Pyruvate Dehydrogenase

Pyruvate Dehydrogenase is the linker between

the glycolytic pathway which provides the pyruvate and the tricarboxylic acid cycle which uses acetyl CoA

Enzyme Structure

It comprises two E1 alpha subunits and two E1 beta subunits forming the E1 enzyme.

The E1 beta subunit is made by the protein-coding gene, PDHB (Pyruvate Dehydrogenase) which forms sheets.

Beta sheets are beta strands connected side by side via three backbone hydrogen bonds.

Alpha helices are secondary portion structures made of an amino acid chain wound up and arranged in a spiral to form a right-hand helix and held in shape

Reaction Catalysed

Their function is to help the reaction of converting pyruvate into acetyl-CoA by catalyzing it removing the H+ of the acyl CoA and adding it to the NAD+.

This method is also an oxidative decarboxylation method because it replaces the CO2 from the pyruvate molecule with acyl CoA.

Cofactors and Coenzymes employed

Pyruvate dehydrogenase has five cofactors

Thiamine Pyrophosphate (TPP): After pyruvate has its carbon dioxide removed (non-oxidative decarboxylation), TPP and a hydrogen ion are added to it to form hydroxyethyl-TPP
Lipoamide: Accepts the acetyl residues that will be transferred to acetyl-CoA later. This is done by dihydrolipoyl transacetylase, an E2 enzyme apart of the large Pyruvate dehydrogenase complex, which oxidizes lipoamide to acetyl-dihydrolipoamide.
Flavin Adenine Dinucleotide (FAD): Takes the hydrogen from the reduced form of lipoamide, oxidizing it via dihydrolipoyl dehydrogenase to form FADH2
Coenzyme A (CoA): Takes the acetyl residues from acetyl-dihydrolipoamide to join with itself to make acetyl-CoA while reducing (by adding hydrogen) acetyl-dihydrolipoamide to the reduced form of lipoamide.
Nicotinamide Adenine Dinucleotide (NAD): Oxidizes FADH2 using its oxidized form (NAD+) to form NADH which is used in the electron transport chain to make 2.5 ATP

Metabolic Regulation

Pyruvate dehydrogenase is used to regulate the metabolic process between glucose and fatty acid oxidation.

It itself is regulated in three ways:

Type of regulation	Substance	Inhibitors	Activators
Substrate level	NAD+/NADH	High levels of NADH inhibit it by preventing the lipoamide from returning to its active oxidized state since NAD+ is needed to remove the H+ from FADH2	High levels of NAD+ activate the enzyme as the process would occur at a much greater rate as there would be more NAD+ to remove the H+ ions from the FADH2
Allosteric	ATP/ ADP, AMP	High levels of ATP, cause a decrease in glycolysis activity hence inhibiting pyruvate dehydrogenase	High levels of ADP and AMP stimulate glycolysis which needs pyruvate dehydrogenase to be activated in order to continue
Covalent Modification	PDH kinase/ PDH Phospohtase	Pyruvate dehydrogenase kinase inhibits pyruvate dehydrogenase by adding a phosphate (phosphorylation) to the PDH from an ATP (→ ADP)	Pyruvate dehydrogenase phosphatase activates pyruvate dehydrogenase by removing phosphate from the PDH to an ADP (→ ATP)