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, 10 likely-pathogenic (top 8% of genes corpus-wide)
• GTEx eGene: eQTL in 13 tissues, sQTL in 14 (q < 0.05)
• Phenotypes (HPO): 56
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.76 (unconstrained)
• MANE Select transcript: NM_001931
• Interaction hub: 2,458 STRING partners (top 4% of genes corpus-wide)

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: 39 — 22 protein_coding, 13 nonsense_mediated_decay, 3 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000280346

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 2, TSL 5: 2

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, ENST00000990660, ENST00000990661, ENST00001029974, ENST00001029975, ENST00001029980, ENST00001029981, ENST00001029982, ENST00001084781, ENST00001126413

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
ENSE00004798017	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.

Highest expression (Bgee): heart right ventricle, biceps brachii, ventricle myocardium, diaphragm, vastus lateralis.

Genetic regulation across tissues (GTEx eQTL / sQTL)

DLAT is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 13 tissues and its splicing (sQTL) in 14 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 27 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Muscle Skeletal	sqtl	4.1e-75	+0.91	11:112007120:A:G
Cells Cultured fibroblasts	sqtl	3.0e-35	+0.82	11:112003207:G:A
Cells EBV-transformed lymphocytes	sqtl	5.1e-22	+0.94	11:112027017:C:T
Adipose Subcutaneous	sqtl	3.7e-17	+0.53	11:112006093:C:T
Adipose Visceral Omentum	sqtl	9.3e-17	+0.61	11:111995718:GAC:G
Skin Sun Exposed Lower leg	eqtl	1.5e-13	+0.17	11:111955787:T:G
Heart Atrial Appendage	sqtl	8.7e-13	+0.63	11:112007493:GAC:G
Esophagus Mucosa	sqtl	3.0e-12	+0.60	11:112027500:C:T
Muscle Skeletal	eqtl	3.1e-12	-0.10	11:112006093:C:T
Skin Sun Exposed Lower leg	sqtl	1.9e-10	+0.46	11:111938152:C:G
Breast Mammary Tissue	sqtl	8.4e-09	+0.49	11:112024530:G:T
Cells EBV-transformed lymphocytes	eqtl	9.6e-06	-0.15	11:112041359:A:G
Adrenal Gland	sqtl	1.8e-05	+0.58	11:111995291:C:G
Skin Not Sun Exposed Suprapubic	eqtl	3.4e-05	+0.12	11:112084778:C:T
Artery Coronary	sqtl	5.7e-05	+0.58	11:111750675:C:CA
Liver	eqtl	8.5e-04	+2.15	11:112778884:G:A
Minor Salivary Gland	sqtl	3.1e-03	+0.77	11:112025600:C:T
Esophagus Mucosa	eqtl	4.0e-03	+0.07	11:111920351:C:T
Adipose Subcutaneous	eqtl	4.9e-03	-0.31	11:111927485:T:A
Brain Cerebellar Hemisphere	eqtl	2.1e-02	+0.11	11:111995291:C:G

