pyruvate dehydrogenase reaction

The pyruvate dehydrogenase reaction brings about conversion of pyruvate into acetyl-CoA . The reaction is catalyzed by an enzyme-complex incorporating the allosteric enzyme pyruvate dehydrogenase (PDC).

PDC constitution
The components of PDC are species dependent. The E.coli complex comprises 60 subunits: 24 of pyruvate dehydrogenase, 24 of dihydrolipoyl transacetylase, and 12 of dihydrolipoyl dehydrogenase (often denoted E1, E2, and E3).

E1: 24 molecules of pyruvate dehydrogenase incorporates the coenzyme TPP (thiamin pyrophosphate).
E2: 24 dihydrolipoyl transacetylase incorporates lipoate and coenzyme A.
E3: 12 dihydrolipoyl dehydrogenase incorporates the coenzymes FAD and NAD+.

In contrast to E.coli, eukaryotes and gram-positive bacteria such as Bacillus stearothermophilus have a central PDC core that contains 60 E2 molecules arranged into an icosahedron. Eukaryotes also contain 12 copies of an additional core protein, E3 binding protein (E3BP). (more detail)

The PDC comples utilizes 5 different cofactors, of which multiple copies may be required:
1. TPP (Thiamine pyrophosphate) - Hydroxyethyl Carrier
2. CoA (Coenzyme A) - Substituted onto the Acetyl group to form Acetyl-CoA
3. R-Lipoic acid - Utilized as a Lysine Tether to transport Acetyl group to acitve site for CoA addition
4. FAD (Flavin Adenine Dinucleotide) - Oxidizing agent to oxidize the lipoyllysine sulfaring to repeat process.
5. 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.

Reaction of PDC
Pyruvate is decarboxylated in a complex reaction and converted into acetaldehyde, then attached to coenzyme A while NAD+ is subsequently reduced to NADH and H+:

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

Regulation of PDC
Pyruvate dehydrogenase is inhibited by increase in any of the ratios : ATP/ADP, NADH/NAD+ and acetyl-CoA/CoASH.

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


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