Tca Cycle

Tricarboxylic Acid Cycle Dr Imran Siddiqui (MBBS, MPhil) College of Medicine King Saud Bin Abdulaziz University for Health Sciences

Fate of Pyruvate Glucose glycolysis Anaerobic

2 Pyruvate 2CO2

2 Ethanol + 2 CO2 (in yeast)

Anaerobic

aerobic

2 Lactate 2 Acetyl CoA

(in contracting muscle, RBCs)

citric acid cycle

4 CO2 + 4 H2O (animal, plant, and microorganisms under aerobic conditions)

Anaerobic Aerobic

Citric Acid Cycle and Oxidative Phosphorylation Glycolysis gives only a fraction of the ATP available from glucose. Complete oxidation to CO2 takes place in the citric acid cycle. In oxidative phosphorylation, electrons removed in oxidation, reduce O2 and synthesize large amounts of ATP.

Formation of acetyl CoA Under aerobic conditions, pyruvate is not reduced to lactate, but decarboxylated to acetate, which links to Coenzyme A.

• Catalyzed by pyruvate dehydrogenase (PDH) multienzyme complex consisting of 3 catalytic subunits and several cofactors. • PDH is directly inhibited by NADH, acetyl CoA, and ATP. • PDH exists in phosphorylated (inactive) and dephosphorylated (active) states. Insulin stimulates dephosphorylation. •Deficiency of PDH causes Congenital Lactic Acidosis resulting psychomotor retardation to death Protein kinase PDH PDH-PO4 (active) Phosphatase (inactive)

Insulin +

Regulation of Pyruvate Dehydrogenase

Overview of citric acid cycle (TCA or Krebs cycle) Oxidation of two-carbon units, producing 2 CO2, 1 GTP, and high-energy electrons in the form of NADH and FADH2.

citrate

Mitochondrial matrix

Pyruvate dehydrogenase Aconitase

Citrate synthase Pyruvate

Citrate

NAD

H2O

NADH CO2

cis-Aconitate

Oxaloacetate

Malate dehydrogenase

H2O

NADH NAD

Isocitrate

Citric acid cycle

Malate

Aconitase

Isocitrate dehydrogenase

For reference only

Fumarase H2O

NAD Fumarate

NADH

FADH2

NADH

FAD

Succinate dehydrogenase

CO2

GTP

Succinyl-CoA synthetase

CO2 Isocitrate dehydrogenase

NAD

GDP α -Ketoglutarate

Succinate

α -Ketoglutarate dehydrogenase Succinyl-CoA

Oxalosuccinate

Overview of control points for the citric acid cycle

Energy-generating capacity of glycolysis and the citric acid cycle A total of ~38 ATP molecules are formed from 1 glucose under aerobic conditions Every NADH that is produced needs to be re-oxidized to NAD+ Glycolysis This re-oxidation occurs by transferring the electrons from NADH and FADH2 into the electron transport chain Electron transport chain results in the electrons going into O2 to produce H2O and oxidative phosphorylation uses the energy accumulated by the electron transport chain to drive ATP synthesis For every 1 NADH ~ 3 ATP are made For every 1 FADH2 ~ 2 ATP are made

Citric Acid Cycle

Animation • No. 1 • No. 2