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

showing 100 of 299 tissues 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
lateral nuclear group of thalamus	UBERON:0002736	90.72	gold quality
vena cava	UBERON:0004087	90.69	gold quality
rectum	UBERON:0001052	90.60	gold quality
jejunum	UBERON:0002115	90.56	gold quality
pons	UBERON:0000988	89.95	gold quality
substantia nigra pars compacta	UBERON:0001965	89.90	gold quality
apex of heart	UBERON:0002098	89.77	gold quality
jejunal mucosa	UBERON:0000399	89.63	gold quality
superior surface of tongue	UBERON:0007371	89.23	gold quality
tibialis anterior	UBERON:0001385	89.18	gold quality
pharyngeal mucosa	UBERON:0000355	88.94	gold quality
gluteal muscle	UBERON:0002000	88.90	gold quality
bronchial epithelial cell	CL:0002328	88.72	gold quality
mucosa of transverse colon	UBERON:0004991	88.71	gold quality
oral cavity	UBERON:0000167	88.56	gold quality
CA1 field of hippocampus	UBERON:0003881	88.38	gold quality
orbitofrontal cortex	UBERON:0004167	88.16	gold quality
choroid plexus epithelium	UBERON:0003911	88.01	gold quality
adult mammalian kidney	UBERON:0000082	87.60	gold quality
epithelium of bronchus	UBERON:0002031	87.26	gold quality
prefrontal cortex	UBERON:0000451	87.03	gold quality
bronchus	UBERON:0002185	86.86	gold quality
ventricular zone	UBERON:0003053	86.71	gold quality
duodenum	UBERON:0002114	86.69	gold quality
superior vestibular nucleus	UBERON:0007227	86.63	gold quality
esophagus mucosa	UBERON:0002469	86.60	gold quality
kidney	UBERON:0002113	86.47	gold quality
substantia nigra pars reticulata	UBERON:0001966	86.42	gold quality
esophagus squamous epithelium	UBERON:0006920	86.37	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.32	gold quality
cerebellar vermis	UBERON:0004720	86.28	gold quality
epithelium of esophagus	UBERON:0001976	86.22	gold quality
right adrenal gland cortex	UBERON:0035827	86.17	gold quality
transverse colon	UBERON:0001157	86.10	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	85.96	gold quality
large intestine	UBERON:0000059	85.88	gold quality
right adrenal gland	UBERON:0001233	85.87	gold quality
renal medulla	UBERON:0000362	85.79	gold quality
adrenal gland	UBERON:0002369	85.75	gold quality
adipose tissue	UBERON:0001013	85.74	gold quality
colon	UBERON:0001155	85.69	gold quality
right uterine tube	UBERON:0001302	85.46	gold quality
endometrium	UBERON:0001295	85.45	gold quality
connective tissue	UBERON:0002384	85.44	gold quality
metanephros cortex	UBERON:0010533	85.35	gold quality
left adrenal gland	UBERON:0001234	85.27	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	85.27	gold quality
medial globus pallidus	UBERON:0002477	85.17	gold quality
frontal cortex	UBERON:0001870	85.16	gold quality
hypothalamus	UBERON:0001898	85.12	gold quality
tendon	UBERON:0000043	85.06	gold quality
esophagus	UBERON:0001043	85.05	gold quality
vermiform appendix	UBERON:0001154	85.03	gold quality
secondary oocyte	CL:0000655	85.00	gold quality
nasal cavity mucosa	UBERON:0001826	84.99	gold quality
caecum	UBERON:0001153	84.95	gold quality
intestine	UBERON:0000160	84.90	gold quality
neocortex	UBERON:0001950	84.90	gold quality
adrenal cortex	UBERON:0001235	84.87	gold quality
calcaneal tendon	UBERON:0003701	84.77	gold quality
subcutaneous adipose tissue	UBERON:0002190	84.75	gold quality
Brodmann (1909) area 9	UBERON:0013540	84.68	gold quality
left adrenal gland cortex	UBERON:0035825	84.66	gold quality
sigmoid colon	UBERON:0001159	84.59	gold quality
tonsil	UBERON:0002372	84.59	gold quality
oviduct epithelium	UBERON:0004804	84.58	gold quality
nasal cavity epithelium	UBERON:0005384	84.58	gold quality
caudate nucleus	UBERON:0001873	84.57	gold quality
cortical plate	UBERON:0005343	84.54	gold quality
adipose tissue of abdominal region	UBERON:0007808	84.46	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

