Pyruvate dehydrogenase complex

Last updated
Pyruvate dehydrogenase complex 153-PyruvateDehydrogenaseComplex pyruvatedehydrogenase.tif
Pyruvate dehydrogenase complex

Pyruvate dehydrogenase complex (PDC) is a complex of three enzymes that converts pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. [1] Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration, and this complex links the glycolysis metabolic pathway to the citric acid cycle. Pyruvate decarboxylation is also known as the "pyruvate dehydrogenase reaction" because it also involves the oxidation of pyruvate. [2]

Contents

This multi-enzyme complex is related structurally and functionally to the oxoglutarate dehydrogenase and branched-chain oxo-acid dehydrogenase multi-enzyme complexes.

Reaction

The reaction catalysed by pyruvate dehydrogenase complex is:

pyruvate pyruvate dehydrogenase complex acetyl CoA
Pyruvate wpmp.png   Acetyl co-A wpmp.svg
CoA-SH + NAD+CO2+ NADH + H+
Biochem reaction arrow forward YYNN horiz med.svg
 
 

Structure

Pyruvate dehydrogenase (E1)

Pymol-generated image of E1 subunit of pyruvate dehydrogenase complex in E. Coli E1 Subunit Ecoli.png
Pymol-generated image of E1 subunit of pyruvate dehydrogenase complex in E. Coli

The E1 subunit, called the pyruvate dehydrogenase subunit, is either a homodimer (comprising two “ɑ” chains, e.g. in Escherichia coli ) or a heterotetramer of two different chains (two “ɑ” and two “ꞵ” chains). A magnesium ion forms a 4-coordinate complex with three, polar amino acid residues (Asp, Asn, and Tyr) located on the alpha chain, and the thiamine diphosphate (TPP) cofactor directly involved in decarboxylation of the pyruvate. [3] [4]

Dihydrolipoyl transacetylase (E2)

The E2 subunit, or dihydrolipoyl acetyltransferase, for both prokaryotes and eukaryotes, is generally composed of three domains. The N-terminal domain (the lipoyl domain), consists of 1–3 lipoyl groups of approximately 80 amino acids each. The peripheral subunit binding domain (PSBD), serves as a selective binding site for other domains of the E1 and E3 subunits. Finally, the C-terminal (catalytic) domain catalyzes the transfer of acetyl groups and acetyl-CoA synthesis. [5]

Dihydrolipoyl dehydrogenase (E3)

Pymol-generated E3 subunit of pyruvate dehydrogenase complex in Pseudomonas putida E3 Subunit Putida.png
Pymol-generated E3 subunit of pyruvate dehydrogenase complex in Pseudomonas putida

The E3 subunit, called the dihydrolipoyl dehydrogenase enzyme, is characterized as a homodimer protein wherein two cysteine residues, engaged in disulfide bonding, and the FAD cofactor in the active site facilitate its main purpose as an oxidizing catalyst. One example of E3 structure, found in Pseudomonas putida , is formed such that each individual homodimer subunit contains two binding domains responsible for FAD binding and NAD binding, as well as a central domain and an interface domain. [6] [7]

Dihydrolipoyl dehydrogenase Binding protein (E3BP)

An auxiliary protein unique to most eukaryotes is the E3 binding protein (E3BP), which serves to bind the E3 subunit to the PDC complex. In the case of human E3BP, hydrophobic proline and leucine residues in the BP interact with the surface recognition site formed by the binding of two identical E3 monomers. [8]

Mechanism

EnzymesAbbrev. Cofactors # subunits prokaryotes# subunits eukaryotes
pyruvate dehydrogenase
(EC 1.2.4.1)
E1 TPP (thiamine pyrophosphate) magnesium 2430
dihydrolipoyl transacetylase
(EC 2.3.1.12)
E2alpha-lipoic acid (lipoate)
coenzyme A
2460
dihydrolipoyl dehydrogenase
(EC 1.8.1.4)
E3 FAD
NAD +
1212
PDC Mechanism with pyruvate (R=H) PDH schema.png
PDC Mechanism with pyruvate (R=H)

Pyruvate dehydrogenase (E1)

