DLAT

Summary

DLAT (dihydrolipoamide S-acetyltransferase, HGNC:2896) is a protein-coding gene on chromosome 11q23.1, encoding Dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex, mitochondrial (P10515). The pyruvate dehydrogenase (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.

This gene encodes component E2 of the multi-enzyme pyruvate dehydrogenase complex (PDC). PDC resides in the inner mitochondrial membrane and catalyzes the conversion of pyruvate to acetyl coenzyme A. The protein product of this gene, dihydrolipoamide acetyltransferase, accepts acetyl groups formed by the oxidative decarboxylation of pyruvate and transfers them to coenzyme A. Dihydrolipoamide acetyltransferase is the antigen for antimitochondrial antibodies. These autoantibodies are present in nearly 95% of patients with the autoimmune liver disease primary biliary cirrhosis (PBC). In PBC, activated T lymphocytes attack and destroy epithelial cells in the bile duct where this protein is abnormally distributed and overexpressed. PBC enventually leads to cirrhosis and liver failure. Mutations in this gene are also a cause of pyruvate dehydrogenase E2 deficiency which causes primary lactic acidosis in infancy and early childhood.

Source: NCBI Gene 1737 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pyruvate dehydrogenase E2 deficiency (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 401 total — 7 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 56
• Druggable target: yes
• MANE Select transcript: NM_001931

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2896
Approved symbol	DLAT
Name	dihydrolipoamide S-acetyltransferase
Location	11q23.1
Locus type	gene with protein product
Status	Approved
Aliases	PDC-E2, E2
Ensembl gene	ENSG00000150768
Ensembl biotype	protein_coding
OMIM	608770
Entrez	1737

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 21 protein_coding, 5 nonsense_mediated_decay, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000280346, ENST00000393051, ENST00000527231, ENST00000531306, ENST00000533297, ENST00000679368, ENST00000679466, ENST00000679614, ENST00000679815, ENST00000679829, ENST00000679878, ENST00000680010, ENST00000680154, ENST00000680331, ENST00000680411, ENST00000681316, ENST00000681328, ENST00000681339, ENST00000681638, ENST00000713569, ENST00000873897, ENST00000873898, ENST00000915653, ENST00000915654, ENST00000915655, ENST00000915656, ENST00000915657, ENST00000915658, ENST00000915659, ENST00000915660

RefSeq mRNA: 13 — MANE Select: NM_001931 NM_001372031, NM_001372032, NM_001372033, NM_001372034, NM_001372035, NM_001372036, NM_001372037, NM_001372038, NM_001372039, NM_001372040, NM_001372041, NM_001372042, NM_001931

CCDS: CCDS8354, CCDS91587, CCDS91588, CCDS91589, CCDS91590, CCDS91591, CCDS91592, CCDS91593

Canonical transcript exons

ENST00000280346 — 14 exons

Exon	Start	End
ENSE00003475660	112033404	112033530
ENSE00003478322	112059903	112060065
ENSE00003493490	112045863	112045970
ENSE00003503313	112045138	112045230
ENSE00003512633	112043466	112043533
ENSE00003530133	112026198	112026299
ENSE00003574513	112061038	112061174
ENSE00003641378	112028515	112028639
ENSE00003643475	112037273	112037460
ENSE00003664933	112051234	112051349
ENSE00003673493	112028792	112028945
ENSE00003674893	112039244	112039397
ENSE00004020348	112025408	112025751
ENSE00004020349	112062406	112064404

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 97.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.4515 / max 672.5818, expressed in 1809 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
116692	21.6423	1799
116689	3.1645	937
116688	2.8759	1002
116693	0.7730	266
116690	0.4249	106
116696	0.3094	31
116691	0.1364	30
116697	0.0927	19
116695	0.0324	20

