Alpha-ketoglutarate dehydrogenase

Also known as alpha oxoglutarate dehydrogenase.

Alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase are both similar in terms that they both catalyze an oxidative decarboxylation reaction.

Enzyme Structure

Just like pyruvate dehydrogenase, it is a multi-sub-unit complex made of a large number of multiple copies of the same three sub-units, which are all made up of 2 E1 alpha sub-units and 2 E1 beta subunits:

• α-ketoacid decarboxylase (E1): This subunit is TPP-dependent hence it adds TPP to an α-ketoglutarate by removing CO2 to form succinyl TPP.

• dihydrolipoyl transacetylase(E2): Converts lipoate to succinyl lipoate by removing the succinyl group off of succinyl TPP and giving it the lipoate

• dihydrolipoamide dehydrogenase (E3): Helps in converting dihydrolipoate to lipoate by removing two H+ ions and giving it to FAD+ to be reduced to FADH.

Reaction Catalysed

Their function is to help the reaction of converting α-ketoglutarate to succinyl CoA by catalyzing the removal of CO2 from the α-ketoglutarate and the addition of H+ on the NAD+ molecule after removing it from the acyl CoA.

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

Cofactors and Coenzymes employed

Since α-ketoglutarate dehydrogenase and pyruvate dehydrogenase has the same sub-unit structure, they both have five cofactors:

1. Thiamine Pyrophosphate (TPP): After α-ketoglutarate has its carbon dioxide removed (non-oxidative decarboxylation), TPP is added to it to form succinyl TPP.
2. Lipoate (the conjugate base of lipoic acid, which is the non-functional form of lipoamide): Accepts the succinyl residues that will be transferred to CoA by succinyl lipoate later. This is done by dihydrolipoyl transacetylase, which removes the succinyl group from the TPP and places it on the lipoate to form succinyl lipoate.
3. Flavin Adenine Dinucleotide (FAD): Takes the hydrogen from the reduced form of lipoate which is dihydrolipoate (converting it to lipoate) and oxidises it via dihydrolipoyl amide dehydrogenase to form FADH2
4. Coenzyme A (CoA): Takes the succinyl residues from succinyl lipoate to join with itself to make succinyl-CoA while adding hydrogen to succinyl-lipoate to the reduced form of lipoate, which is dihydrolipoate.
5. 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

It can be regulated through the inhibition of

[ATP]/[ADP], [succinyl-CoA]/[CoASH], and [NADH]/[NAD+], and stimulated by Ca2+.