Initially, pyruvate and thiamine pyrophosphate (TPP or vitamin B1) are bound by pyruvate dehydrogenase subunits. [1] The thiazolium ring of TPP is in a zwitterionic form, and the anionic C2 carbon performs a nucleophilic attack on the C2 (ketone) carbonyl of pyruvate. The resulting hemithioacetal undergoes decarboxylation to produce an acyl anion equivalent (see cyanohydrin or aldehyde-dithiane umpolung chemistry, as well as benzoin condensation). This anion attacks S1 of an oxidized lipoate species that is attached to a lysine residue. In a ring-opening SN2-like mechanism, S2 is displaced as a sulfide or sulfhydryl moiety. Subsequent collapse of the tetrahedral hemithioacetal ejects thiazole, releasing the TPP cofactor and generating a thioacetate on S1 of lipoate. The E1-catalyzed process is the rate-limiting step of the whole pyruvate dehydrogenase complex.

Dihydrolipoyl transacetylase (E2)

At this point, the lipoate-thioester functionality is translocated into the dihydrolipoyl transacetylase (E2) active site, [1] where a transacylation reaction transfers the acetyl from the "swinging arm" of lipoyl to the thiol of coenzyme A. This produces acetyl-CoA, which is released from the enzyme complex and subsequently enters the citric acid cycle. E2 can also be known as lipoamide reductase-transacetylase.

Dihydrolipoyl dehydrogenase (E3)

The dihydrolipoate, still bound to a lysine residue of the complex, then migrates to the dihydrolipoyl dehydrogenase (E3) active site, [1] where it undergoes a flavin-mediated oxidation, identical in chemistry to disulfide isomerase. First, FAD oxidizes dihydrolipoate back to its lipoate resting state, producing FADH2. Then, a NAD+ cofactor oxidizes FADH2 back to its FAD resting state, producing NADH and H.

Structural differences between species

PDC is a large complex composed of multiple copies of 3 or 4 subunits depending on species.

Gram-negative bacteria

In Gram-negative bacteria, e.g. Escherichia coli , PDC consists of a central cubic core made up from 24 molecules of dihydrolipoyl transacetylase (E2). Up to 32 copies of pyruvate dehydrogenase (E1) and 16 molecules of dihydrolipoyl dehydrogenase (E3) bind to the E2 PSBD around the E2 core. In Gammaproteobacteria the specificity of PSBD for binding either E1 or E3 is determined by its oligomeric state. [9]

Gram-positive bacteria and eukaryotes

In contrast, in Gram-positive bacteria (e.g. Bacillus stearothermophilus ) and eukaryotes the central PDC core contains 60 E2 molecules arranged into an icosahedron. This E2 subunit “core” coordinates to 30 subunits of E1 and 12 copies of E3.

Eukaryotes also contain 12 copies of an additional core protein, E3 binding protein (E3BP) which bind the E3 subunits to the E2 core. [10] The exact location of E3BP is not completely clear. Cryo-electron microscopy has established that E3BP binds to each of the icosahedral faces in yeast. [11] However, it has been suggested that it replaces an equivalent number of E2 molecules in the bovine PDC core.

Up to 60 E1 or E3 molecules can associate with the E2 core from Gram-positive bacteria - binding is mutually exclusive. In eukaryotes E1 is specifically bound by E2, while E3 associates with E3BP. It is thought that up to 30 E1 and 6 E3 enzymes are present, although the exact number of molecules can vary in vivo and often reflects the metabolic requirements of the tissue in question.

Regulation

Pyruvate dehydrogenase is inhibited when one or more of the three following ratios are increased: ATP/ADP, NADH/NAD+ and acetyl-CoA/CoA.[ citation needed ]

In eukaryotes PDC is tightly regulated by its own specific pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase (PDP), deactivating and activating it respectively. [12]

Products of the reaction act as allosteric inhibitors of the PDC, because they activate PDK. Substrates in turn inhibit PDK, reactivating PDC.

