Pyruvate dehydrogenase complex

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The pyruvate dehydrogenase complex ( PDC ) is a very large multi- enzyme complex that catalyzes the irreversible oxidative decarboxylation of pyruvate . It is essential for the production of energy from carbohydrates , for example D - glucose , because it connects glycolysis with the citric acid cycle .

A functioning pyruvate dehydrogenase complex has been found in every aerobic eukaryote as well as aerobic prokaryote . In facultative anaerobic bacteria, the complex is inactive under anaerobic conditions. Obligatory anaerobic bacteria such as clostridia or aerobic archaea , on the other hand, use a pyruvate ferredoxin oxidoreductase .

construction

The complex is found in eukaryotes in the mitochondrial matrix, in prokaryotes in the cytoplasm and in plants also in plastids . It consists of multiple copies of three enzyme subunits, each of which catalyzes a partial reaction. The active centers of the respective subunits are closely adjacent:

The entire complex is one of the largest known multienzyme complexes in eukaryotes . It has a diameter of about 500 Å and a molar mass of 9.5 megadaltons . The core structure, a dodecahedron , is made up of 60 E 2 subunits that form trimers at the 20 corners of the dodecahedron. 30 E 1 heterotetramers and 12 E 3 homodimers are located on this core structure . In addition, there is an E 3 binding protein (E3BP) which binds the E 3 subunits to the overall complex.

Bacteria have a slightly different composition of the complex. The one from Escherichia coli has been studied best , which goes back to the work of Lester Reed . There the PDC consists of 24 E 1 subunits, 24 E 2 subunits and 12 E 3 subunits. It has a mass of about 4.6 MDa and a diameter of about 300 Å. Its E 2 subunits form a cube with trimers located at each corner. But there are also a few Gram-negative bacteria whose core structure is similar to that of eukaryotes.

Numerous cofactors are involved in the enzymatic reactions : TPP , protein-bound liponamide and FAD are catalytic cofactors, while coenzyme A and NAD + function as stoichiometric cofactors.

The reaction

Reaction scheme for oxidative decarboxylation, in the specific case of PDC, R = H

In the oxidative decarboxylation , carbon dioxide (CO 2 ) is split off from the pyruvate (C 3 ) and an NADH is obtained. An energy-rich thioester bond is formed between coenzyme A and the acetate residue, so that acetyl-CoA is formed. The energy for this comes from decarboxylation. The conversion of pyruvate to acetyl-CoA is irreversible under physiological conditions.

Partial steps

  • The decarboxylation of pyruvate takes place with the help of the pyruvate dehydrogenase (E 1 ) of the pyruvate dehydrogenase complex ( A ). In this catalyzed reaction, thiamine pyrophosphate (TPP) is the prosthetic group and forms an atomic bond with pyruvate. The reaction product is hydroxyethyl TPP and CO 2 . This hydroxyethyl group is oxidized to an acetyl group and taken over by liponamide, so that an energy-rich thioester bond, S-acetylliponamide ( B ), is formed. Liponamide is covalently linked to the transacetylase subunit. The disulfide group of the liponamide is reduced to the disulfhydryl form in this reaction.
  • The acetyl residue of acetylliponamide is transferred to coenzyme A , thus creating acetyl-CoA and dihydroliponamide ( C ). This is catalyzed by dihydrolipoyl transacetylase (E 2 ). Formally, a transesterification takes place in this reaction, whereby the high-energy thioester bond is retained.
  • Dihydroliponamide is regenerated to liponamide by the dihydrolipoyl dehydrogenase (E 3 ) subunit. A covalently bound FAD is reduced to FADH 2 ( D ), which is regenerated by the reduction of NAD + ( E ). The transfer of electrons normally takes place in the opposite direction from NADH to FAD. However, the electron transfer potential of FADs is sufficiently increased due to its covalent bond with the protein so that the reaction can take place.

This results in the following overall reaction:

By generating acetyl-CoA from pyruvate, a connection is established between glycolysis and the citric acid cycle. The resulting acetyl-CoA can then be further converted into citrate with oxaloacetate by the citrate synthase . The NADH / H + can be reoxidized again through the respiratory chain .

Vitamin B 1 essentiality and deficiency

The pyruvate dehydrogenase complex is, according to the reaction described, necessary for all (net) energy production from carbohydrates (as opposed to fats ). With the proportion of vitamin B 1 (thiamine), a vitamin is also necessary for this, i.e. a substance that has to be supplied from the outside. There is an increased need for thiamine with greatly increased carbohydrate intake. With a normal, healthy diet without alcohol consumption, an additional thiamine intake is not necessary.

regulation

The end products acetyl-CoA and also NADH can lead to an inhibition of the pyruvate dehydrogenase complex (product inhibition). In addition, the complex is also regulated by two modifications. A pyruvate dehydrogenase kinase (PDK) and a phosphopyruvate dehydrogenase phosphatase (PDP) catalyze the reversible phosphorylation of the cytosolic PDC. In mammals, three highly conserved serine residues of the E 1 subunit are phosphorylated by the PDK with consumption of ATP , and in plants two . This causes a complete inactivation of the PDC. The phosphatase reverses the phosphorylation and thus activates the entire complex.

