Pyruvate dehydrogenase (lipoamide) alpha 1

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Pyruvate dehydrogenase (lipoamide) alpha 1
Protein PDHA1 PDB 1ni4.png
PDB rendering based on 1ni4.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols PDHA1 ; PDHA; PDHCE1A; PHE1A
External IDs OMIM300502 MGI97532 HomoloGene121491 ChEMBL: 2092 GeneCards: PDHA1 Gene
EC number 1.2.4.1
RNA expression pattern
PBB GE PDHA1 200980 s at tn.png
PBB GE PDHA1 200979 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 5160 18597
Ensembl ENSG00000131828 ENSMUSG00000031299
UniProt P08559 P35486
RefSeq (mRNA) NM_000284 NM_008810
RefSeq (protein) NP_000275 NP_032836
Location (UCSC) Chr X:
19.36 – 19.38 Mb
Chr X:
160.12 – 160.14 Mb
PubMed search [1] [2]

Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial is an enzyme that in humans is encoded by the PDHA1 gene.The pyruvate dehydrogenase complex is a nuclear-encoded mitochondrial matrix multienzyme complex that provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle by catalyzing the irreversible conversion of pyruvate into acetyl-CoA. The PDH complex is composed of multiple copies of 3 enzymes: E1 (PDHA1); dihydrolipoyl transacetylase (DLAT) (E2; EC 2.3.1.12); and dihydrolipoyl dehydrogenase (DLD) (E3; EC 1.8.1.4). The E1 enzyme is a heterotetramer of 2 alpha and 2 beta subunits. The E1-alpha subunit contains the E1 active site and plays a key role in the function of the PDH complex.[1]

Structure[edit]

The PDHA1 gene has about 17 kilobase pairs; it contains 11 exons, which range from 61 to 174 base pairs, and introns, whose sizes range from 600 base pairs to 5.7 kilobase pairs. The splice donor and acceptor sites present within the gene all conform to GT/AC rule of splicing. The DNA sequence in the transcription initiation site is very GC-rich. There is a "TATA box"-like sequence and a "CAAT present upstream from the cap site. There are also several sets of repeats, sequences resembling the Sp1 transcription factor binding site, and two cAMP receptor binding sites upstream of the cap.[2]

The preliminary peptide encoded by this gene was 29 amino acids at the very start of the sequence that correspond to a typical mitochondrial targeting leader sequence. The remaining 361 amino acids, starting at the N terminus with phenylalanine, represent the mature mitochondrial E1 alpha peptide.[3] Two of these mature PDHA proteins come together with two PDHB proteins to from a heterotetrameric E1 subunit. Crystal Structures allowed for a model in which the enzyme undergoes a 2-A shuttle-like motion of its heterodimers to perform the catalysis.[4] The protein encoded by the human PDHA1 gene is part of the pyruvate dehydrogenase multienzyme complex. The entire human complex is 9.5 MDa in size, and has been described as 60-meric, meaning there are over 60 components that are assembled to make the entire complex. These subunits are conserved across many species, as the function of this complex is essential for the generation of ATP for all eukaryotes.[5] Each component is responsible for the catalysis of one step in this pathway; this complex exists for the purpose of channeling the intermediates of each reaction to the next enzyme, thus greatly increasing the rate of reaction.[6]

Function[edit]

The pyruvate dehydrogenase complex is responsible for the oxidative decarboxylation of pyruvate, with the final product being Acetyl CoA. Overall the complex catalyzes five reactions, with the overall reaction being:

Pyruvate + CoA + NAD+ → acetyl-CoA + CO2

There are three different coenzymes required throughout the 5 steps that this complex carries out: thiamine pyrophosphate (TPP), lipoamide, and coenzyme A. This step is only one of the central metabolic pathway carried out by eukaryotes, in which glucose is oxidized to form carbon dioxide, water, and ATP. The E1 complex specifically uses the TPP cofactor to cleave the Calpha-C(=O) bond of pyruvate, and then transfer the acetyl group to the TPP coenzyme, thus resulting in an intermediate, hydroxylethyl-Tpp*E1, and producing CO2. The thiazolium ring on the TPP is ideal for adding to carbonyl groups and acting as an electron sink, or a group that can pull electrons from a reaction and stabilize an electron-deficient intermediate.[6]

Regulation[edit]