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Tongue	tissue	83.5
Hippocampal formation	tissue	76.9
Cerebral cortex	tissue	74.8	high
Somatosensory cortex	tissue	74.8
Pons	tissue	73.2
Thalamus	tissue	71.5
Occipital cortex	tissue	70.8
Skeletal muscle	tissue	70.6	low
Motor cortex	tissue	67.6
Superior colliculi	tissue	66.6
Prefrontal cortex	tissue	65.4
Heart muscle	tissue	64.9	medium
Midbrain	tissue	64.5
Temporal cortex	tissue	63.1
Retrosplenial and cingulate cortex	tissue	62.9
Entorhinal cortex	tissue	62.3
Putamen	tissue	61.3
Septum	tissue	61.1
Retrosplenial cortex	tissue	60.7
Medulla oblongata	tissue	59.7
Ventral forebrain	tissue	59.7
Basal ganglia	tissue	59.4	medium
Hypothalamus	tissue	59.3
Periaqueductal gray	tissue	58.5
Substantia nigra	tissue	56.7
Insular cortex	tissue	56.3
Cerebellum	tissue	55.1	high
Amygdala	tissue	54.5
Spinal cord	tissue	52.5
Olfactory bulb	tissue	49.1
Frontal cortex	tissue	43.0
Caudate putamen	tissue	40.6
Corpus callosum	tissue	34.4
Kidney	tissue	31.6	high
Parathyroid gland	tissue	29.8	medium
Rectum	tissue	24.4	medium
Adipose tissue	tissue	23.2	not detected
Colon	tissue	23.2	medium
Thyroid gland	tissue	18.9	low
Esophagus	tissue	18.4	medium
Duodenum	tissue	17.2	medium
Tonsil	tissue	17.1	medium
Salivary gland	tissue	15.8	medium
Small intestine	tissue	15.6	medium
Adrenal gland	tissue	15.6	medium
Lymph node	tissue	15.1	medium
Liver	tissue	14.5	low
Seminal vesicle	tissue	14.0
Choroid plexus	tissue	13.6
Prostate	tissue	13.6	medium
Breast	tissue	13.5	medium
Stomach 1	tissue	13.5	low
Urinary bladder	tissue	13.3	low
Epididymis	tissue	12.7	medium
Smooth muscle	tissue	12.6	medium
Appendix	tissue	12.6	medium
Placenta	tissue	12.3	medium
Fallopian tube	tissue	12.3	medium
Thymus	tissue	11.9
Locus coeruleus	tissue	11.7

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Dorsal hippocampus (76.9), Ventral hippocampus (75.6), Subiculum (68.3), Ventral spinal cord (52.5), Dorsal spinal cord (45.8).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting DLAT by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 113 miRNAs:

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

Functional genomics

gnomAD constraint: pLI 3.18e-06, LOEUF 0.759, missense Z 1.33 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000280346 — one region, missense o/e 0.91.

