krebs cycle mitochondria citric acid cycle

The Krebs cycle, also known as the citric acid cycle is a set of chemical reactions which release stored energy through oxidation of acetyl-CoA. Precursors of certain amino acids, and the reducing agent NADH are also produced. The pathway name comes from a tricarboxylic acid, often called citrate.  Acetyl-CoA and water, reduces NAD+ to NADH, releasing CO2. The NADH is then fed into the oxidative phosphorylation pathway. The conclusion is the oxidation of nutrients to produce chemical energy, as ATP.



What is the Krebs cycle?

In the 1930s Szent-Györgyi, received the Nobel Prize in Physiology for his discovery of fumaric acid. The citric acid cycle was actually demonstrated in 1937 by Hans Adolf Krebs and William Arthur Johnson. The citric acid cycle starts with the transfer of a 2C acetyl group from acetyl-CoA to the 4C acceptor compound oxaloacetate to form citrate, a compound consisting of 6 carbons.

The citrate loses two carboxyl groups as CO2. The carbons lost as CO2 originate from oxaloacetate. The carbons become part of the oxaloacetate carbon structure. Electrons made by the oxidative steps are transferred to NAD+, producing NADH. For each acetyl group that enters the citric acid cycle, three molecules of NADH are output. 

Electrons from the succinate oxidation step are transferred first to the FAD, of succinate dehydrogenase, reducing it to FADH2. This ultimately reduces to ubiquinone (Q) in the mitochondrial membrane as ubiquinol (QH2). For every NADH and FADH2 created, 2.5 and 1.5 ATP molecules are generated in oxidative phosphorylation. At the close, the 4C oxaloacetate has been recreated, and the cycle progresses.


Citric acid cycle (Krebs cycle) steps


1 Citrate Synthase

The enzyme citrate synthase starts the cycle. The pyruvate dehydrogenase joins an acetyl group to coenzyme A. Citrate synthase removes the acetyl group, adding it to oxaloacetate, forming citric acid. The reaction is known as the aldol condensation, which is irreversible.

2 Aconitase

The second step transfers an oxygen atom to build the isocitrate molecule. This hydration/dehydration step is achieved by the Aconitase enzyme. This is an isomerisation reaction.

3 Isocitrate Dehydrogenase

Isocitrate dehydrogenase then removes one of the carbon atoms, forming carbon dioxide, transferring electrons to NADH. This is oxidation. Decarboxylation generates the 5C molecule.

4 α-Ketoglutarate dehydrogenase, Thiamine pyrophosphate,

Lipoic acid, Mg++,transsuccinytase

The oxidative decarboxylation is an irreversible stage which creates NADH and regenerates the 4C chain molecule.



5 Succinyl-CoA Synthetase

The bond between succinate and coenzyme A is unstable, releasing the energy needed to create a molecule of ATP. A substrate level phosphorylation reaction.

6 Succinate dehydrogenase


The sixth step involves a protein complex and it integrates directly to the electron transport chain. The enzyme removes hydrogen atoms from succinate, transferring them to the carrier FAD. With the help of several iron-sulfur clusters and a heme, these are then transferred to the mobile carrier ubiquinone. The two electrons transferred to QH2 during Complex II of the ETC, where they generate the equivalent of 1.5 ATP.

7 Fumarase

Fumarase is the enzyme in part seven, which adds a water to the molecule in preparation for the last stage. There is a hydration of the C-C double bond.


8 Malate Dehydrogenase


Finally, oxaloacetate is recreated, transferring electrons to NADH in the process. Malate dehydrogenase is found in both the mitochondrion and the cytoplasm. Instead, the two forms of malate dehydrogenase form part of a shuttle. In the cytoplasm, NADH is used up to convert oxaloacetate to malate. Malate is then transported into the mitochondrion and is used to recreate NADH by conversion of malate to oxaloacetate.



Krebs cycle products and efficiency

Products of the cycle are one GTP (or ATP), three NADH, one QH2 and two CO2. Two cycles are required per glucose molecule. Therefore, at the end of two cycles, the products are: two GTP, six NADH, two QH2, and four CO2. In total, between 30 and 38 ATP molecules obtained after complete oxidation of one glucose in glycolysis, citric acid cycle, and oxidative phosphorylation.


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