During starvation, PDK increases in amount in most tissues, including skeletal muscle, via increased gene transcription. Under the same conditions, the amount of PDP decreases. The resulting inhibition of PDC prevents muscle and other tissues from catabolizing glucose and gluconeogenesis precursors. Metabolism shifts toward fat utilization, while muscle protein breakdown to supply gluconeogenesis precursors is minimized, and available glucose is spared for use by the brain.[ citation needed ]

Calcium ions have a role in regulation of PDC in muscle tissue, because it activates PDP, stimulating glycolysis on its release into the cytosol - during muscle contraction. Some products of these transcriptions release H2 into the muscles. This can cause calcium ions to decay over time.[ citation needed ]

Localization of pyruvate decarboxylation

In eukaryotic cells the pyruvate decarboxylation occurs inside the mitochondrial matrix, after transport of the substrate, pyruvate, from the cytosol. The transport of pyruvate into the mitochondria is via the transport protein pyruvate translocase. Pyruvate translocase transports pyruvate in a symport fashion with a proton (across the inner mitochondrial membrane), which may be considered to be a form of secondary active transport, but further confirmation/support may be needed for the usage of "secondary active transport" desciptor here (Note: the pyruvate transportation method via the pyruvate translocase appears to be coupled to a proton gradient according to S. Papa et al., 1971, seemingly matching secondary active transport in definition). [13]

Alternative sources say "transport of pyruvate across the outer mitochondrial membrane appears to be easily accomplished via large non-selective channels such as voltage-dependent anion channels, which enable passive diffusion" and transport across inner mitochondrial membrane is mediated by mitochondrial pyruvate carrier 1 (MPC1) and mitochondrial pyruvate carrier 2 (MPC2). [14]

Upon entry into the mitochondrial matrix, the pyruvate is decarboxylated, producing acetyl-CoA (and carbon dioxide and NADH). This irreversible reaction traps the acetyl-CoA within the mitochondria (the acetyl-CoA can only be transported out of the mitochondrial matrix under conditions of high oxaloacetate via the citrate shuttle, a TCA intermediate that is normally sparse). The carbon dioxide produced by this reaction is nonpolar and small, and can diffuse out of the mitochondria and out of the cell.[ citation needed ]

In prokaryotes, which have no mitochondria, this reaction is either carried out in the cytosol, or not at all.[ citation needed ]

Evolutionary history

It was found that pyruvate dehydrogenase enzyme found in the mitochondria of eukaryotic cells closely resembles an enzyme from Geobacillus stearothermophilus , which is a species of gram-positive bacteria. Despite similarities of the pyruvate dehydrogenase complex with gram-positive bacteria, there is little resemblance with those of gram-negative bacteria.  Similarities of the quaternary structures between pyruvate dehydrogenase and enzymes in gram-positive bacteria point to a shared evolutionary history which is distinctive from the evolutionary history of corresponding enzymes found in gram-negative bacteria. Through an endosymbiotic event, pyruvate dehydrogenase found in the eukaryotic mitochondria points to ancestral linkages dating back to gram-positive bacteria. [15]

Pyruvate dehydrogenase complexes share many similarities with branched chain 2-oxoacid dehydrogenase (BCOADH), particularly in their substrate specificity for alpha-keto acids. Specifically, BCOADH catalyzes the degradation of amino acids and these enzymes would have been prevalent during the periods on prehistoric Earth dominated by rich amino acid environments. The E2 subunit from pyruvate dehydrogenase evolved from the E2 gene found in BCOADH while both enzymes contain identical E3 subunits due to the presence of only one E3 gene. Since the E1 subunits have a distinctive specificity for particular substrates, the E1 subunits of pyruvate dehydrogenase and BCOADH vary but share genetic similarities. The gram-positive bacteria and cyanobacteria that would later give rise to mitochondria and chloroplast found in eukaryotic cells retained the E1 subunits that are genetically related to those found in the BCOADH enzymes. [16] [17]

Clinical relevance

Pyruvate dehydrogenase deficiency (PDCD) can result from mutations in any of the enzymes or cofactors used to build the complex. Its primary clinical finding is lactic acidosis. [18] Such PDCD mutations, leading to subsequent deficiencies in NAD and FAD production, hinder oxidative phosphorylation processes that are key in aerobic respiration. Thus, acetyl-CoA is instead reduced via anaerobic mechanisms into other molecules like lactate, leading to an excess of bodily lactate and associated neurological pathologies. [19]