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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2385311) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 5 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased exploration in new environment	1
prenatal lethality	1
decreased incidence of tumors by chemical induction	1
decreased prepulse inhibition	1
preweaning lethality, complete penetrance	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Mycobacterium tuberculosis variant bovis AF2122/97	P65634	100.0%	Diamond
Mycobacterium tuberculosis CDC1551	P9WIS6	100.0%	Diamond
Mycobacterium tuberculosis H37Rv	P9WIS7	100.0%	Diamond
Rickettsia felis Marseille-URRWFXCal2	Q4ULG1	95.9%	Diamond
Rickettsia conorii str. Malish 7	Q92HK7	95.9%	Diamond
Bos taurus	P22439	92.6%	Diamond
Rickettsia typhi str. Wilmington	Q68WK6	91.9%	Diamond
Rickettsia prowazekii str. Madrid E	Q9ZD20	91.9%	Diamond
Sus scrofa	Q9N0F1	88.4%	Diamond
Pseudomonas aeruginosa PAO1	Q9I3D2	86.6%	Diamond
Mesocricetus auratus	P86197	82.6%	Diamond
Rickettsia bellii RML369-C	Q1RJT3	81.3%	Diamond
Arabidopsis thaliana	Q5M729	80.7%	Diamond
Staphylococcus haemolyticus JCSC1435	Q4L6C3	77.6%	Diamond
Thermochaetoides thermophila DSM 1495	G0S4X6	77.4%	Diamond
Neurospora crassa OR74A	P20285	77.4%	Diamond
Sinorhizobium meliloti 1021	Q9R9N3	76.8%	Diamond
Geobacillus stearothermophilus	P11961	74.2%	Diamond
Bacillus subtilis subsp. subtilis str. 168	P21883	73.5%	Diamond
Buchnera aphidicola str. Sg (Schizaphis graminum)	Q8K9N2	72.4%	Diamond
Mycoplasmoides genitalium G37	P47514	71.2%	Diamond
Mycoplasmoides pneumoniae M129	P75392	71.2%	Diamond
Fusarium oxysporum f. sp. lycopersici 4287	A0A0D2Y5A7	70.9%	Diamond
Azotobacter vinelandii	P10802	69.5%	Diamond
Escherichia coli K-12	P06959	68.7%	Diamond
Haemophilus influenzae Rd KW20	P45118	68.1%	Diamond
Buchnera aphidicola str. APS (Acyrthosiphon pisum)	P57389	65.5%	Diamond
Schizosaccharomyces pombe 972h-	O94681	64.3%	Diamond
Saccharomyces cerevisiae S288C	P19262	64.3%	Diamond
Cupriavidus necator H16	P52993	63.2%	Diamond
Zymomonas mobilis subsp. mobilis ZM4 = ATCC 31821	O66119	57.8%	Diamond
Corynebacterium glutamicum ATCC 13032	Q8NNJ2	56.5%	Diamond
Dictyostelium discoideum	P36413	54.4%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
CRYAB	protein-coding	1410
HSPB2	protein-coding	3316
CFAP68	protein-coding	64776
DIXDC1	protein-coding	85458
C11orf52	protein-coding	91894
PIH1D2	protein-coding	120379
TIMM8B	protein-coding	26521
NKAPD1	protein-coding	55216
HSPB2-C11orf52	ncRNA	100528019
SDHD	protein-coding	6392
TEX12-AS1	ncRNA	107987164
IL18	protein-coding	3606

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)

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

UniProt features (75 total): strand 27, helix 14, sequence variant 7, modified residue 6, binding site 5, domain 3, sequence conflict 3, region of interest 3, active site 2, compositionally biased region 2, transit peptide 1, chain 1, turn 1

Structure

Experimental structures (PDB)

13 structures by resolution:

PDB	Title	Method	Resolution (Å)
3CRK	Crystal structure of the PDHK2-L2 complex.	X-RAY DIFFRACTION	2.3
1Y8O	Crystal structure of the PDK3-L2 complex	X-RAY DIFFRACTION	2.48
2PNR	Crystal Structure of the asymmetric Pdk3-l2 Complex	X-RAY DIFFRACTION	2.5
1Y8N	Crystal structure of the PDK3-L2 complex	X-RAY DIFFRACTION	2.6
2Q8I	Pyruvate dehydrogenase kinase isoform 3 in complex with antitumor drug radicicol	X-RAY DIFFRACTION	2.6
3CRL	Crystal structure of the PDHK2-L2 complex.	X-RAY DIFFRACTION	2.61
1Y8P	Crystal structure of the PDK3-L2 complex	X-RAY DIFFRACTION	2.63
8PIU	60-meric complex of dihydrolipoamide acetyltransferase (E2) of the human pyruvate …	ELECTRON MICROSCOPY	2.9
6CT0	Atomic Structure of the E2 Inner Core of Human Pyruvate Dehydrogenase Complex	ELECTRON MICROSCOPY	3.1
6H55	core of the human pyruvate dehydrogenase (E2)	ELECTRON MICROSCOPY	6
3B8K	Structure of the Truncated Human Dihydrolipoyl Acetyltransferase (E2)	ELECTRON MICROSCOPY	8.8
1FYC	INNER LIPOYL DOMAIN FROM HUMAN PYRUVATE DEHYDROGENASE (PDH) COMPLEX, NMR, 1 STRUCTURE	SOLUTION NMR
2DNE	Solution Structure of RSGI RUH-058, a lipoyl domain of human 2-oxoacid dehydrogenase	SOLUTION NMR