The activity of the PDH complex in mammalian tissues is largely determined by the phosphorylation of certain subunits within the complex. As such, the absolute amounts of site-specific kinases and phosphates expressed in the mitochondria directly affect PDH activity.[7] Specifically, a tyrosine reside, Tyr-301, can be phosphorylated on PDHA1 and therefore inhibit its activity; this is done by blocking the substrate binding of pyruvate. This phosphorylation is in tandem with phosphorylation of the Ser-293 residue.[8] Phosphorylation of another site, Ser-264, can regulate function. A phosphorylated serine residue at this position prevents TPP from ordering two loops within E1 that contain three phosphorylation sites. The disorder is the direct result of steric clash between the new phosphate group at Ser-264 and another serine, Ser-266, which destabilizes the hydrogen-bonding network that keeps the loops in place. Overall, this disorder results in the inactivation of the catalytic machinery.[9]

The PDH complex can be regulated in a variety of conditions. The PDHA1 subunit has been shown to be regulated by free fatty acids during bouts of exercise. The presence of free fatty acids increases the level of phosphorylation, thereby decreasing PDH activity. During exercise, however, these effects are overruled, and there is a much higher level of dephosphorylated PDHA1 in the cells.[10] In certain muscles, such as the triceps, the metabolic enzyme profile seems to directly affect the level of PDH activity, which can result in higher levels of lactate in muscles with these characteristics.[11]

Clinical significance[edit]

Mutations in the PDHA1 gene have been known to cause one form of pyruvate dehydrogenase deficiency. Pyruvate dehydrogenase deficiency is characterized by the buildup of a chemical called lactic acid in the body and a variety of neurological problems. Signs and symptoms of this condition usually first appear shortly after birth, and they can vary widely among affected individuals. The most common feature is a potentially life-threatening buildup of lactic acid (lactic acidosis), which can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat. People with pyruvate dehydrogenase deficiency usually have neurological problems as well. Most have delayed development of mental abilities and motor skills such as sitting and walking. Other neurological problems can include intellectual disability, seizures, weak muscle tone (hypotonia), poor coordination, and difficulty walking. Some affected individuals have abnormal brain structures, such as underdevelopment of the tissue connecting the left and right halves of the brain (corpus callosum), wasting away (atrophy) of the exterior part of the brain known as the cerebral cortex, or patches of damaged tissue (lesions) on some parts of the brain. Because of the severe health effects, many individuals with pyruvate dehydrogenase deficiency do not survive past childhood, although some may live into adolescence or adulthood.[1] Most cases result from mutations in this gene, and countless types of mutations have been identified. The mutations in this gene range from missense mutations, in which one nucleotide is substituted, to much larger deletions of many nucleotide base pairs.[12][13][14]

While most of the clinical presentation is homogenous with the general disease, some cases have been identified in which there was focal dilatation of the right lateral ventricle with unilateral periventricular leukomalacia (PVL) with subependymal cyst.[15]

In women, this deficiency can be much harder to detect. This is because of the chance that there will be a skewed X inactivation pattern enzyme measurement in fibroblasts, meaning that the enzyme activity measurement may not be entirely accurate. Because the clinical presentation of this disorder overlaps heavily with deficiencies in oxidative phosphorylation, it is recommended to perform a detailed biochemical analysis on a muscle biopsy in females with a suspected pyruvate dehydrogenase deficiency, followed by molecular genetic analysis of the PDHA1 gene.[16]

Interactive pathway map[edit]

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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GlycolysisGluconeogenesis_WP534 go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to Entrez go to article go to article go to article go to article go to article go to WikiPathways go to article go to Entrez go to article
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Glycolysis and Gluconeogenesis edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534". 

References[edit]

