Pyruvate Oxidation

Goal

in the presence of O₂ pyruvate —> acetyl CoA to generate important precursors for citric acid cycle

3 enzymes to synthesize acetyl-CoA

1. pyruvate dehydrogenase (E1)

2. dihydrolipoyl transacetylase (E2)

3. dihydrolipoyl dehydrogenase (E3)

Pyruvate dehydrogenase (E1)

prosthetic group = TPP

oxidative decarboxylation of pyruvate

Dihydrolipoyl transacetylase (E2)

prosthetic group = lipoamide

transfer of acetyl group to CoA

Dihydrolipoyl dehydrogenase (E3) 

prosthetic group = FAD

regeneration of the oxidized form of lipoamide 

Step 1: Decarboxylation

TPP + pyruvate + 2H+ —> hydroxyethyl-TPP + CO2

Step 1 enzyme

pyruvate dehydrogenase (E1)

Step 3: Oxidation 

hydroxyethyl-TPP + lipoamide —> carbanion TPP + acetyl lipoamide 

Acetyl lipoamide 

formation of energy-rich thioester bond 

Step 2 enzyme

pyruvate dehydrogenase (E1)

Step 3: Formation of Acetyl CoA

A) CoA + acetyl lipoamide —> acetyl CoA + dihydrolipoamide

B) dihydrolipoamide + FAD —> lipoamide + FADH2 + NAD+ —> FAD + NADH

Step 3 enzymes

A) dihydrolipoyl transacetylase (E2) 

B) dihydrolipoamide dehydrogenase (E3) 

Acetyl CoA

after pyruvate oxidation, it can go to 2 places…

1. metabolism via citric acid cycle

2. incorporation into fatty acids

E1/E2/E3 complex regulation

allosteric inhibition by acetyl CoA and NADH

high acetyl CoA - inhibits E2

high NADH - inhibits E3

high ATP - inhibits complex 

high ADP + pyruvate - stimulates complex 

Pyruvate dehydrogenase regulation 

kinase - phosphorylates and inactivates E1

phosphatase - removes phosphate and activates E1

Kinase regulation

high levels of ATP and NADH stimulate the kinase

Phosphatase regulation 

Ca²⁺ stimulates phosphatase