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Metabolic proteins, Predicted intracellular proteins, Citric acid cycle related proteins, Disease related genes, Potential drug targets, Human disease related genes, Congenital disorders of metabolism, Congenital disorders of carbohydrate metabolism

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): mitochondria; connecting piece

Antibody reliability (HPA): IH supported · IF supported

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)

Position	Role
620
624

Ligand- & substrate-binding residues (5)

Position	Role
461	CoA
475	CoA
566	CoA
567	CoA
591	CoA

Post-translational modifications (6)

Type	Positions
Phosphoserine	100
N6-lipoyllysine	132, 259
N6-acetyllysine	466
N6-succinyllysine	473, 547

Function

Pathways and Gene Ontology

Reactome pathways

4 curated (TAS) of 12; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

12 pathways:

ID	Pathway	Evidence
R-HSA-9861559	PDH complex synthesizes acetyl-CoA from PYR	curated
R-HSA-9857492	Protein lipoylation	curated
R-HSA-204174	Regulation of pyruvate dehydrogenase (PDH) complex	curated
R-HSA-5362517	Signaling by Retinoic Acid	curated
R-HSA-1428517	Aerobic respiration and respiratory electron transport	—
R-HSA-1430728	Metabolism	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-597592	Post-translational protein modification	—
R-HSA-70268	Pyruvate metabolism	—
R-HSA-9861718	Regulation of pyruvate metabolism	—
R-HSA-162582	Signal Transduction	—
R-HSA-9006931	Signaling by Nuclear Receptors	—

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 (3): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), pyruvate dehydrogenase complex (GO:0045254)

Reactome top-level categories

8 top-level categories:

Category	Pathways
Pyruvate metabolism	2
Regulation of pyruvate metabolism	1
Signaling by Nuclear Receptors	1
Post-translational protein modification	1
Metabolism	1
Metabolism of proteins	1
Aerobic respiration and respiratory electron transport	1
Signal Transduction	1

GO top-level categories

23 GO namespaces:

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

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 5 of 14 annotations. The rest are phylogenetic / computational / electronic (IEA).

5 experimentally-supported GO terms:

GO term	NS	Evidence
pyruvate decarboxylation to acetyl-CoA	BP	direct assay
mitochondrion	CC	direct assay
pyruvate dehydrogenase complex	CC	direct assay
dihydrolipoyllysine-residue acetyltransferase activity	MF	direct assay
identical protein binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 2,458 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DLAT	LIPT1	Q9Y234	981
DLAT	PDHB	P11177	977
DLAT	DLD	P09622	962
DLAT	PDHA1	P08559	961
DLAT	GCSH	P23434	922
DLAT	LIAS	O43766	895
DLAT	FDX1	P10109	880
DLAT	PDP2	Q9P2J9	857
DLAT	PDP1	Q9P0J1	774
DLAT	SLC31A1	O15431	759
DLAT	DIXDC1	Q155Q3	746
DLAT	LIPT2	A6NK58	743
DLAT	ATP7B	P35670	723
DLAT	GLS	O94925	718
DLAT	GLS2	Q9UI32	718

IntAct

Human interaction partners of DLAT in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

10 partners by confidence:

Partner	Interaction type	MIscore	Records
PDK3	direct interaction	0.690	1
PDHB	direct interaction	0.670	7
SIRT4	colocalization	0.610	4
SIRT3	deacetylation reaction	0.440	1
HMGB1	physical association	0.370	1
PDHX	physical association	0.370	1
PRKD3	physical association	0.370	1
ARHGEF16	association	0.350	1
CNTROB	association	0.350	1
HUNK	physical association	0.000	1