While pyruvate dehydrogenase deficiency is rare, there are a variety of different genes when mutated or nonfunctional that can induce this deficiency. First, the E1 subunit of pyruvate dehydrogenase contains four different subunits: two alpha subunits designated as E1-alpha and two beta subunits designated as E1-beta. The PDHA1 gene found in the E1-alpha subunits, when mutated, causes 80% of the cases of pyruvate dehydrogenase deficiency because this mutation abridges the E1-alpha protein. Decreased functional E1 alpha prevents pyruvate dehydrogenase from sufficiently binding to pyruvate, thus reducing the activity of the overall complex. [20] When the PDHB gene found in the E1 beta subunit of the complex is mutated, this also leads to pyruvate dehydrogenase deficiency. [21] Likewise, mutations found on other subunits of the complex, like the DLAT gene found on the E2 subunit, the PDHX gene found on the E3 subunit, as well as a mutation on a pyruvate dehydrogenase phosphatase gene, known as PDP1, have all been traced back to pyruvate dehydrogenase deficiency, while their specific contribution to the disease state is unknown. [22] [23] [24]

See also

Related Research Articles

<span class="mw-page-title-main">Mitochondrial matrix</span> Space within the inner membrane of the mitochondrion

In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ribosomes, soluble enzymes, small organic molecules, nucleotide cofactors, and inorganic ions.[1] The enzymes in the matrix facilitate reactions responsible for the production of ATP, such as the citric acid cycle, oxidative phosphorylation, oxidation of pyruvate, and the beta oxidation of fatty acids.

The oxoglutarate dehydrogenase complex (OGDC) or α-ketoglutarate dehydrogenase complex is an enzyme complex, most commonly known for its role in the citric acid cycle.

The branched-chain α-ketoacid dehydrogenase complex is a multi-subunit complex of enzymes that is found on the mitochondrial inner membrane. This enzyme complex catalyzes the oxidative decarboxylation of branched, short-chain alpha-ketoacids. BCKDC is a member of the mitochondrial α-ketoacid dehydrogenase complex family, which also includes pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, key enzymes that function in the Krebs cycle.

Pyruvate dehydrogenase deficiency is a rare neurodegenerative disorder associated with abnormal mitochondrial metabolism. PDCD is a genetic disease resulting from mutations in one of the components of the pyruvate dehydrogenase complex (PDC). The PDC is a multi-enzyme complex that plays a vital role as a key regulatory step in the central pathways of energy metabolism in the mitochondria. The disorder shows heterogeneous characteristics in both clinical presentation and biochemical abnormality.

<span class="mw-page-title-main">Dihydrolipoyl transacetylase</span>

Dihydrolipoyl transacetylase is an enzyme component of the multienzyme pyruvate dehydrogenase complex. The pyruvate dehydrogenase complex is responsible for the pyruvate decarboxylation step that links glycolysis to the citric acid cycle. This involves the transformation of pyruvate from glycolysis into acetyl-CoA which is then used in the citric acid cycle to carry out cellular respiration.

Oxidative decarboxylation is a decarboxylation reaction caused by oxidation. Most are accompanied by α- Ketoglutarate α- Decarboxylation caused by dehydrogenation of hydroxyl carboxylic acids such as carbonyl carboxylic acid, malic acid, isocitric acid, etc.

<span class="mw-page-title-main">Pyruvate dehydrogenase</span> Class of enzymes

Pyruvate dehydrogenase is an enzyme that catalyzes the reaction of pyruvate and a lipoamide to give the acetylated dihydrolipoamide and carbon dioxide. The conversion requires the coenzyme thiamine pyrophosphate.

<span class="mw-page-title-main">Pyruvate dehydrogenase kinase</span> Class of enzymes

Pyruvate dehydrogenase kinase is a kinase enzyme which acts to inactivate the enzyme pyruvate dehydrogenase by phosphorylating it using ATP.

<span class="mw-page-title-main">Dihydrolipoamide dehydrogenase</span> Protein-coding gene in the species Homo sapiens

Dihydrolipoamide dehydrogenase (DLD), also known as dihydrolipoyl dehydrogenase, mitochondrial, is an enzyme that in humans is encoded by the DLD gene. DLD is a flavoprotein enzyme that oxidizes dihydrolipoamide to lipoamide.

