Pyruvate dehydrogenase

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Pyruvate dehydrogenase (EC 1.2.1.51) is an allosteric enzyme that transforms pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration. Pyruvate decarboxylation is also known as the "pyruvate dehydrogenase reaction" because it is catalyzed by this enzyme.

1 Structure & function
- 1.1 Cofactors
- 1.2 Regulation
2 Related links

[edit] Structure & function

Pyruvate dehydrogenase complex (PDC) is a large complex composed of multiple copies of 3 or 4 subunits depending on species: in Gram-negative bacteria, e.g. Escherichia coli, PDC consists of a central octahedral core made up from 24 molecules of dihydrolipoyl transacetylase (E2). Up to 24 copies of pyruvate decarboxylase (E1) and 12 molecules of dihydrolipoyl dehydrogenase (E3) bind to the outside of the E2 core. In contrast, in Gram-positive bacteria (e.g. Bacillus stearothermophilus) and eukaryotes the central PDC core contains 60 E2 molecules arranged into an icosahedron. Eukaryotes also contain 12 copies of an additional core protein, E3 binding protein (E3BP). 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. 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 E2 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.

E1 catalyses the rate-limiting reaction within PDC. It requires thiamine pyrophosphate (TPP) as a cofactor and catalyses the decarboxylation of pyruvate. The TPP remains bound to the acetate through a thioester bond. This bond brings the acetate in proximity to an oxidized lipoyllysine, to which it becomes esterified. The acetate is trans-esterified from the sulfide of the lipoyl 'swinging arm' to coenzyme A (CoA), where it forms acetyl-CoA. The reduced lipoyllysine becomes reoxidized, by concomitant reduction of flavin adenine dinucleotide (FAD) present in E3. FADH then reduces nicotinamide adenine dinucleotide (NAD), returning the pyruvate dehydrogenase complex to is original redox state. The acetyl-CoA is free to enter the TCA cycle.

The multi-enzyme complex is related (structurally and functionally) to the similar oxoglutarate dehydrogenase and branched-chain oxo-acid dehydrogenase multi-enzyme complexes.

The global reaction catalysed by pyruvate dehydrogenase is:

Pyruvate + Coenzyme A + NAD⁺ ⇒ acetyl-CoA + NADH + H⁺ + CO₂

[edit] Cofactors

5 different cofactors are required for this complex:

TPP (Thiamine pyrophosphate) - Hydroxyethyl Carrier
CoA (Coenzyme A) - Substituted onto the Acetyl group to form Acetyl-CoA
R-Lipoic acid - Utilized as a Lysine Tether to transport Acetyl group to acitve site for CoA addition
FAD (Flavin Adenine Dinucleotide) - Oxidizing agent to oxidize the lipoyllysine sulfaring to repeat process.
NAD (Nicotinamide adenine dinucleotide)- Oxidizes FADH₂ in order to repeat process. NADH is then used for oxidative phosphorylation or may be used somewhere else in the cytosol.

Multiple copies of each different cofactor may be necessary for proper function of this complex.

[edit] Regulation

Pyruvate dehydrogenase is inhibited when either of the three following ratios are increased: ATP/ADP, NADH/NAD⁺ and acetyl-CoA/CoASH.

In eukaryotes PDC is tightly regulated by its own specific PDC kinase (PDK) and phosphatase (PDP). PDK phosphorylates three specific lysine residues on E1 with different affinities. Phosphorylation of any one of them renders E1 (and in consequence the entire complex) inactive. Dephosphorylation of E1 by PDP reinstates complex activity.