BioGRID (319 interactions; top human partners by supporting records): PDHX (Reconstituted Complex; 9 records), PDHB (Affinity Capture-MS; 8 records), DLD (Affinity Capture-MS; 7 records), PDHA1 (Co-fractionation; 4 records), C1QBP (Affinity Capture-MS; 3 records), CS (Co-fractionation; 3 records), MYC (Affinity Capture-MS; 3 records), PDK3 (Affinity Capture-MS; 3 records), ACAD9 (Proximity Label-MS; 2 records), CLEC4D (Affinity Capture-MS; 2 records), DLST (Co-fractionation; 2 records), FOXD4 (Affinity Capture-MS; 2 records), HECTD1 (Affinity Capture-MS; 2 records), LRPPRC (Co-fractionation; 2 records), OGDH (Co-fractionation; 2 records)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
DLAT	“form complex”	PDH	binding

Disease & clinical

Genetic variants

Variant evidence for DLAT: 401 ClinVar records (17 pathogenic / likely pathogenic); 3 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	10
Uncertain significance	167
Likely benign	138
Benign	45

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 17 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
2196317	NM_001931.5(DLAT):c.412G>T (p.Glu138Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
2793499	NM_001931.5(DLAT):c.1303C>T (p.Arg435Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
208790	NM_001931.5(DLAT):c.470T>G (p.Val157Gly)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	5
2764118	NM_001931.5(DLAT):c.802del (p.Glu268fs)	Pathogenic	criteria provided, single submitter	1
2778456	NM_001931.5(DLAT):c.723dup (p.Val242fs)	Pathogenic	criteria provided, single submitter	1
2916183	NM_001931.5(DLAT):c.568C>T (p.Gln190Ter)	Pathogenic	criteria provided, single submitter	1
1252016	NM_001931.5(DLAT):c.975G>A (p.Pro325=)	Likely pathogenic	criteria provided, single submitter	2
432159	NM_001931.5(DLAT):c.1129+2T>C	Likely pathogenic	criteria provided, single submitter	1
1211510	NM_001931.5(DLAT):c.1598G>A (p.Gly533Glu)	Likely pathogenic	criteria provided, single submitter	1
2782037	NM_001931.5(DLAT):c.381+1G>T	Likely pathogenic	criteria provided, single submitter	1
3234969	NM_001931.5(DLAT):c.476del (p.Ile159fs)	Likely pathogenic	criteria provided, single submitter	1
3598993	NM_001931.5(DLAT):c.1030del (p.Cys344fs)	Likely pathogenic	criteria provided, single submitter	1
3598994	NM_001931.5(DLAT):c.1515-1G>T	Likely pathogenic	criteria provided, single submitter	1
3912013	NM_001931.5(DLAT):c.156T>A (p.Tyr52Ter)	Likely pathogenic	criteria provided, single submitter	1
4883119	NM_001931.5(DLAT):c.1022C>A (p.Ser341Ter)	Likely pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore DLAT’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 26 predictions of 918):

Position(s)	Effect	Δscore	Sites
11:112026196–112026197	acceptor_loss	1.0000	5
11:112026300	donor_loss	1.0000	2
11:112028513–112028514	acceptor_loss	1.0000	6
11:112028640–112028641	donor_loss	1.0000	5
11:112037271	acceptor_gain	1.0000
11:112037271–112037272	acceptor_loss	1.0000	3
11:112039240	acceptor_gain	1.0000
11:112039243	acceptor_loss	1.0000
11:112039326	donor_gain	1.0000
11:112043539	donor_gain	1.0000