<span class="mw-page-title-main">E3 binding protein</span> Protein-coding gene in the species Homo sapiens

E3 binding protein also known as pyruvate dehydrogenase protein X component, mitochondrial is a protein that in humans is encoded by the PDHX gene. The E3 binding protein is a component of the pyruvate dehydrogenase complex found only in eukaryotes. Defects in this gene are a cause of pyruvate dehydrogenase deficiency which results in neurological dysfunction and lactic acidosis in infancy and early childhood. This protein is also a minor antigen for antimitochondrial antibodies. These autoantibodies are present in nearly 95% of patients with primary biliary cholangitis, an autoimmune disease of the liver. In primary biliary cholangitis, activated T lymphocytes attack and destroy epithelial cells in the bile duct where this protein is abnormally distributed and overexpressed. Primary biliary cholangitis eventually leads to liver failure.

<span class="mw-page-title-main">HADHA</span> Protein-coding gene in the species Homo sapiens

Trifunctional enzyme subunit alpha, mitochondrial also known as hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, alpha subunit is a protein that in humans is encoded by the HADHA gene. Mutations in HADHA have been associated with trifunctional protein deficiency or long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.

<span class="mw-page-title-main">Pyruvate dehydrogenase phosphatase</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase phosphatase catalytic subunit 1, also known as protein phosphatase 2C, is an enzyme that in humans is encoded by the PDP1 gene. PDPC 1 is an enzyme which serves to reverse the effects of pyruvate dehydrogenase kinase upon pyruvate dehydrogenase, activating pyruvate dehydrogenase.

<span class="mw-page-title-main">Pyruvate dehydrogenase (lipoamide) alpha 1</span> Protein-coding gene in the species Homo sapiens

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) ; and dihydrolipoyl dehydrogenase (DLD). 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.

<span class="mw-page-title-main">BCKDHA</span> Protein-coding gene in the species Homo sapiens

A 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial is an enzyme that in humans is encoded by the BCKDHA gene.

<span class="mw-page-title-main">DBT (gene)</span> Mammalian protein found in Homo sapiens

Lipoamide acyltransferase component of branched-chain alpha-keto acid dehydrogenase complex, mitochondrial is an enzyme that in humans is encoded by the DBT gene.

<span class="mw-page-title-main">BCKDHB</span> Protein-coding gene in the species Homo sapiens

2-Oxoisovalerate dehydrogenase subunit beta, mitochondrial is an enzyme that in humans is encoded by the BCKDHB gene.

In chemistry, a compartment is a part of a protein that serves a specific function. They are essentially protein subunits with the added condition that a compartment has distinct functionality, rather than being just a structural component.

<span class="mw-page-title-main">Pyruvate dehydrogenase (lipoamide) alpha 2</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase (lipoamide) alpha 2, also known as pyruvate dehydrogenase E1 component subunit alpha, testis-specific form, mitochondrial or PDHE1-A type II, is an enzyme that in humans is encoded by the PDHA2 gene.

<span class="mw-page-title-main">Pyruvate dehydrogenase (lipoamide) beta</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase (lipoamide) beta, also known as pyruvate dehydrogenase E1 component subunit beta, mitochondrial or PDHE1-B is an enzyme that in humans is encoded by the PDHB gene. The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO2, and provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle. The PDH complex is composed of multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and lipoamide dehydrogenase (E3). The E1 enzyme is a heterotetramer of two alpha and two beta subunits. This gene encodes the E1 beta subunit. Mutations in this gene are associated with pyruvate dehydrogenase E1-beta deficiency.

<span class="mw-page-title-main">Citrate–malate shuttle</span>

The citrate-malate shuttle is a series of chemical reactions, commonly referred to as a biochemical cycle or system, that transports acetyl-CoA in the mitochondrial matrix across the inner and outer mitochondrial membranes for fatty acid synthesis. Mitochondria are enclosed in a double membrane. As the inner mitochondrial membrane is impermeable to acetyl-CoA, the shuttle system is essential to fatty acid synthesis in the cytosol. It plays an important role in the generation of lipids in the liver.