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
heart right ventricle	UBERON:0002080	97.70	gold quality
biceps brachii	UBERON:0001507	96.43	gold quality
left ventricle myocardium	UBERON:0006566	96.32	gold quality
diaphragm	UBERON:0001103	96.10	gold quality
vastus lateralis	UBERON:0001379	96.06	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.91	gold quality
quadriceps femoris	UBERON:0001377	95.54	gold quality
body of tongue	UBERON:0011876	95.20	gold quality
myocardium	UBERON:0002349	95.17	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.09	gold quality
skeletal muscle tissue	UBERON:0001134	94.88	gold quality
adrenal tissue	UBERON:0018303	94.58	gold quality
cardiac ventricle	UBERON:0002082	94.57	gold quality
heart left ventricle	UBERON:0002084	94.49	gold quality
muscle organ	UBERON:0001630	94.22	gold quality
skeletal muscle organ	UBERON:0014892	94.22	gold quality
muscle tissue	UBERON:0002385	93.84	gold quality
muscle of leg	UBERON:0001383	93.76	gold quality
gastrocnemius	UBERON:0001388	93.74	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.69	gold quality
cardiac muscle of right atrium	UBERON:0003379	93.25	gold quality
deltoid	UBERON:0001476	93.06	gold quality
heart	UBERON:0000948	92.74	gold quality
cardiac atrium	UBERON:0002081	92.17	gold quality
right atrium auricular region	UBERON:0006631	91.97	gold quality
triceps brachii	UBERON:0001509	91.90	gold quality
tongue	UBERON:0001723	91.60	gold quality
colonic mucosa	UBERON:0000317	90.91	gold quality
islet of Langerhans	UBERON:0000006	90.89	gold quality
mucosa of sigmoid colon	UBERON:0004993	90.82	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.01

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

113 targeting DLAT, 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-5692A	100.00	74.40	6850
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-7978	99.86	66.90	856
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-609	99.82	64.26	505
HSA-MIR-4760-5P	99.80	69.88	1619

Literature-anchored findings (GeneRIF, showing 21)

• a novel HLA-A*0201-restricted epitope PDC-E2 165 to 174 was defined in patients with primary biliary cirrhosis. (PMID:12395322)
• study of facilitated interaction between the pyruvate dehydrogenase kinase isoform 2 and the dihydrolipoyl acetyltransferase (PMID:12816949)
• model of the pyruvate dehydrogenase complex formed by E2 and E2 plus the E3-binding protein and binding of the E1 and E3 components (PMID:14638692)
• Having found that there is an excellent and almost unique match between the PDC-E2 autoepitope and a sequence in mycobacterial hsp65s, we tested the corresponding peptides for cross-reactivity using sera from 90 Spanish and British PBC patients. (PMID:15120760)
• This study report two unrelated patients with pyruvate dehydrogenase deficiency caused by defects in the E2 subunit. (PMID:16049940)
• epitope specificity of these PDC-E2 autoantibodies was distinctive suggesting that the mechanisms leading to loss of tolerance in the transplantation patients are distinct from primary biliary cirrhosis (PMID:17068145)
• Species specificity in the interaction between hE1beta and hE2 in pyruvate dehydrogenase complex. (PMID:18206651)
• tissue specificity of the autoimmune injury in primary biliary cirrhosis is a consequence of the unique characteristics of HIBECs during apoptosis and can be explained by exposure to immune system of intact immunoreactive PDC-E2 within apoptotic blebs. (PMID:19185000)
• Data suggest that the catalytic site of pyruvate dehydrogenase complex E2 rather than the previously reported lipoyl binding peptide may contain immunodominant epitopes recognized by antimitochondrial antibodies in primary biliary cirrhosis. (PMID:20180236)
• Solution structure and characterisation of the human pyruvate dehydrogenase complex core assembly (PMID:20361979)
• These findings were used to identify potentially antigenic sequences within PDC-E2 (an important hepatic autoantigen) that contain a DR0801 motif. (PMID:23543758)
• Results show that DLAT and ACAT2 as upstream acetyltransferases of K76 and K294 in 6PGD protein. (PMID:25042803)
• ongoing activation of PDCE2-specific B-cells in primary biliary cirrhosis (PMID:25043065)
• DLAT interacts with C1QBP in mitochondria. (PMID:26753982)
• p-STAT3 is a PDC-E2 interacting partner in human cholangiocytes and hepatocytes with potential pathobiological implications. (PMID:34737337)
• Externalization of Mitochondrial PDCE2 on Irradiated Endothelium as a Target for Radiation-Guided Drug Delivery and Precision Thrombosis of Pathological Vasculature. (PMID:36012169)
• Roles of cuproptosis-related gene DLAT in various cancers: a bioinformatic analysis and preliminary verification on pro-survival autophagy. (PMID:36949759)
• Cuproptosis-Related Gene DLAT as a Novel Biomarker Correlated with Prognosis, Chemoresistance, and Immune Infiltration in Pancreatic Adenocarcinoma: A Preliminary Study Based on Bioinformatics Analysis. (PMID:36975441)
• Systematic pan-cancer analysis identifies cuproptosis-related gene DLAT as an immunological and prognostic biomarker. (PMID:37199628)
• DLAT is a promising prognostic marker and therapeutic target for hepatocellular carcinoma: a comprehensive study based on public databases. (PMID:37828099)
• Novel Insights Into DLAT’s Role in Alzheimer’s Disease-Related Copper Toxicity Through Microglial Exosome Dynamics. (PMID:39428563)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dlat	ENSDARG00000015918
mus_musculus	Dlat	ENSMUSG00000000168
rattus_norvegicus	Dlat	ENSRNOG00000009994
drosophila_melanogaster	muc	FBGN0283658
caenorhabditis_elegans		WBGENE00009082