AlphaMissense

1,560 missense substitutions predicted likely pathogenic (of 4,159 scored), across 366 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M230	9	0.976	0.998
M103	9	0.941	0.994
M570	9	0.887	0.968
D258	8	0.998	1.000
D619	8	0.998	0.999
H620	8	0.996	0.999
D131	8	0.994	0.999
D624	8	0.992	0.998
F576	8	0.986	0.999
H445	8	0.985	0.996
D478	8	0.974	0.989
F303	8	0.958	0.996
D510	8	0.954	0.994
F176	8	0.947	0.995
N495	8	0.940	0.998
D388	8	0.939	0.970
F635	8	0.916	0.996
F137	8	0.903	0.993
F264	8	0.903	0.991
S617	8	0.901	0.999

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	2.14e-10
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	3.42e-05

Disease associations

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

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
pyruvate dehydrogenase E2 deficiency	Definitive	Autosomal recessive	6

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
Leigh syndrome	Moderate	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (14 panels, 10 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

14 panels:

Panel	Rating
DDG2P	green
Dystonia, chorea or related movement disorder, childhood onset	green
Early onset dystonia	green
Likely inborn error of metabolism	green
Mitochondrial disorders	green
Possible mitochondrial disorder, nuclear genes	green
Pyruvate dehydrogenase (PDH) deficiency	green
Structural basal ganglia disorders	green
Undiagnosed metabolic disorders	green
Unexplained death in infancy and sudden unexplained death in childhood	green
Hypotonic infant	amber
Intellectual disability	amber
Leukodystrophy, childhood onset	amber
Paediatric disorders	amber

Mondo (1): pyruvate dehydrogenase E2 deficiency (MONDO:0009502)

Orphanet (2): Pyruvate dehydrogenase deficiency (Orphanet:765), Pyruvate dehydrogenase E2 deficiency (Orphanet:79244)

HPO phenotypes

56 phenotypes (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
HP:0002395	Lower limb hyperreflexia
HP:0002454	Eye of the tiger anomaly of globus pallidus
HP:0002465	Poor speech
HP:0002928	Decreased activity of the pyruvate dehydrogenase complex
HP:0003128	Lactic acidosis
HP:0003487	Babinski sign
HP:0003593	Infantile onset
HP:0004302	Functional motor deficit
HP:0005656	Positional foot deformity
HP:0006961	Jerky head movements
HP:0007325	Generalized dystonia
HP:0007994	Peripheral visual field loss
HP:0010864	Severe intellectual disability
HP:0011098	Speech apraxia
HP:0011968	Feeding difficulties
HP:0012043	Pendular nystagmus
HP:0012379	Abnormal circulating enzyme concentration or activity
HP:0020045	Esodeviation
HP:0025331	Upgaze palsy
HP:0025335	Delayed ability to stand
HP:0031139	Frog-leg posture
HP:0031936	Delayed ability to walk
HP:0031960	Arm dystonia
HP:0032988	Persistent head lag
HP:0100503	Decreased circulating vitamin B1 concentration
HP:0500231	Abnormal CSF pyruvate family amino acid concentration

GWAS associations

3 associations:

Study	Trait	p-value
GCST010703_218	Brain morphology (MOSTest)	4e-13
GCST012228_335	Waist-hip index	3e-8
GCST012230_135	Waist-to-hip ratio adjusted for BMI	4e-8

EFO canonical traits (from GWAS)

2 canonical traits:

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

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
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 (CPIC guideline: no)

Binding affinities (BindingDB)

2 measured of 2 human assays (3 total across all organisms); most potent 2 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM
HYPERFORIN	IC50	2300 nM

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	increases expression, affects cotreatment	3
bisphenol A	decreases expression, increases expression	3
bisphenol S	increases expression, increases methylation	3
Valproic Acid	decreases expression, affects expression, decreases methylation, affects cotreatment	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	decreases expression, increases abundance, increases 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	increases expression, affects cotreatment	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	affects cotreatment, decreases expression	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)

Via MONDO — disease-level, not drug-specific.

