Human Gene PDHA1 (ENST00000422285.7) from GENCODE V44
Description: Homo sapiens pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1), transcript variant 1, mRNA; nuclear gene for mitochondrial product. (from RefSeq NM_000284) RefSeq Summary (NM_000284): The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle. The PDH complex is composed of multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and lipoamide dehydrogenase (E3). The E1 enzyme is a heterotetramer of two alpha and two beta subunits. This gene encodes the E1 alpha 1 subunit containing the E1 active site, and plays a key role in the function of the PDH complex. Mutations in this gene are associated with pyruvate dehydrogenase E1-alpha deficiency and X-linked Leigh syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2010]. Gencode Transcript: ENST00000422285.7 Gencode Gene: ENSG00000131828.14 Transcript (Including UTRs) Position: hg38 chrX:19,343,927-19,361,718 Size: 17,792 Total Exon Count: 11 Strand: + Coding Region Position: hg38 chrX:19,344,038-19,359,653 Size: 15,616 Coding Exon Count: 11
ID:ODPA_HUMAN DESCRIPTION: RecName: Full=Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial; EC=1.2.4.1; AltName: Full=PDHE1-A type I; Flags: Precursor; FUNCTION: The pyruvate dehydrogenase complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2). It contains multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and lipoamide dehydrogenase (E3). CATALYTIC ACTIVITY: Pyruvate + [dihydrolipoyllysine-residue acetyltransferase] lipoyllysine = [dihydrolipoyllysine-residue acetyltransferase] S-acetyldihydrolipoyllysine + CO(2). COFACTOR: Thiamine pyrophosphate. ENZYME REGULATION: E1 activity is regulated by phosphorylation (inactivation) and dephosphorylation (activation) of the alpha subunit. SUBUNIT: Tetramer of 2 alpha and 2 beta subunits. SUBCELLULAR LOCATION: Mitochondrion matrix. TISSUE SPECIFICITY: Ubiquitous. PTM: Phosphorylation at Ser-293 by PDK family kinases blocks the access to active site, and inactivates the enzyme. DISEASE: Defects in PDHA1 are a cause of pyruvate dehydrogenase E1-alpha deficiency (PDHAD) [MIM:312170]. An enzymatic defect causing primary lactic acidosis in children. It is associated with a broad clinical spectrum ranging from fatal lactic acidosis in the newborn to chronic neurologic dysfunction with structural abnormalities in the central nervous system without systemic acidosis. DISEASE: Defects in PDHA1 are the cause of X-linked Leigh syndrome (X-LS) [MIM:308930]. X-LS is an early-onset progressive neurodegenerative disorder with a characteristic neuropathology consisting of focal, bilateral lesions in one or more areas of the central nervous system, including the brainstem, thalamus, basal ganglia, cerebellum, and spinal cord. The lesions are areas of demyelination, gliosis, necrosis, spongiosis, or capillary proliferation. Clinical symptoms depend on which areas of the central nervous system are involved. The most common underlying cause is a defect in oxidative phosphorylation. LS may be a feature of a deficiency of any of the mitochondrial respiratory chain complexes. SEQUENCE CAUTION: Sequence=AAA60055.1; Type=Erroneous initiation; Sequence=AAB59581.1; Type=Frameshift; Positions=106, 175; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PDHA1";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P08559
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Gene Ontology (GO) Annotations with Structured Vocabulary
Molecular Function: GO:0004738 pyruvate dehydrogenase activity GO:0004739 pyruvate dehydrogenase (acetyl-transferring) activity GO:0005515 protein binding GO:0016491 oxidoreductase activity GO:0016624 oxidoreductase activity, acting on the aldehyde or oxo group of donors, disulfide as acceptor GO:0034604 pyruvate dehydrogenase (NAD+) activity
Biological Process: GO:0005975 carbohydrate metabolic process GO:0006006 glucose metabolic process GO:0006086 acetyl-CoA biosynthetic process from pyruvate GO:0006099 tricarboxylic acid cycle GO:0008152 metabolic process GO:0055114 oxidation-reduction process GO:0061732 mitochondrial acetyl-CoA biosynthetic process from pyruvate
BioCyc Knowledge Library PWY66-407 - superpathway of conversion of glucose to acetyl CoA and entry into the TCA cycle PYRUVDEHYD-PWY - pyruvate decarboxylation to acetyl CoA
BioCarta from NCI Cancer Genome Anatomy Project h_malatexPathway - Shuttle for transfer of acetyl groups from mitochondria to the cytosol
Reactome (by CSHL, EBI, and GO)
Protein P08559 (Reactome details) participates in the following event(s):
R-HSA-203946 PDK isoforms phosphorylate lipo-PDH R-HSA-204169 PDP dephosphorylates p-lipo-PDH R-HSA-6792572 LIPT1 transfers lipoyl group from lipoyl-GCSH to DHs R-HSA-71397 lipo-PDH decarboxylates PYR to Ac-CoA R-HSA-204174 Regulation of pyruvate dehydrogenase (PDH) complex R-HSA-5362517 Signaling by Retinoic Acid R-HSA-389661 Glyoxylate metabolism and glycine degradation R-HSA-70268 Pyruvate metabolism R-HSA-9006931 Signaling by Nuclear Receptors R-HSA-71291 Metabolism of nitrogenous molecules R-HSA-71406 Pyruvate metabolism and Citric Acid (TCA) cycle R-HSA-162582 Signal Transduction R-HSA-1430728 Metabolism R-HSA-1428517 The citric acid (TCA) cycle and respiratory electron transport