In humans, PDP is stimulated by calcium and magnesium ions . An increase in the calcium level can also be caused by α-sympathomimetics and vasopressin . The PDK, however, is stimulated by acetyl-CoA and NADH, while pyruvate, ADP and calcium ions have an inhibitory effect. The activity of the kinase is higher in plants than that of the phosphatase, so that there it has to be additionally regulated. Here ammonium (NH 4 + ) activates the PDK, while pyruvate and ADP inhibit it.

Inhibitors

Arsenite toxicity to sulfhydryl groups
Toxicity of organic arsenic compounds with sulfhydryl groups

Arsenic (III) compounds such as arsenite (AsO 3 3− ) or organic arsenic compounds form covalent compounds with sulfhydryl groups. Therefore, they are able to inactivate the liponamide from the PDC and thus have a toxic effect.

PDC in plastids

In plants, the pyruvate dehydrogenase complex occurs not only in mitochondria, but also in plastids . There he is involved in the provision of acetyl-CoA for fatty acid synthesis . However, the activity of the complex - depending on the stage of development of the cell - is rather low. Most of the acetyl-CoA is obtained from acetate , which is ATP-catalysed by an acetyl-CoA synthetase.

See also

literature

  • Zhou, ZH. et al. (2001): The remarkable structural and functional organization of the eukaryotic pyruvate dehydrogenase complexes . In: Proc Natl Acad Sci USA 98 (26); 14802-14807; PMID 11752427 ; PDF (free full text access)

Individual evidence

  1. ↑ Garabed Antranikian: Applied Microbiology. Springer, Berlin 2006; ISBN 978-3-540-24083-9 ; P. 52f.
  2. ↑ Katharina Munk (ed.): Pocket textbook Biology: Microbiology . Thieme Verlag Stuttgart 2008, ISBN 978-3-13-144861-3 , p. 355.
  3. ↑ Caroline Bowsher, Martin W. Steer, Alyson K. Tobin: Plant Biochemistry . Garland Pub, New York, NY 2008, ISBN 978-0-8153-4121-5 . P. 157
  4. ^ A b Reginald Garrett and Charles M. Grisham: Biochemistry . (International Student Edition). Cengage learning services; 4th edition 2009; ISBN 978-0-495-11464-2 ; Pp. 566-571
  5. ↑ Caroline Bowsher, Martin W. Steer, Alyson K. Tobin: Plant Biochemistry . Garland Pub, New York, NY 2008, ISBN 978-0-8153-4121-5 . P. 160
  6. ↑ Donald Voet, Judith G. Voet, Alfred Maelicke (ed.), Werner Müller-Esterl (ed.): Biochemie . Wiley-VCH 1992. ISBN 3-527-28242-4 ; P. 185
  7. ↑ Zhou, ZH. et al. (2001): The remarkable structural and functional organization of the eukaryotic pyruvate dehydrogenase complexes . In: Proc Natl Acad Sci USA 98 (26); 14802-14807; PMID 11752427 ; PDF (free full text access)
  8. ↑ Jeremy M. Berg, John L. Tymoczko, Lubert Stryer: Biochemistry . 6 edition. Spectrum Academic Publishing House, Heidelberg 2007; ISBN 978-3-8274-1800-5 ; P. 534
  9. ↑ a b Jeremy M. Berg, John L. Tymoczko, Lubert Stryer: Biochemie . 6 edition. Spectrum Academic Publishing House, Heidelberg 2007; ISBN 978-3-8274-1800-5 ; P. 536
  10. ↑ Sauberlich et al .: Thiamin requirement of the adult human. At J Clin Nutr. 1979 Nov; 32 (11): 2237-48. PMID 495541
  11. ^ Book page on thiamine consumption from "Nutritional Medicine", Thieme Verlag
  12. ↑ Tasevska N, Runswick SA, McTaggart A, Bingham SA: Twenty-four-hour urinary thiamine as a biomarker for the assessment of thiamine intake . In: Eur J Clin Nutr . 62, No. 9, September 2008, pp. 1139-47. doi : 10.1038 / sj.ejcn.1602829 . PMID 17565356 . . PMID 17565356 .
  13. ↑ Iber FL, Blass JP, Brin M, Leevy CM: Thiamin in the elderly - relation to alcoholism and to neurological degenerative disease . In: Am. J. Clin. Nutr. . 36, No. 5 Suppl, November 1982, pp. 1067-82. PMID 6765072 .
  14. ↑ Webster MJ, Scheett TP, Doyle MR, Branz M: The effect of a thiamin derivative on exercise performance . In: Eur J Appl Physiol Occup Physiol . 75, No. 6, 1997, pp. 520-4. PMID 9202948 .
  15. ↑ Caroline Bowsher, Martin W. Steer, Alyson K. Tobin: Plant Biochemistry . Garland Pub, New York, NY 2008, ISBN 978-0-8153-4121-5 . P. 162ff.
  16. ↑ Melanie Königshoff and Timo Brandenburger: Short textbook biochemistry. According to the new GK 1 . Thieme, Stuttgart 2004; ISBN 3-13-136411-4 ; P. 124
  17. ↑ Hans W. Heldt, Birgit Piechulla: Plant biochemistry . 4th edition. Spectrum Academic Publishing House, Heidelberg 2008; ISBN 978-3-8274-1961-3 ; P. 354

Web links

Wikibooks: Pyruvate Dehydrogenase Complex  - Learning and Teaching Materials
Wikibooks: Biochemistry and Pathobiochemistry: Citric Acid Cycle  - Learning and Teaching Materials