References

  1. 1 2 3 4 DeBrosse SD, Kerr DS (2016-01-01), Saneto RP, Parikh S, Cohen BH (eds.), "Chapter 12 - Pyruvate Dehydrogenase Complex Deficiency", Mitochondrial Case Studies, Boston: Academic Press, pp. 93–101, doi:10.1016/b978-0-12-800877-5.00012-7, ISBN   978-0-12-800877-5 , retrieved 2020-11-16
  2. J. M. Berg, J. L. Tymoczko, L. Stryer (2007). Biochemistry (6th ed.). Freeman. ISBN   978-0-7167-8724-2.
  3. Sgrignani J, Chen J, Alimonti A (2018). "How phosphorylation influences E1 subunit pyruvate dehydrogenase: A computational study". Scientific Reports. 8 (14683): 14683. Bibcode:2018NatSR...814683S. doi: 10.1038/s41598-018-33048-z . PMC   6168537 . PMID   30279533. S2CID   52910721.
  4. [PBD ID: 2QTC] Kale S, Arjunan P, Furey W, Jordan F (2007). "A dynamic loop at the active center of the Escherichia coli pyruvate dehydrogenase COMPLEX E1 component Modulates SUBSTRATE utilization and CHEMICAL communication with the E2 component". Journal of Biological Chemistry. 282 (38): 28106–28116. doi: 10.1074/jbc.m704326200 . PMID   17635929. S2CID   25199383.
  5. Patel MS, Nemeria NS, Furey W, Jordan F (2014). "The pyruvate dehydrogenase complexes: structure-based function and regulation". The Journal of Biological Chemistry. 289 (24): 16615–16623. doi: 10.1074/jbc.R114.563148 . PMC   4059105 . PMID   24798336.
  6. Billgren ES, Cicchillo RM, Nesbitt NM, Booker SJ (2010). "Lipoic Acid Biosynthesis and Enzymology". Comprehensive Natural Products. 2 (7): 181–212. doi:10.1016/B978-008045382-8.00137-4.
  7. [PDB ID: 1LVL] Mattevia A, Obmolova G, Sokatch JR, Betzel C, Hol WG (1992). "The refined crystal STRUCTURE of pseudomonas Putida LIPOAMIDE DEHYDROGENASE complexed with NAD+ at 2.45 Å resolution". Proteins: Structure, Function, and Genetics. 13 (4): 336–351. doi:10.1002/prot.340130406. PMID   1325638. S2CID   23288363.
  8. Ciszak EM, Makal A, Hong YS, Vettaikkorumakankauv AK, Korotchkina LG, Patel MS (2006). "How dihydrolipoamide dehydrogenase-binding protein binds dihydrolipoamide dehydrogenase in the human pyruvate dehydrogenase complex". Journal of Biological Chemistry. 281 (1): 648–655. doi: 10.1074/jbc.m507850200 . PMID   16263718. S2CID   26797600.
  9. Meinhold S, Zdanowicz R, Giese C, Glockshuber R (2024). "Dimerization of a 5-kDa domain defines the architecture of the 5-MDa gammaproteobacterial pyruvate dehydrogenase complex". Sci. Adv. 10 (6): eadj6358. doi: 10.1126/sciadv.adj6358 . PMC   10849603 . PMID   38324697.
  10. Brautigam CA, Wynn RM, Chuang JL, Machius M, Tomchick DR, Chuang DT (2006). "Structural insight into interactions between Dihydrolipoamide Dehydrogenase (E3) and E3 binding protein of Human pyruvate dehydrogenase complex". Structure. 14 (3): 611–621. doi:10.1016/j.str.2006.01.001. PMC   2879633 . PMID   16442803.
  11. Stoops, J.K., Cheng, R.H., Yazdi, M.A., Maeng, C.Y., Schroeter, J.P., Klueppelberg, U., Kolodziej, S.J., Baker, T.S., Reed, L.J. (1997) On the unique structural organization of the Saccharomyces cerevisiae pyruvate dehydrogenase complex. J. Biol. Chem. 272, 5757-5764.
  12. 1 2 3 Pelley JW (2012-01-01), Pelley JW (ed.), "6 - Glycolysis and Pyruvate Oxidation", Elsevier's Integrated Review Biochemistry (Second Edition), Philadelphia: W.B. Saunders, pp. 49–55, doi:10.1016/b978-0-323-07446-9.00006-4, ISBN   978-0-323-07446-9 , retrieved 2020-11-16
  13. Papa S (30 January 1971). "The transport of pyruvate in rat liver mitochondria". FEBS Lett. 12 (5): 285–288. doi: 10.1016/0014-5793(71)80200-4 . PMID   11945601.