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT00029224	Phase 4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	Phase 4	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	Phase 4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	Phase 4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	Phase 4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	Phase 4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	Phase 4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	Phase 4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	Phase 4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	Phase 4	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	Phase 4	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	Phase 4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	Phase 4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	Phase 4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	Phase 4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	Phase 4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	Phase 4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	Phase 4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	Phase 4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	Phase 4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	Phase 4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	Phase 4	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	Phase 4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	Phase 4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	Phase 4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	Phase 4	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	Phase 4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	Phase 4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	Phase 4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	Phase 4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	Phase 4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	Phase 4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	Phase 4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	Phase 4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	Phase 4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	Phase 4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	Phase 4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	Phase 4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	Phase 4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	Phase 4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer
NCT01673984	Phase 4	TERMINATED	GP Extended Action Triptorelin
NCT01753297	Phase 4	COMPLETED	A Study of Immediate 9 Months Adjuvant Hormone Therapy With Triptorelin 11.25 mg Versus Active Surveillance After Radical Prostatectomy in High Risk Prostate Cancer Patients.
NCT01794793	Phase 4	COMPLETED	Study to Allow Access to Pasireotide for Patients Benefiting From Pasireotide Treatment in Novartis-sponsored Studies
NCT01950871	Phase 4	TERMINATED	Prostate Guided Biopsy Study Evaluating the Diagnostic Performance of Prostate HistoScanning
NCT01995513	Phase 4	COMPLETED	Safety Study of Continued Enzalutamide Treatment In Prostate Cancer Patients
NCT02102646	Phase 4	COMPLETED	MRI Substudy; Metabolic Changes Due to Iatrogenic Hypogonadism
NCT02116582	Phase 4	COMPLETED	A Study to Evaluate Enzalutamide After Abiraterone in Metastatic Castration-Resistant Prostate Cancer
NCT02149628	Phase 4	COMPLETED	The Effect of Propofol Based Total Intravenous Anesthesia on Oxidative Stress and Nitric Oxide
NCT02405858	Phase 4	COMPLETED	A Study of Abiraterone Acetate in Metastatic Castration-Resistant Prostate Cancer Participants Who Responded Poorly to the First-line Combined Androgen Blockade Therapy
NCT02441517	Phase 4	TERMINATED	A Study of Enzalutamide Re-treatment in Metastatic Castration-resistant Prostate Cancer After Docetaxel and/or Cabazitaxel Treatment
NCT02441894	Phase 4	COMPLETED	Combination of Cabazitaxel With Prednisolone With Primary Prophylaxis With PEG-G-CSF in Treatment of Patients With Prostate Cancer
NCT02475057	Phase 4	COMPLETED	Endothelial Function in Prostate Cancer Patients on Degarelix vs. Luteinizing Hormone-Releasing Hormone Agonists
NCT02511665	Phase 4	UNKNOWN	Metformin And Longevity
NCT02651948	Phase 4	COMPLETED	Transperineal, MRI-guided, Prostate Biopsy
NCT02721433	Phase 4	COMPLETED	4-weekly Versus 12-weekly Administration of Bone-targeted Agents in Patients With Bone Metastases
NCT02726009	Phase 4	COMPLETED	A Trial to Evaluate Safety of Firmagon® (Degarelix) in Indian Patients Diagnosed With Advanced Hormone-dependent Prostate Cancer
NCT02749825	Phase 4	TERMINATED	Comparison of Trelstar Versus Lupron or Zoladex in Advanced Prostate Cancer
NCT02757365	Phase 4	UNKNOWN	Efficiency Study of Aspirin to Prevent the Occurrence of Prostate Cancer
NCT02773251	Phase 4	COMPLETED	The Effect of Guardix-solution for the Prevention of Postoperative Intestinal Adhesion and Intestinal Obstruction After Laparoscopic Pelvic Cavity Surgery
NCT02812186	Phase 4	COMPLETED	Deep Versus Moderate Neuromuscular Blockade During Laparoscopic Surgery

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for DLAT across ~30M SureChEMBL compounds — explore on Sugi Predict.