Krebs Cycle

The Krebs Cycle or the Citric Acid Cycle (TCA)

The citric acid cycle — also known as the tricarboxylic acid cycle (TCA cycle), the Krebs cycle, or the Szent-Györgyi-Krebs cycle^[1][2] — is a series of chemical reactions which is used by all aerobic living organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and proteins into carbon dioxide and water. In addition, the cycle provides precursors for the biosynthesis of compounds including certain amino acids as well as the reducing agent NADH that is used in numerous biochemical reactions. Its central importance to many biochemical pathways suggests that it was one of the earliest established components of cellular metabolism and may have originated abiogenically.^[3]
The name of this metabolic pathway is derived from citric acid which is first consumed and then regenerated by the pathway to complete the cycle. In addition, the cycle consumes acetate in the form of acetyl-CoA, reduces NAD⁺ to NADH, and produces carbon dioxide. The NADH generated by the TCA cycle is fed into the oxidative phosphorylation pathway. The net result of these two closely linked pathways is the oxidation of nutrients to produce energy in the form of ATP.
In eukaryotic cells, the citric acid cycle occurs in the matrix of the mitochondrion. Bacteria also use the TCA cycle to generate energy, but since they lack mitochondria, the reaction sequence is performed in the cytosol.
The components and reactions of the citric acid cycle were established in the 1930s by seminal work from the Nobel laureates Albert Szent-Györgyi^[4] and Hans Adolf Krebs.^[5]

The citric acid cycle is a key component of the metabolic pathway by which all aerobic organisms generate energy. Through catabolism of sugars, fats, and proteins, a two carbon organic product acetate in the form of acetyl-CoA is produced. Acetyl-CoA along with two equivalents of water (H₂O) are consumed by the citric acid cycle producing two equivalents of carbon dioxide (CO₂) and and one equivalent of HS-CoA. In addition, one cycle of the pathway converts three equivalents of nicotinamide adenine dinucleotide (NAD⁺) into three equivalent of reduced NAD⁺ (NADH), one equivalent of ubiquinone (Q) of into one equivalent of reduced ubiquinone (QH₂), and one equivalent each of guanosine diphosphate (GDP) and inorganic phosphate (P_i) into one equivalent of guanosine triphosphate (GTP). The NADH and QH₂ that is generated by the citric acid cycle is in turn used by oxidative phosphorylation pathway to generate energy rich adenosine triphosphate (ATP).

One of the primary sources of acetyl-CoA are sugars that are broken down by glycolysis to produce pyruvate that in turn is decarboxylated by the enzyme pyruvate dehydrogenase generating acetyl-CoA according to the following reaction scheme:

• CH₃C(=O)C(=O)O^– (pyruvate) + HSCoA + NAD⁺ → CH₃C(=O)SCoA (acetyl-CoA) + NADH + H⁺ + CO₂

The product of this reaction, acetyl-CoA, is the starting point for the citric acid cycle. Below is a schematic outline of the cycle:

• The citric acid cycle begins with the transfer of a two-carbon acetyl group from acetyl-CoA to the four-carbon acceptor compound (oxaloacetate) to form a six-carbon compound (citrate).
• The citrate then goes through a series of chemical transformations, losing two carboxyl groups as CO₂. The carbons lost as CO₂ originate from what was oxaloacetate, not directly from acetyl-CoA. The carbons donated by acetyl-CoA become part of the oxaloacetate carbon backbone after the first turn of the citric acid cycle. Loss of the acetyl-CoA-donated carbons as CO₂ requires several turns of the citric acid cycle. However, because of the role of the citric acid cycle in anabolism, they may not be lost, since many TCA cycle intermediates are also used as precursors for the biosynthesis of other molecules.^[8]
• Most of the energy made available by the oxidative steps of the cycle is transferred as energy-rich electrons to NAD⁺, forming NADH. For each acetyl group that enters the citric acid cycle, three molecules of NADH are produced.
• Electrons are also transferred to the electron acceptor Q, forming QH₂.
• At the end of each cycle, the four-carbon oxaloacetate has been regenerated, and the cycle continues.

Products

Products of the first turn of the cycle are: one GTP (or ATP), three NADH, one QH₂, two CO₂.

Because two acetyl-CoA molecules are produced from each glucose molecule, 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

 

Description	Reactants	Products
The sum of all reactions in the citric acid cycle is:	Acetyl-CoA + 3 NAD+ + Q + GDP + Pi + 2 H2O	→ CoA-SH + 3 NADH + 3 H+ + QH2 + GTP + 2 CO2
Combining the reactions occurring during the pyruvate oxidation with those occurring during the citric acid cycle, the following overall pyruvate oxidation reaction is obtained:	Pyruvate ion + 4 NAD+ + Q + GDP + Pi + 2 H2O	→ 4 NADH + 4 H+ + QH2 + GTP + 3 CO2
Combining the above reaction with the ones occurring in the course of glycolysis, the following overall glucose oxidation reaction (excluding reactions in the respiratory chain) is obtained:	Glucose + 10 NAD+ + 2 Q + 2 ADP + 2 GDP + 4 Pi + 2 H2O	→ 10 NADH + 10 H+ + 2 QH2 + 2 ATP + 2 GTP + 6 CO2

 

The above reactions are balanced if P_i represents the H₂PO₄^- ion, ADP and GDP the ADP^2- and GDP^2- ions, respectively, and ATP and GTP the ATP^3- and GTP^3- ions, respectively.

The total number of ATP obtained after complete oxidation of one glucose in glycolysis, citric acid cycle, and oxidative phosphorylation is estimated to be between 30 and 38. A recent assessment of the total ATP yield with the updated proton-to-ATP ratios provides an estimate of 29.85 ATP per glucose molecule.