  14. Rutter J (23 January 2013). "The long and winding road to the mitochondrial pyruvate carrier". Cancer & Metabolism. 1 (1): 6. doi: 10.1186/2049-3002-1-6 . PMC   3834494 . PMID   24280073.
  15. Henderson CE, Perham RN, Finch JT (May 1979). "Structure and symmetry of B. stearothermophilus pyruvate dehydrogenase multienzyme complex and implications for eucaryote evolution". Cell. 17 (1): 85–93. doi:10.1016/0092-8674(79)90297-6. ISSN   0092-8674. PMID   455461. S2CID   35282258.
  16. Schreiner ME, Fiur D, Holátko J, Pátek M, Eikmanns BJ (2005-09-01). "E1 Enzyme of the Pyruvate Dehydrogenase Complex in Corynebacterium glutamicum: Molecular Analysis of the Gene and Phylogenetic Aspects". Journal of Bacteriology. 187 (17): 6005–6018. doi:10.1128/jb.187.17.6005-6018.2005. ISSN   0021-9193. PMC   1196148 . PMID   16109942.
  17. Schnarrenberger C, Martin W (2002-02-01). "Evolution of the enzymes of the citric acid cycle and the glyoxylate cycle of higher plants". European Journal of Biochemistry. 269 (3): 868–883. doi: 10.1046/j.0014-2956.2001.02722.x . ISSN   0014-2956. PMID   11846788.
  18. "Pyruvate dehydrogenase deficiency". Genetics Home Reference. Retrieved March 17, 2013.
  19. Gupta N, Rutledge C (2019). "Pyruvate Dehydrogenase Complex Deficiency: An Unusual Cause of Recurrent Lactic Acidosis in a Paediatric Critical Care Unit". The Journal of Critical Care Medicine. 5 (2): 71–75. doi: 10.2478/jccm-2019-0012 . PMC   6534940 . PMID   31161145.
  20. Lissens W, De Meirleir L, Seneca S, Liebaers I, Brown GK, Brown RM, Ito M, Naito E, Kuroda Y, Kerr DS, Wexler ID (March 2000). "Mutations in the X-linked pyruvate dehydrogenase (E1) ? subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency". Human Mutation. 15 (3): 209–219. doi: 10.1002/(sici)1098-1004(200003)15:3<209::aid-humu1>3.0.co;2-k . ISSN   1059-7794. PMID   10679936. S2CID   29926332.
  21. Okajima K, Korotchkina L, Prasad C, Rupar T, Phillips III J, Ficicioglu C, Hertecant J, Patel M, Kerr D (April 2008). "Mutations of the E1β subunit gene (PDHB) in four families with pyruvate dehydrogenase deficiency". Molecular Genetics and Metabolism. 93 (4): 371–380. doi:10.1016/j.ymgme.2007.10.135. ISSN   1096-7192. PMID   18164639.
  22. Head RA, Brown RM, Zolkipli Z, Shahdadpuri R, King MD, Clayton PT, Brown GK (2005-07-27). "Clinical and genetic spectrum of pyruvate dehydrogenase deficiency: Dihydrolipoamide acetyltransferase (E2) deficiency". Annals of Neurology. 58 (2): 234–241. doi:10.1002/ana.20550. ISSN   0364-5134. PMID   16049940. S2CID   38264402.
  23. Pavlu-Pereira H, Silva MJ, Florindo C, Sequeira S, Ferreira AC, Duarte S, Rodrigues AL, Janeiro P, Oliveira A, Gomes D, Bandeira A, Martins E, Gomes R, Soares S, Tavares de Almeida I, Vicente JB, Rivera I (December 2020). "Pyruvate dehydrogenase complex deficiency: updating the clinical, metabolic and mutational landscapes in a cohort of Portuguese patients". Orphanet Journal of Rare Diseases. 15 (1): 298. doi: 10.1186/s13023-020-01586-3 . PMC   7579914 . PMID   33092611.
  24. Heo HJ, Kim HK, Youm JB, Cho SW, Song I, Lee SY, Ko TH, Kim N, Ko KS, Rhee BD, Han J (August 2016). "Mitochondrial pyruvate dehydrogenase phosphatase 1 regulates the early differentiation of cardiomyocytes from mouse embryonic stem cells". Experimental & Molecular Medicine. 48 (8): e254. doi:10.1038/emm.2016.70. ISSN   2092-6413. PMC   5007642 . PMID   27538372.

3D structures