PDC-pyruvate dehydrogenase complex

how it works

the PDC is composed of…

3 enzyme subunits and 5 different cofactors

it covnertws pyruvate to acetyl CoA

occurs in the mitochondrial matrix

the co factors and their roles

1. Thiamine Pyrophosphate (TPP)— bound to E1, derived from Vitamin B1, forms a reactive carbanion easily, carries aldehydes, promotes decarboxylation

2. Lipoamide—bound to E2, lipoic acid can be attached to a Lys on E2 forming lipoamide, lipoamide oxidizes aldehydes to acyl groups resulting in the acyl group being bound to the disulfide group, acts a “robotic arm”

3. NAD⁺— free floating

4. FAD⁺—bound to E3

5. CoASH—free floating, composed of ADP and pantothenate (vitamin B5) and beta-mercaptor ethylamine, carrier of acyl groups, forms high energy thioester bonds

Mechanism of the PDC

1. Pyruvate enters E1, binds to TPP and is decarboxylated (forming Co₂) to form the intermediate hydroxyethyl-TPP

2. Lipoamide arm (oxidized) enters E1

3. The hydroxyethyl group is oxidized to a acetyl group and is bound to the now reduced lipoamide arm (which we now call a dihydrolipoyl group)

4. The reduced arm carrying the acetyl unit moves into E2 and the acetyl group is transferred to CoA forming acetyl CoA. Acetyl CoA leaves the enzyme

5. The reduced dihydrolipoyl lipoamide arm moves into E3 where it is oxidized by FAD. FAD is reduced to FADH₂

6. NAD⁺ enters E3 and reoxidizes FADH₂ back to FAD. NAD⁺ is reduced to NADH, which leaves E3. Now back at step 1

Regulation of the PDC

• Increase of [acetyl CoA] allostreically inhibit E2

• Increase of [NADH] allosterically inhibit E3

• But the main control is on E1, where phosphorylation of a serine by a kinase leads to the inhibition of E1 and thus the entire complex. 

• This kinase is called the PDC associated kinase (always hanging around the PDC)

• Acetyl CoA, NADH, and ATP all stimulate the kinase, causing the PDC to slow

• Pyruvate, NAD⁺ and ADP all inhibit the kinase resulting in the PDC gradually becoming active again

• General phosphatases will gradually (ie. slowly) dephosphorylate E1, resulting in it becoming more active again. 

• Cell signalling such as an increase in [Ca²⁺] and insulin activates the PDC associated phosphatase (PDCAP) which rapidly dephosphorylates E1, leading to a rapid increase in activity.

overall reaction of the PDC

Pyruvate + NAD⁺ + CoASH —> Acetyl CoA + CO₂ + NADH + H⁺

involves a decarboxylation/oxidation of pyruvate to acetate in the form of a thioester, followed by the formation of acetyl coA

the 3 enzymes of the PDC

E1=pyruvate dehydrogenase

E2=dihydrolipoyl transacetylase

E3=dihydrolipoyl dehydrogenase

Co Enzyme A aka coA, CoASH structure

TPP structure

Lipoamide and Lipoic Acid