Paralogs (3): PDHX (ENSG00000110435), DLST (ENSG00000119689), DBT (ENSG00000137992)

Protein

Protein identifiers

Dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex, mitochondrial — P10515 (reviewed: P10515)

Alternative names: 70 kDa mitochondrial autoantigen of primary biliary cirrhosis, Dihydrolipoamide acetyltransferase component of pyruvate dehydrogenase complex, M2 antigen complex 70 kDa subunit, Pyruvate dehydrogenase complex component E2

All UniProt accessions (15): P10515, A0A7P0T997, A0A7P0T9N8, A0A7P0TA47, A0A7P0TAG1, A0A7P0TAX2, A0A7P0TBE2, A0A7P0TBK2, A0A7P0Z423, A0A7P0Z459, A0A7P0Z4G4, E9PEJ4, E9PKC7, H0YDD4, Q86YI5

UniProt curated annotations — full annotation on UniProt →

Function. The pyruvate dehydrogenase (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);. Within this complex, the catalytic function of this enzyme is to accept, and to transfer to coenzyme A, acetyl groups from acetyl-lipoyl moiety generated by the pyruvate dehydrogenase, leading to acetyl-CoA formation.

Subunit / interactions. Part of the pyruvate dehydrogenase (PDH) complex that is a multi-enzyme complex composed of multiple copies of three enzymes, pyruvate dehydrogenase (subunits PDH1A and PDHB, E1 component), dihydrolipoamide acetyltransferase (DLAT, E2 component), and dihydrolipoamide dehydrogenase (DLD, E3 component) to which is added an additional protein the E3-binding protein (PDHX, E3BP). In terms of structural architecture, the E2 and E3BP components assemble into a 60meric central core with icosahedral symmetry. The central core is decorated with E1 and E3 proteins. Currently, two alternative models for the E2:E3BP stoichiometry are considered as being either 48:12 (E2(48)-E3BP(12)) or 40:20 (E2(40)-E3BP(20)). Interacts with PDK2 and PDK3. Interacts with SIRT4. Interacts with PDHB.

Subcellular location. Mitochondrion matrix.

Post-translational modifications. Delipoylated at Lys-132 and Lys-259 by SIRT4, delipoylation decreases the PHD complex activity.

Disease relevance. Primary biliary cirrhosis is a chronic, progressive cholestatic liver disease characterized by the presence of antimitochondrial autoantibodies in patients’ serum. It manifests with inflammatory obliteration of intra-hepatic bile duct, leading to liver cell damage and cirrhosis. Patients with primary biliary cirrhosis show autoantibodies against the E2 component of pyruvate dehydrogenase complex. Pyruvate dehydrogenase E2 deficiency (PDHE2 deficiency) [MIM:245348] Pyruvate dehydrogenase (PDH) deficiency is a major cause of primary lactic acidosis and neurological dysfunction in infancy and early childhood. In this form of PDH deficiency episodic dystonia is the major neurological manifestation, with other more common features of pyruvate dehydrogenase deficiency, such as hypotonia and ataxia, being less prominent. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 2 lipoyl cofactors covalently.

Similarity. Belongs to the 2-oxoacid dehydrogenase family.

