Krebs Cycle (Tricarboxylic Acid Cycle)

 

The pyruvic acid that results from glycolysis is subjected to activation during which an acetyl-CoA molecule is formed which goes into the Krebs cycle (tricarboxylic acid cycle). These transformations, as well as the cycle itself occur in the mitochondrial matrix.

The Krebs cycle is a succession of oxidative decarboxylation reactions, of dehydrogenation reactions, water fixation or elimination reactions which result in the formation of a series of intermediary products: citric acid → isocitric acid → ketoglutaric acid → succinic acid → fumaric acid → malic acid → oxaloacetic acid (the latter is converted into citric acid when pyruvate is provided and the cycle restarts).

In the mitochondrial matrix different transformations occur that can be grouped in 5 important phases (Fig. 5.7):

1. Oxidative decarboxylation of the pyruvic acid, along with substrate dehydrogenation in the presence of the dehydrogenase, which transports the electrons and protons to O2 resulting in water formation. Through acetylation acetyl coenzyme A is formed (an important metabolic and energetic compound, which includes a macroergic bond of 11 kcal) with the participation of thiamine pyrophosphate which serves as a coenzyme for pyruvate dehydrogenase.

Coenzyme A is a derivative of adenine, which consists of pantothenic acid, thio-ethanolamine amino acid and three phosphoric acid residues. The high energetic activity of acetyl coenzyme A is determined by the sulfhydryl group SH from the thio-ethanolamine, which is linked to the molecule through a macroergic bond.

Fig. 5.7 Krebs cycle and its importance

 

2. Coupling of acetyl coenzyme A with oxaloacetic acid in the presence of a synthetase, and formation of the citric acid (with coenzyme A release).

1. Isocitric acid formation occurs through water loss when citric acid is converted to cis-aconitic acid, and isocitric acid is formed as a result of aconitase action.

2. Formation of di- and tricarboxylic acids occurs via dehydration, decarboxylation and water fixation reactions, having the α-ketoglutaric, succinic, fumaric, abd malic acids as intermediary forms, with intercalation of a molecule of succinyl coenzyme A before the formation of the succinic acid.

3. Reinitiation of the pyruvic acid cycle. By malic acid dehydrogenation, under the action of malate dehydrogenase enzyme and of the energetic group NAD+, oxaloacetic acid is formed, which, through decarboxylation, is converted into pyruvic acid or is coupled with acetyl coenzyme A, producing the citric acid, reactions which reenter the Krebs cycle.

Importance of the Krebs cycle

•  It is the universal pathway of substrate degradation.
• Pairs of electrons are gradually released and stored in intermediates like NAD and FAD to be latter used in the ETC for ATP synthesis.
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• Plants are supplied with energy and metabolites, hence its role not only in catabolism but also in anabolism (keto acids are used in the synthesis of amino acids and other valuable organic substances, acetyl coenzyme A participates in the process of fatty acid synthesis).

This reaction cycle is the universal pathway of respiratory substrate degradation for carbohydrates as well as for other organic substances and represents the main link in cellular metabolism. Most of the intermediary products are used in other metabolic cycles .

During respiratory substrate oxidation a step wise release of metabolic energy occurs. During each cycle one molecule of GTP (equivalent to 1 ATP) and 4 molecules of reduced coenzyme are generated, which, when transported to the ETC, are subjected to oxidative phosphorylation.