  1. ^ a b "Entrez Gene: PDHA1 pyruvate dehydrogenase (lipoamide) alpha 1". 
  2. ^ Maragos C, Hutchison WM, Hayasaka K, Brown GK, Dahl HH (Jul 1989). "Structural organization of the gene for the E1 alpha subunit of the human pyruvate dehydrogenase complex". The Journal of Biological Chemistry 264 (21): 12294–8. PMID 2745444. 
  3. ^ Ho L, Wexler ID, Liu TC, Thekkumkara TJ, Patel MS (Jul 1989). "Characterization of cDNAs encoding human pyruvate dehydrogenase alpha subunit". Proceedings of the National Academy of Sciences of the United States of America 86 (14): 5330–4. PMID 2748588. 
  4. ^ Ciszak EM, Korotchkina LG, Dominiak PM, Sidhu S, Patel MS (Jun 2003). "Structural basis for flip-flop action of thiamin pyrophosphate-dependent enzymes revealed by human pyruvate dehydrogenase". The Journal of Biological Chemistry 278 (23): 21240–6. doi:10.1074/jbc.M300339200. PMID 12651851. 
  5. ^ Hiromasa Y, Fujisawa T, Aso Y, Roche TE (Feb 2004). "Organization of the cores of the mammalian pyruvate dehydrogenase complex formed by E2 and E2 plus the E3-binding protein and their capacities to bind the E1 and E3 components". The Journal of Biological Chemistry 279 (8): 6921–33. doi:10.1074/jbc.M308172200. PMID 14638692. 
  6. ^ a b Voet DJ, Voet JG, Pratt CW (2010). "Chapter 17, Citric Acid Cycle". Principles of Biochemistry (4th ed.). Wiley. p. 550. ISBN 978-0-470-23396-2. 
  7. ^ Kolobova E, Tuganova A, Boulatnikov I, Popov KM (Aug 2001). "Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites". The Biochemical Journal 358 (Pt 1): 69–77. PMID 11485553. 
  8. ^ Fan J, Kang HB, Shan C, Elf S, Lin R, Xie J et al. (Sep 2014). "Tyr-301 phosphorylation inhibits pyruvate dehydrogenase by blocking substrate binding and promotes the Warburg effect". The Journal of Biological Chemistry 289 (38): 26533–41. doi:10.1074/jbc.M114.593970. PMID 25104357. 
  9. ^ Kato M, Wynn RM, Chuang JL, Tso SC, Machius M, Li J et al. (Dec 2008). "Structural basis for inactivation of the human pyruvate dehydrogenase complex by phosphorylation: role of disordered phosphorylation loops". Structure 16 (12): 1849–59. doi:10.1016/j.str.2008.10.010. PMID 19081061. 
  10. ^ Pilegaard H, Birk JB, Sacchetti M, Mourtzakis M, Hardie DG, Stewart G et al. (Nov 2006). "PDH-E1alpha dephosphorylation and activation in human skeletal muscle during exercise: effect of intralipid infusion". Diabetes 55 (11): 3020–7. doi:10.2337/db06-0152. PMID 17065338. 
  11. ^ Kiilerich K, Birk JB, Damsgaard R, Wojtaszewski JF, Pilegaard H (Jan 2008). "Regulation of PDH in human arm and leg muscles at rest and during intense exercise". American Journal of Physiology. Endocrinology and Metabolism 294 (1): E36–42. doi:10.1152/ajpendo.00352.2007. PMID 17957032. 
  12. ^ Giribaldi G, Doria-Lamba L, Biancheri R, Severino M, Rossi A, Santorelli FM et al. (May 2012). "Intermittent-relapsing pyruvate dehydrogenase complex deficiency: a case with clinical, biochemical, and neuroradiological reversibility". Developmental Medicine and Child Neurology 54 (5): 472–6. doi:10.1111/j.1469-8749.2011.04151.x. PMID 22142326. 
  13. ^ Magner M, Vinšová K, Tesařová M, Hájková Z, Hansíková H, Wenchich L et al. (2011). "Two patients with clinically distinct manifestation of pyruvate dehydrogenase deficiency due to mutations in PDHA1 gene". Prague Medical Report 112 (1): 18–28. PMID 21470495. 
  14. ^ Imbard A, Boutron A, Vequaud C, Zater M, de Lonlay P, de Baulny HO et al. (Dec 2011). "Molecular characterization of 82 patients with pyruvate dehydrogenase complex deficiency. Structural implications of novel amino acid substitutions in E1 protein". Molecular Genetics and Metabolism 104 (4): 507–16. doi:10.1016/j.ymgme.2011.08.008. PMID 21914562. 
  15. ^ Sharma R, Sharrard MJ, Connolly DJ, Mordekar SR (May 2012). "Unilateral periventricular leukomalacia in association with pyruvate dehydrogenase deficiency". Developmental Medicine and Child Neurology 54 (5): 469–71. doi:10.1111/j.1469-8749.2011.04108.x. PMID 21895644. 
  16. ^ Willemsen M, Rodenburg RJ, Teszas A, van den Heuvel L, Kosztolanyi G, Morava E (Jun 2006). "Females with PDHA1 gene mutations: a diagnostic challenge". Mitochondrion 6 (3): 155–9. doi:10.1016/j.mito.2006.03.001. PMID 16713755. 

Further reading[edit]