RefSeq proteins (13): NP_001358960, NP_001358961, NP_001358962, NP_001358963, NP_001358964, NP_001358965, NP_001358966, NP_001358967, NP_001358968, NP_001358969, NP_001358970, NP_001358971, NP_001922* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000089	Biotin_lipoyl	Domain
IPR001078	2-oxoacid_DH_actylTfrase	Domain
IPR003016	2-oxoA_DH_lipoyl-BS	Binding_site
IPR004167	PSBD	Domain
IPR006257	LAT1	Family
IPR011053	Single_hybrid_motif	Homologous_superfamily
IPR023213	CAT-like_dom_sf	Homologous_superfamily
IPR036625	E3-bd_dom_sf	Homologous_superfamily
IPR045257	E2/Pdx1	Family

Pfam: PF00198, PF00364, PF02817

Enzyme classification (BRENDA):

• EC 1.2.1.104 — pyruvate dehydrogenase system (BRENDA: 46 organisms, 32 substrates, 100 inhibitors, 83 Km, 12 kcat entries)
• EC 2.3.1.12 — dihydrolipoyllysine-residue acetyltransferase (BRENDA: 27 organisms, 17 substrates, 9 inhibitors, 18 Km, 4 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
PYRUVATE	0.0002–1	44
NAD+	0.01–0.27	14
COA	0.0005–0.61	12
DIHYDROLIPOAMIDE	1.08–6.4	7
ACETYL-COA	0.013–0.052	5
THIAMINE DIPHOSPHATE	0.0016–0.05	3
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
N-ACETYL-GDLLAEIETDK(LIPOYLATED)ATIG-AMIDE	—	0

Catalyzed reactions (Rhea), 1 shown:

• N(6)-[(R)-dihydrolipoyl]-L-lysyl-[protein] + acetyl-CoA = N(6)-[(R)-S(8)-acetyldihydrolipoyl]-L-lysyl-[protein] + CoA (RHEA:17017)

UniProt features (71 total): strand 26, helix 10, sequence variant 7, modified residue 6, binding site 5, domain 3, sequence conflict 3, region of interest 3, active site 2, turn 2, compositionally biased region 2, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
3CRK	X-RAY DIFFRACTION	2.3
1Y8O	X-RAY DIFFRACTION	2.48
2PNR	X-RAY DIFFRACTION	2.5
1Y8N	X-RAY DIFFRACTION	2.6
2Q8I	X-RAY DIFFRACTION	2.6
3CRL	X-RAY DIFFRACTION	2.61
1Y8P	X-RAY DIFFRACTION	2.63
8PIU	ELECTRON MICROSCOPY	2.9
6CT0	ELECTRON MICROSCOPY	3.1
6H55	ELECTRON MICROSCOPY	6
3B8K	ELECTRON MICROSCOPY	8.8
1FYC	SOLUTION NMR
2DNE	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P10515-F1	72.59	0.27

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 (2): 620; 624

Ligand- & substrate-binding residues (5): 461; 475; 566; 567; 591

Post-translational modifications (6): 100, 132, 259, 466, 473, 547

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-9857492	Protein lipoylation
R-HSA-9861559	PDH complex synthesizes acetyl-CoA from PYR

MSigDB gene sets: 328 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, HORIUCHI_WTAP_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, TGACCTY_ERR1_Q2, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, KEGG_GLYCOLYSIS_GLUCONEOGENESIS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ACETYL_COA_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, PUJANA_CHEK2_PCC_NETWORK, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS

GO Biological Process (5): glucose metabolic process (GO:0006006), pyruvate decarboxylation to acetyl-CoA (GO:0006086), tricarboxylic acid cycle (GO:0006099), pyruvate catabolic process (GO:0042867), pyruvate metabolic process (GO:0006090)

GO Molecular Function (6): dihydrolipoyllysine-residue acetyltransferase activity (GO:0004742), identical protein binding (GO:0042802), protein binding (GO:0005515), acetyltransferase activity (GO:0016407), transferase activity (GO:0016740), acyltransferase activity (GO:0016746)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), pyruvate dehydrogenase complex (GO:0045254), sperm head-tail coupling apparatus (GO:0120212)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Regulation of pyruvate metabolism	1
Signaling by Nuclear Receptors	1
Post-translational protein modification	1
Pyruvate metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
pyruvate metabolic process	2
aerobic respiration	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
primary metabolic process	1
monocarboxylic acid catabolic process	1
monocarboxylic acid metabolic process	1
S-acetyltransferase activity	1
catalytic activity, acting on a protein	1
protein binding	1
binding	1
acyltransferase activity, transferring groups other than amino-acyl groups	1
catalytic activity	1
transferase activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
alpha-ketoacid dehydrogenase complex	1
acetyltransferase complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

