex is downregulated to inhibit PDH activity under conditions of prolonged hypoxia which establishs the specific mechanism through which PDH acts as an oncogenic factor by tuning glycolytic metabolism in cancer cells. (PMID:29436427)
• Pyruvate dehydrogenase B regulates myogenic differentiation via the FoxP1-Arih2 axis. (PMID:36564038)
• Integrated single-cell and bulk characterization of cuproptosis key regulator PDHB and association with tumor microenvironment infiltration in clear cell renal cell carcinoma. (PMID:37350959)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pdhb	ENSDARG00000021346
mus_musculus	Pdhb	ENSMUSG00000021748
rattus_norvegicus	Pdhb	ENSRNOG00000007895
drosophila_melanogaster	Pdhb	FBGN0039635
caenorhabditis_elegans		WBGENE00015413

Paralogs (4): TKTL1 (ENSG00000007350), BCKDHB (ENSG00000083123), TKTL2 (ENSG00000151005), TKT (ENSG00000163931)

Protein

Protein identifiers

Pyruvate dehydrogenase E1 component subunit beta, mitochondrial — P11177 (reviewed: P11177)

All UniProt accessions (4): P11177, A0A384MDR8, C9J634, F8WF02

UniProt curated annotations — full annotation on UniProt →

Function. Together with PDHA1 forms the heterotetrameric E1 subunit of the pyruvate dehydrogenase (PDH) complex. The PDH complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links cytoplasmic glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle. It contains multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and dihydrolipoamide dehydrogenase (E3). The E1 subunit catalyzes both the thiamine pyrophosphate (TPP)-dependent decarboxylation of pyruvate and the reductive acetylation of a lipoyl group covalently linked to the lipoyl-bearing domains of E2.

Subunit / interactions. Heterotetramer of two PDHA1 and two PDHB subunits. The heterotetramer interacts with DLAT, and is part of the multimeric pyruvate dehydrogenase (PDH) complex that contains multiple copies of pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3). These subunits are bound to an inner core composed of about 48 DLAT and 12 PDHX molecules. Interacts with DLAT.

Subcellular location. Mitochondrion matrix.

Disease relevance. Pyruvate dehydrogenase E1-beta deficiency (PDHBD) [MIM:614111] An enzymatic defect causing primary lactic acidosis in children. It is associated with a broad clinical spectrum ranging from fatal lactic acidosis in the newborn to chronic neurologic dysfunction with structural abnormalities in the central nervous system without systemic acidosis. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
P11177-1	1	yes
P11177-2	2
P11177-3	3

RefSeq proteins (3): NP_000916, NP_001166939, NP_001302465 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005475	Transketolase-like_Pyr-bd	Domain
IPR009014	Transketo_C/PFOR_II	Homologous_superfamily
IPR027110	PDHB_mito-type	Family
IPR029061	THDP-binding	Homologous_superfamily
IPR033248	Transketolase_C	Domain

Pfam: PF02779, PF02780

Enzyme classification (BRENDA):

• EC 1.2.1.104 — pyruvate dehydrogenase system (BRENDA: 46 organisms, 32 substrates, 100 inhibitors, 83 Km, 12 kcat entries)
• EC 1.2.4.1 — pyruvate dehydrogenase (acetyl-transferring) (BRENDA: 29 organisms, 58 substrates, 114 inhibitors, 56 Km, 45 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
PYRUVATE	0.0002–1	44
PYRUVATE	0.0011–1.7	32
NAD+	0.01–0.27	14
THIAMINE DIPHOSPHATE	0.0006–0.065	14
COA	0.0005–0.61	12
THIAMINE DIPHOSPHATE	0.0016–0.05	3
LIPOYL DOMAIN	0.024–0.027	2
2-OXOBUTANOATE	1.35	1
2-OXOBUTYRATE	1.66	1
2-OXOISOVALERATE	1.27	1
COENZYME A	0.003	1
HYDROXYETHYL THIAMINE DIPHOSPHATE	0.0082	1
LIPOYL DOMAIN	0.02	1
N-ACETYL-GDLLAEIETDK(LIPOYL)-ATIG-AMIDE	15	1
N-TERMINAL LIPOYL DOMAIN	0.052	1

Catalyzed reactions (Rhea), 1 shown:

• N(6)-[(R)-lipoyl]-L-lysyl-[protein] + pyruvate + H(+) = N(6)-[(R)-S(8)-acetyldihydrolipoyl]-L-lysyl-[protein] + CO2 (RHEA:19189)

UniProt features (66 total): strand 16, helix 16, mutagenesis site 7, turn 7, binding site 6, sequence conflict 4, sequence variant 3, modified residue 2, splice variant 2, transit peptide 1, chain 1, site 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
2OZL	X-RAY DIFFRACTION	1.9
1NI4	X-RAY DIFFRACTION	1.95
3EXE	X-RAY DIFFRACTION	1.98
3EXI	X-RAY DIFFRACTION	2.2
3EXH	X-RAY DIFFRACTION	2.44
6CER	X-RAY DIFFRACTION	2.69
6CFO	X-RAY DIFFRACTION	2.7
3EXF	X-RAY DIFFRACTION	3
3EXG	X-RAY DIFFRACTION	3.01

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P11177-F1	94.18	0.91

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): 319 (important for interaction with dlat)

Ligand- & substrate-binding residues (6): 89; 142; 190; 191; 193; 195

Post-translational modifications (2): 354, 67

Mutagenesis-validated functional residues (7):

Position	Phenotype
259	does not affect interaction with dlat.
262	does not affect interaction with dlat.
264	does not affect interaction with dlat.
319	inhibits interaction with dlat. does not affect pyruvate decarboxylase activity. loss of multienzyme pyruvate dehydrogen
319	reduces interaction with dlat. reduces multienzyme pyruvate dehydrogenase complex activity. does not affect pyruvate dec
359	reduces pyruvate decarboxylase and multienzyme pyruvate dehydrogenase complex activity. does not affect interaction with

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-204174	Regulation of pyruvate dehydrogenase (PDH) complex
R-HSA-5362517	Signaling by Retinoic Acid
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-9861559	PDH complex synthesizes acetyl-CoA from PYR

MSigDB gene sets: 220 (showing top): STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, MORF_HDAC1, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, MORF_HDAC2, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, KEGG_GLYCOLYSIS_GLUCONEOGENESIS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ACETYL_COA_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_SULFUR_COMPOUND_BIOSYNTHETIC_PROCESS, WATANABE_RECTAL_CANCER_RADIOTHERAPY_RESPONSIVE_UP, GOBP_AMIDE_METABOLIC_PROCESS

GO Biological Process (4): glucose metabolic process (GO:0006006), pyruvate decarboxylation to acetyl-CoA (GO:0006086), tricarboxylic acid cycle (GO:0006099), purine-containing compound biosynthetic process (GO:0072522)

GO Molecular Function (4): pyruvate dehydrogenase (acetyl-transferring) activity (GO:0004739), metal ion binding (GO:0046872), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), pyruvate dehydrogenase complex (GO:0045254)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Regulation of pyruvate metabolism	1
Signaling by Nuclear Receptors	1
Metabolism of proteins	1
Pyruvate metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
aerobic respiration	2
intracellular membrane-bounded organelle	2
hexose metabolic process	1
dihydrolipoyl dehydrogenase (NADH) activity	1
pyruvate dehydrogenase (acetyl-transferring) activity	1
dihydrolipoyllysine-residue acetyltransferase activity	1
acetyl-CoA biosynthetic process	1
pyruvate metabolic process	1
primary metabolic process	1
biosynthetic process	1
purine-containing compound metabolic process	1
oxidoreductase activity, acting on the aldehyde or oxo group of donors, disulfide as acceptor	1
cation binding	1
binding	1
catalytic activity	1
nuclear lumen	1
cellular anatomical structure	1
cytoplasm	1
mitochondrion	1
intracellular organelle lumen	1
alpha-ketoacid dehydrogenase complex	1
acetyltransferase complex	1

Protein interactions and networks

STRING

3220 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDHB	PDHA1	P08559	999
PDHB	PDHX	O00330	997
PDHB	DLAT	P10515	995
PDHB	PDHA2	P29803	913
PDHB	PDP2	Q9P2J9	904
PDHB	DLD	P09622	891
PDHB	PDP1	Q9P0J1	852
PDHB	IDH3G	P51553	741
PDHB	IDH3A	P50213	710
PDHB	PKM	P14618	710
PDHB	PLG	P00747	693
PDHB	MDH2	P40926	677
PDHB	GAPDH	P00354	668
PDHB	OGDH	Q02218	665
PDHB	SUCLA2	Q9P2R7	665

IntAct

142 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
PDHB	PDHA1	psi-mi:“MI:0407”(direct interaction)	0.690
DLAT	PDHB	psi-mi:“MI:0407”(direct interaction)	0.670
PDHB	DLAT	psi-mi:“MI:0407”(direct interaction)	0.670
STAT5A	PDHA1	psi-mi:“MI:0914”(association)	0.640
PDHB	SHANK3	psi-mi:“MI:0915”(physical association)	0.550
DLD	PDHB	psi-mi:“MI:0914”(association)	0.530
FOXD4	PDHX	psi-mi:“MI:0914”(association)	0.530
STAT5A	PDHX	psi-mi:“MI:0914”(association)	0.530
CFAP20	KPNA4	psi-mi:“MI:0914”(association)	0.510
NDUFAB1	MIEF1	psi-mi:“MI:0915”(physical association)	0.490
sseJ	AGPS	psi-mi:“MI:0914”(association)	0.460
DUSP29	PDHB	psi-mi:“MI:0914”(association)	0.420
DUSP29	PDHB	psi-mi:“MI:2364”(proximity)	0.420
PDHB	ADORA2A	psi-mi:“MI:0915”(physical association)	0.370
PDHB	FCER1A	psi-mi:“MI:0915”(physical association)	0.370
PDHB	GNB2	psi-mi:“MI:0915”(physical association)	0.370
PDHB	ITGB1	psi-mi:“MI:0915”(physical association)	0.370
PDHB	ANXA7	psi-mi:“MI:0915”(physical association)	0.370
CDKN1A	PDHB	psi-mi:“MI:0915”(physical association)	0.370
GRB7	PDHB	psi-mi:“MI:0915”(physical association)	0.370
PDHB	PFDN1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (422): PDHB (Affinity Capture-MS), PDHB (Affinity Capture-MS), PDHB (Affinity Capture-MS), PDHX (Affinity Capture-MS), DLD (Affinity Capture-MS), PDK2 (Affinity Capture-MS), PDK1 (Affinity Capture-MS), PDK3 (Affinity Capture-MS), PPP3CB (Affinity Capture-MS), PPP3CC (Affinity Capture-MS), PPP3CA (Affinity Capture-MS), ARMC8 (Affinity Capture-MS), DLAT (Affinity Capture-MS), RMND5A (Affinity Capture-MS), PPP3R1 (Affinity Capture-MS)

ESM2 similar proteins: A2CI50, G0RYE0, O34591, O44451, O64688, O66113, P09061, P0A0A1, P0A0A2, P0A0A3, P11177, P11966, P21874, P21882, P26269, P27746, P32473, P35488, P47515, P49432, P52904, P75391, P99063, Q09171, Q0J0H4, Q10G39, Q1XDM1, Q2QM55, Q38799, Q4UKQ7, Q55FN7, Q5HGZ0, Q5HQ75, Q5RE79, Q68XA8, Q6ABX8, Q6GAC0, Q6GHZ1, Q6Z1G7, Q7K5K3

Diamond homologs: A2CI50, G0RYE0, O34591, O44451, O64688, O66113, P09061, P0A0A1, P0A0A2, P0A0A3, P11177, P11966, P21839, P21874, P21882, P21953, P26269, P27746, P32473, P35488, P35738, P37941, P47515, P49432, P51266, P52904, P75391, P99063, P9WF02, P9WIS0, P9WIS1, Q09171, Q0J0H4, Q10G39, Q1ACL0, Q1RJX3, Q1XDM1, Q2QM55, Q32RM2, Q32RS0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PDHB	“form complex”	PDH	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 129 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
Regulation of pyruvate dehydrogenase (PDH) complex	6	46.5×	1e-06
Signaling by Retinoic Acid	5	22.2×	7e-04
Signaling by ALK fusions and activated point mutants	6	9.8×	4e-03
Signaling by Interleukins	8	5.6×	4e-03
Cytokine Signaling in Immune system	10	4.4×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to epidermal growth factor stimulus	5	14.3×	5e-03
epidermal growth factor receptor signaling pathway	5	11.2×	9e-03
autophagy	8	7.9×	2e-03
cell population proliferation	7	6.5×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	20
Uncertain significance	94
Likely benign	214
Benign	24

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
13189	NM_000925.4(PDHB):c.1030C>T (p.Pro344Ser)	Pathogenic
217513	NM_000925.4(PDHB):c.300_303+7del	Pathogenic
2501782	NM_000925.4(PDHB):c.1A>G (p.Met1Val)	Pathogenic
2760571	NM_000925.4(PDHB):c.714dup (p.Val239fs)	Pathogenic
2799883	NM_000925.4(PDHB):c.495G>A (p.Trp165Ter)	Pathogenic
2834403	NM_000925.4(PDHB):c.803del (p.Met268fs)	Pathogenic
2853430	NM_000925.4(PDHB):c.231T>G (p.Tyr77Ter)	Pathogenic
2859779	NM_000925.4(PDHB):c.639_655del (p.Pro214fs)	Pathogenic
2961156	NM_000925.4(PDHB):c.478_479del (p.Gln160fs)	Pathogenic
3003908	NM_000925.4(PDHB):c.533_534delinsAA (p.Trp178Ter)	Pathogenic
3014800	NM_000925.4(PDHB):c.578del (p.Asp193fs)	Pathogenic
3677772	NM_000925.4(PDHB):c.692_695del (p.Glu231fs)	Pathogenic
4721142	NM_000925.4(PDHB):c.650dup (p.Ser218fs)	Pathogenic
4725125	NM_000925.4(PDHB):c.461dup (p.Ala155fs)	Pathogenic
839569	NM_000925.4(PDHB):c.301A>G (p.Met101Val)	Pathogenic
978592	NM_000925.4(PDHB):c.494G>C (p.Trp165Ser)	Pathogenic
978593	NM_000925.4(PDHB):c.302T>C (p.Met101Thr)	Pathogenic
13188	NM_000925.4(PDHB):c.395A>G (p.Tyr132Cys)	Likely pathogenic
214951	NM_000925.4(PDHB):c.419T>A (p.Val140Glu)	Likely pathogenic
2413152	NM_000925.4(PDHB):c.121C>T (p.Gln41Ter)	Likely pathogenic
2445695	NM_000925.4(PDHB):c.818del (p.Pro273fs)	Likely pathogenic
2677595	NM_000925.4(PDHB):c.469C>T (p.Gln157Ter)	Likely pathogenic
2677597	NM_000925.4(PDHB):c.352C>T (p.Gln118Ter)	Likely pathogenic
2677599	NM_000925.4(PDHB):c.934+1G>A	Likely pathogenic
2677601	NM_000925.4(PDHB):c.607G>T (p.Glu203Ter)	Likely pathogenic
2781103	NM_000925.4(PDHB):c.303+1G>C	Likely pathogenic
2975494	NM_000925.4(PDHB):c.304-1G>C	Likely pathogenic
3240066	NM_000925.4(PDHB):c.669dup (p.Pro224fs)	Likely pathogenic
3240067	NM_000925.4(PDHB):c.892_893del (p.Gln298fs)	Likely pathogenic
3776790	NM_000925.4(PDHB):c.575G>A (p.Arg192Gln)	Likely pathogenic

SpliceAI

1013 predictions. Top by Δscore:

Variant	Effect	Δscore
3:58428475:T:A	donor_gain	1.0000
3:58429703:CTCA:C	donor_loss	1.0000
3:58429704:TCACC:T	donor_loss	1.0000
3:58429705:CAC:C	donor_loss	1.0000
3:58429706:A:AC	donor_gain	1.0000
3:58429706:ACCTC:A	donor_loss	1.0000
3:58429707:C:CC	donor_gain	1.0000
3:58429707:C:G	donor_loss	1.0000
3:58430123:CTTA:C	donor_loss	1.0000
3:58430124:TTACC:T	donor_loss	1.0000
3:58430127:CCTTG:C	donor_gain	1.0000
3:58430131:G:A	donor_gain	1.0000
3:58430234:CACCA:C	acceptor_gain	1.0000
3:58430235:ACCA:A	acceptor_gain	1.0000
3:58430236:CCA:C	acceptor_gain	1.0000
3:58430236:CCAC:C	acceptor_gain	1.0000
3:58430237:CA:C	acceptor_gain	1.0000
3:58430237:CAC:C	acceptor_gain	1.0000
3:58430238:ACTGA:A	acceptor_loss	1.0000
3:58430239:C:CC	acceptor_gain	1.0000
3:58430248:A:C	acceptor_gain	1.0000
3:58431872:GTTAC:G	donor_loss	1.0000
3:58431873:TTA:T	donor_loss	1.0000
3:58431874:TAC:T	donor_loss	1.0000
3:58431875:A:T	donor_loss	1.0000
3:58431984:CCTG:C	acceptor_loss	1.0000
3:58431985:C:CA	acceptor_loss	1.0000
3:58431986:T:A	acceptor_loss	1.0000
3:58431996:A:AC	acceptor_gain	1.0000
3:58431996:A:C	acceptor_gain	1.0000

AlphaMissense

2344 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:58430809:C:T	G146E	1.000
3:58430901:G:C	F115L	1.000
3:58430901:G:T	F115L	1.000
3:58430902:A:G	F115S	1.000
3:58430903:A:G	F115L	1.000
3:58430904:A:C	N114K	1.000
3:58430904:A:T	N114K	1.000
3:58430913:C:A	M111I	1.000
3:58430913:C:G	M111I	1.000
3:58430913:C:T	M111I	1.000
3:58431887:C:T	G65E	1.000
3:58431905:T:A	E59V	1.000
3:58430689:A:G	L186P	0.999
3:58430753:A:G	W165R	0.999
3:58430753:A:T	W165R	0.999
3:58430771:A:G	S159P	0.999
3:58430772:G:C	H158Q	0.999
3:58430772:G:T	H158Q	0.999
3:58430773:T:C	H158R	0.999
3:58430774:G:C	H158D	0.999
3:58430802:A:C	N148K	0.999
3:58430802:A:T	N148K	0.999
3:58430810:C:A	G146W	0.999
3:58430810:C:G	G146R	0.999
3:58430810:C:T	G146R	0.999
3:58430811:T:A	R145S	0.999
3:58430811:T:G	R145S	0.999
3:58430815:A:G	F144S	0.999
3:58430818:A:T	V143D	0.999
3:58430866:G:T	A127D	0.999

dbSNP variants (sampled 300 via entrez): RS1000884749 (3:58429990 C>A,T), RS1002128583 (3:58435335 G>A), RS1002366215 (3:58433263 A>G), RS1002388475 (3:58429638 G>A), RS1003377708 (3:58427982 G>A,C), RS1004927563 (3:58428856 CTTT>C,CTT,CTTTTTT), RS1005080856 (3:58435267 G>A), RS1005133675 (3:58435113 G>A), RS1005344936 (3:58428396 C>T), RS1006210232 (3:58432494 C>G,T), RS1006493424 (3:58433960 G>A,C,T), RS1006798214 (3:58430882 G>A), RS1007176075 (3:58431663 A>C,G,T), RS1008487661 (3:58435742 C>G), RS1008600618 (3:58435375 G>T)

Disease associations

OMIM: gene MIM:179060 | disease phenotypes: MIM:614111, MIM:608782, MIM:312170

GenCC curated gene-disease

Disease	Classification	Inheritance
pyruvate dehydrogenase E1-beta deficiency	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Leigh syndrome	Moderate	AR

Mondo (3): pyruvate dehydrogenase E1-beta deficiency (MONDO:0013580), pyruvate dehydrogenase phosphatase deficiency (MONDO:0012120), pyruvate dehydrogenase deficiency (MONDO:0019169)

Orphanet (4): Pyruvate dehydrogenase E1-beta deficiency (Orphanet:255138), Pyruvate dehydrogenase deficiency (Orphanet:765), Pyruvate dehydrogenase phosphatase deficiency (Orphanet:79246), Pyruvate dehydrogenase E1-alpha deficiency (Orphanet:79243)

HPO phenotypes

28 total (28 of 28 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001274	Agenesis of corpus callosum
HP:0001290	Generalized hypotonia
HP:0001302	Pachygyria
HP:0001315	Reduced tendon reflexes
HP:0001321	Cerebellar hypoplasia
HP:0001511	Intrauterine growth retardation
HP:0001987	Hyperammonemia
HP:0001999	Abnormal facial shape
HP:0002079	Hypoplasia of the corpus callosum
HP:0002119	Ventriculomegaly
HP:0002365	Hypoplasia of the brainstem
HP:0002683	Abnormal calvaria morphology
HP:0002928	Decreased activity of the pyruvate dehydrogenase complex
HP:0003128	Lactic acidosis
HP:0004325	Decreased body weight
HP:0006970	Periventricular leukomalacia
HP:0007016	Corticospinal tract hypoplasia
HP:0007109	Periventricular cysts
HP:0007165	Periventricular heterotopia
HP:0007772	Impaired smooth pursuit
HP:0012758	Neurodevelopmental delay
HP:0200012	Short corpus callosum

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST003155_45	Systemic lupus erythematosus	3.000000e-14
GCST005752_17	Systemic lupus erythematosus	2.000000e-08
GCST006197_6	Type 1 diabetes autoantibodies in high risk HLA genotype individuals (time to event)	9.000000e-06
GCST007446_42	vWF levels	6.000000e-09
GCST007446_43	vWF levels	9.000000e-09
GCST007446_82	vWF levels	3.000000e-08
GCST007446_83	vWF levels	5.000000e-09
GCST008570_2	Composite immunoglobulin trait (IgA x IgG/IgM)	3.000000e-08
GCST008576_6	IgG levels	7.000000e-07
GCST010002_426	Refractive error	5.000000e-14
GCST010243_109	Apolipoprotein B levels	3.000000e-12
GCST010245_179	LDL cholesterol levels	7.000000e-14

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0000482	event free survival time
EFO:0004866	autoantibody measurement
EFO:0004615	apolipoprotein B measurement
EFO:0004611	low density lipoprotein cholesterol measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C566729	Pyruvate Dehydrogenase E1-Beta Deficiency (supp.)
C536258	Pyruvate dehydrogenase phosphatase deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4882 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.53	Kd	2944	nM	CHEMBL3752910
5.48	ED50	3326	nM	CHEMBL3752910
5.20	Kd	6356	nM	CHEMBL5653589
5.14	ED50	7182	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 6 total; 2 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148961: Binding affinity to human PDHB incubated for 45 mins by Kinobead based pull down assay	kd	2.9436	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148961: Binding affinity to human PDHB incubated for 45 mins by Kinobead based pull down assay	kd	6.3559	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	3
sodium arsenite	affects expression, decreases expression, increases expression	3
Tobacco Smoke Pollution	decreases expression	2
Valproic Acid	affects expression, decreases expression	2
Cyclosporine	decreases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
sodium arsenate	decreases expression	1
ferric ammonium citrate	decreases reaction, increases expression	1
arsenite	increases reaction, affects binding	1
cobaltous chloride	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
azaspiracid	increases expression	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
UCF 101	increases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	decreases expression	1
tetraarsenic tetrasulfide	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Imatinib Mesylate	affects cotreatment, decreases expression	1
Zoledronic Acid	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Ethanol	increases abundance, affects cotreatment, decreases expression	1
Cadmium	increases abundance, increases expression	1
Deferoxamine	increases expression, decreases reaction	1
Dimethyl Sulfoxide	increases expression	1
Dinitrochlorobenzene	affects binding	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
CHEMBL4118619	Binding	Binding affinity to PDHB in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1PM	Abcam K-562 PDHB KO	Cancer cell line	Female
CVCL_D2L8	Abcam Raji PDHB KO	Cancer cell line	Male
CVCL_WQ23	Abcam Jurkat PDHB KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02616484	PHASE3	ACTIVE_NOT_RECRUITING	Trial of Dichloroacetate in Pyruvate Dehydrogenase Complex Deficiency:
NCT03734263	PHASE2	COMPLETED	Use of Phenylbutyrate Therapy for Patients With Pyruvate Dehydrogenase Complex Deficiency.
NCT06340685	PHASE1	RECRUITING	Triheptanoin for Children With Primary-Specific Pyruvate Dehydrogenase Complex (PDC) Deficiency
NCT05257005	Not specified	UNKNOWN	Natural History Study of Pyruvate Dehydrogenase Deficiency
NCT06931262	Not specified	AVAILABLE	Expanded Access Treatment Protocol With DCA for Patients With PDCD