3426 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DLAT	PDHB	P11177	995
DLAT	DLD	P09622	987
DLAT	PDHA1	P08559	985
DLAT	LIPT1	Q9Y234	932
DLAT	PDHX	O00330	887
DLAT	PDP2	Q9P2J9	878
DLAT	PDHA2	P29803	861
DLAT	GCSH	P23434	802
DLAT	PDP1	Q9P0J1	798
DLAT	DIXDC1	Q155Q3	725
DLAT	OGDH	Q02218	721
DLAT	SP100	P23497	712
DLAT	PDK3	Q15120	654
DLAT	ACO2	Q99798	646
DLAT	SDHA	P31040	625

IntAct

117 interactions, top by confidence:

A	B	Type	Score
DLD	PDHX	psi-mi:“MI:0914”(association)	0.880
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
DLAT	PDK3	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
DLAT	SIRT4	psi-mi:“MI:0403”(colocalization)	0.610
DLAT	SIRT4	psi-mi:“MI:0915”(physical association)	0.610
SIRT4	DLAT	psi-mi:“MI:0212”(lipoprotein cleavage reaction)	0.610
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
SIRT4	PDHX	psi-mi:“MI:0914”(association)	0.560
DLAT	DLAT	psi-mi:“MI:0407”(direct interaction)	0.530
PDK3	PDHX	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
NDUFAB1	MIEF1	psi-mi:“MI:0915”(physical association)	0.490
SIRT3	DLAT	psi-mi:“MI:0197”(deacetylation reaction)	0.440
TGOLN2	PGRMC1	psi-mi:“MI:0914”(association)	0.420
GPC1	SNAP23	psi-mi:“MI:0915”(physical association)	0.400
GPC1	GANAB	psi-mi:“MI:0915”(physical association)	0.400
DLAT		psi-mi:“MI:0915”(physical association)	0.370

BioGRID (311): DLAT (Affinity Capture-MS), DLAT (Affinity Capture-MS), DLAT (Affinity Capture-MS), CS (Co-fractionation), CYC1 (Co-fractionation), DLAT (Co-fractionation), DLAT (Co-fractionation), DLAT (Co-fractionation), DLAT (Co-fractionation), DLD (Co-fractionation), DLST (Co-fractionation), LMAN1 (Co-fractionation), NDUFS2 (Co-fractionation), PDHB (Co-fractionation), DLAT (Affinity Capture-MS)

ESM2 similar proteins: A0A0D2Y5A7, G0S4X6, O00330, O59816, O94681, P08461, P0CN60, P0CN61, P10515, P11141, P11179, P11180, P11961, P12695, P19262, P20285, P21883, P22439, P35489, P36413, P36957, P37900, P45118, P65634, P86197, P9WIS6, P9WIS7, Q01205, Q0WQF7, Q19749, Q1RHI5, Q1RJT3, Q23571, Q4ULG1, Q59638, Q5B0C0, Q5M729, Q5Y223, Q869Y7, Q8BKZ9

Diamond homologs: A0A0D2Y5A7, G0S4X6, G0S5Q0, O00330, O31550, O59816, O66113, O66119, O94709, P06959, P08461, P10515, P11180, P12695, P16263, P16451, P19262, P20285, P20708, P22439, P36413, P36957, P45118, P47514, P52993, P65635, P65636, P75392, P86197, Q0WQF7, Q19749, Q1RJT3, Q49XM4, Q4UKI7, Q4ULG1, Q59098, Q59695, Q59821, Q5HGY9, Q5M729

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
DLAT	“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×	5e-04
Signaling by Interleukins	10	7.0×	5e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	9
Uncertain significance	168
Likely benign	136
Benign	46

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
2109	NM_001931.5(DLAT):c.362_364del (p.Glu121del)	Pathogenic
2196317	NM_001931.5(DLAT):c.412G>T (p.Glu138Ter)	Pathogenic
2424324	NC_000011.9:g.(?111896197)(111899689_?)del	Pathogenic
2764118	NM_001931.5(DLAT):c.802del (p.Glu268fs)	Pathogenic
2778456	NM_001931.5(DLAT):c.723dup (p.Val242fs)	Pathogenic
2793499	NM_001931.5(DLAT):c.1303C>T (p.Arg435Ter)	Pathogenic
2916183	NM_001931.5(DLAT):c.568C>T (p.Gln190Ter)	Pathogenic
1211510	NM_001931.5(DLAT):c.1598G>A (p.Gly533Glu)	Likely pathogenic
1252016	NM_001931.5(DLAT):c.975G>A (p.Pro325=)	Likely pathogenic
208790	NM_001931.5(DLAT):c.470T>G (p.Val157Gly)	Likely pathogenic
2782037	NM_001931.5(DLAT):c.381+1G>T	Likely pathogenic
3234969	NM_001931.5(DLAT):c.476del (p.Ile159fs)	Likely pathogenic
3598993	NM_001931.5(DLAT):c.1030del (p.Cys344fs)	Likely pathogenic
3598994	NM_001931.5(DLAT):c.1515-1G>T	Likely pathogenic
3912013	NM_001931.5(DLAT):c.156T>A (p.Tyr52Ter)	Likely pathogenic
432159	NM_001931.5(DLAT):c.1129+2T>C	Likely pathogenic

SpliceAI

1821 predictions. Top by Δscore:

Variant	Effect	Δscore
11:112026196:A:AG	acceptor_gain	1.0000
11:112026197:G:GC	acceptor_loss	1.0000
11:112026197:G:GG	acceptor_gain	1.0000
11:112026295:CAGAG:C	donor_gain	1.0000
11:112026296:AGAG:A	donor_gain	1.0000
11:112026297:GAG:G	donor_gain	1.0000
11:112026297:GAGG:G	donor_gain	1.0000
11:112026298:AG:A	donor_gain	1.0000
11:112026299:GG:G	donor_gain	1.0000
11:112026300:G:GG	donor_gain	1.0000
11:112026300:GT:G	donor_loss	1.0000
11:112028512:AAGGT:A	acceptor_loss	1.0000
11:112028633:TTGGC:T	donor_gain	1.0000
11:112028636:GCAA:G	donor_gain	1.0000
11:112028640:G:GG	donor_gain	1.0000
11:112028790:A:AG	acceptor_gain	1.0000
11:112028791:G:GG	acceptor_gain	1.0000
11:112037271:A:G	acceptor_gain	1.0000
11:112037272:G:GG	acceptor_gain	1.0000
11:112037272:G:GT	acceptor_loss	1.0000
11:112039239:A:AG	acceptor_gain	1.0000
11:112039239:AAAAG:A	acceptor_gain	1.0000
11:112039240:A:G	acceptor_gain	1.0000
11:112039242:A:AT	acceptor_loss	1.0000
11:112039326:G:T	donor_gain	1.0000
11:112039394:AAAG:A	donor_gain	1.0000
11:112043534:G:GG	donor_gain	1.0000
11:112043539:T:G	donor_gain	1.0000
11:112045133:CATA:C	acceptor_loss	1.0000
11:112045134:ATAG:A	acceptor_gain	1.0000

AlphaMissense

4159 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:112026249:T:A	W111R	1.000
11:112026249:T:C	W111R	1.000
11:112028527:A:G	K132E	1.000
11:112028528:A:T	K132I	1.000
11:112028529:A:C	K132N	1.000
11:112028529:A:T	K132N	1.000
11:112033447:T:A	V235D	1.000
11:112033455:T:A	W238R	1.000
11:112033455:T:C	W238R	1.000
11:112033515:G:C	D258H	1.000
11:112033516:A:T	D258V	1.000
11:112033518:A:G	K259E	1.000
11:112033519:A:T	K259I	1.000
11:112033520:A:C	K259N	1.000
11:112033520:A:T	K259N	1.000
11:112062453:G:C	R621P	1.000
11:112026241:T:A	I108K	0.999
11:112026250:G:C	W111S	0.999
11:112026251:G:C	W111C	0.999
11:112026251:G:T	W111C	0.999
11:112026294:G:C	A126P	0.999
11:112026295:C:A	A126E	0.999
11:112028516:T:A	V128D	0.999
11:112028524:G:C	D131H	0.999
11:112028525:A:T	D131V	0.999
11:112028527:A:C	K132Q	0.999
11:112028530:G:C	A133P	0.999
11:112028623:T:C	C164R	0.999
11:112033440:G:C	G233R	0.999
11:112033441:G:A	G233D	0.999

dbSNP variants (sampled 300 via entrez): RS1000051502 (11:112036745 G>A,C), RS1000299707 (11:112062615 G>A,T), RS1000543248 (11:112041795 T>C), RS1000596505 (11:112048821 C>T), RS1000956761 (11:112026139 C>A,T), RS1000998213 (11:112034909 G>A), RS1001050451 (11:112034266 A>G), RS1001225984 (11:112035419 A>C,T), RS1001305516 (11:112026529 A>G,T), RS1001443769 (11:112042767 T>C), RS1001475776 (11:112061686 C>A), RS1001478072 (11:112050110 T>C), RS1001780458 (11:112043006 A>G), RS1001985972 (11:112055109 T>C), RS1002184206 (11:112033800 C>G,T)

Disease associations

OMIM: gene MIM:608770 | disease phenotypes: MIM:245348, MIM:256000

GenCC curated gene-disease

Disease	Classification	Inheritance
pyruvate dehydrogenase E2 deficiency	Definitive	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 E2 deficiency (MONDO:0009502), prostate cancer (MONDO:0008315), Leigh syndrome (MONDO:0009723)

Orphanet (4): Pyruvate dehydrogenase deficiency (Orphanet:765), Pyruvate dehydrogenase E2 deficiency (Orphanet:79244), Familial prostate cancer (Orphanet:1331), Leigh syndrome (Orphanet:506)

HPO phenotypes

56 total (30 of 56 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000486	Strabismus
HP:0000496	Abnormality of eye movement
HP:0000508	Ptosis
HP:0000546	Retinal degeneration
HP:0000639	Nystagmus
HP:0000657	Oculomotor apraxia
HP:0000707	Abnormality of the nervous system
HP:0000708	Atypical behavior
HP:0000726	Dementia
HP:0000739	Anxiety
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001270	Motor delay
HP:0001276	Hypertonia
HP:0001288	Gait disturbance
HP:0001319	Neonatal hypotonia
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001348	Brisk reflexes
HP:0002136	Broad-based gait
HP:0002180	Neurodegeneration
HP:0002194	Delayed gross motor development
HP:0002268	Paroxysmal dystonia
HP:0002307	Drooling

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST010703_266	Brain morphology (MOSTest)	4.000000e-13
GCST012228_542	Waist-hip index	3.000000e-08
GCST012230_35	Waist-to-hip ratio adjusted for BMI	4.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
C565448	Pyruvate Dehydrogenase E2 Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523180 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.26	Kd	54.52	nM	CHEMBL5653589
7.26	ED50	55.05	nM	CHEMBL5653589
6.24	Kd	578	nM	CHEMBL1237210
5.59	Kd	2551	nM	CHEMBL3752910
5.59	ED50	2576	nM	CHEMBL3752910

PubChem BioAssay actives

3 with measured affinity, of 6 total; 3 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-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148243: Binding affinity to human DLAT incubated for 45 mins by Kinobead based pull down assay	kd	0.0545	uM
(1R,5R,7S,8R)-4-hydroxy-8-methyl-3,5,7-tris(3-methylbut-2-enyl)-8-(4-methylpent-3-enyl)-1-(2-methylpropanoyl)bicyclo[3.3.1]non-3-ene-2,9-dione	1873235: Binding affinity to recombinant GFP fused Dalt (unknown origin) by Lip-SMap analysis	kd	0.5780	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148243: Binding affinity to human DLAT incubated for 45 mins by Kinobead based pull down assay	kd	2.5513	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	affects cotreatment, increases expression	3
bisphenol A	decreases expression, increases expression	3
bisphenol S	increases methylation, increases expression	3
Valproic Acid	affects cotreatment, decreases expression, affects expression, decreases methylation	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
Acetaminophen	decreases expression	2
Cadmium Chloride	increases abundance, increases expression, decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
lasiocarpine	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, increases expression	1
decabromobiphenyl ether	increases expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	decreases expression	1
cupric chloride	affects cotreatment, decreases expression	1
beta-methylcholine	affects expression	1
dinophysistoxin 1	increases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
deguelin	increases expression	1
2-palmitoylglycerol	increases expression	1
K 7174	decreases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
elesclomol	decreases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, increases expression	1
pentabrominated diphenyl ether 100	decreases 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
CHEMBL4333902	Binding	Inhibition of PDHC-E2 activity in human NB4 cells up to 2.4 uM after 3 hrs	A mitochondria-targeted organic arsenical accelerates mitochondrial metabolic disorder and function injury. — 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_D1W3	Abcam A-549 DLAT KO	Cancer cell line	Male
CVCL_SK91	HAP1 DLAT (-) 1	Cancer cell line	Male
CVCL_XN30	HAP1 DLAT (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer