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The citric acid cycle (also known as the tricarboxylic acid cycle, the TCA cycle, or the Krebs cycle) is a series of chemical reactions of central importance in all living cells that utilize oxygen as part of cellular respiration. In aerobic organisms, the citric acid cycle is part of a metabolic pathway involved in the chemical conversion of carbohydrates, fats and proteins into carbon dioxide and water to generate a form of usable energy. It is the second of three metabolic pathways that are involved in fuel molecule catabolism and ATP production, the other two being glycolysis and oxidative phosphorylation.

The citric acid cycle also provides precursors for many compounds such as certain amino acids, and some of its reactions are therefore important even in cells performing fermentation.

Overview

The sum of all reactions in the citric acid cycle is:

Acetyl-CoA + 3 NAD + FAD + GDP + P_i + 2 H₂O + 1 CoA-SH → 2 CoA-SH + 3 NADH + 3 H + FADH₂ + GTP + 2 CO₂ + 1 H₂O

Two carbons are oxidized to CO₂, and the energy from these reactions is stored in GTP , NADH and FADH₂. NADH and FADH₂ are coenzymes (molecules that enable or enhance enzymes) that store energy and are utilized in oxidative phosphorylation.

A simplified view of the process:

• The citric acid cycle begins with the oxidation of pyruvate produced during glycolysis.
• Acetyl-CoA transfers its two-carbon acetyl group to the four-carbon acceptor compound, oxaloacetate, forming citrate, a six-carbon compound.
• The citrate then goes through a series of chemical transformations, losing first one, then a second carboxyl group as CO₂.
• 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 FAD, forming FADH₂.
• At the end of each cycle, the four-carbon oxaloacetate has been regenerated, and the cycle continues. Products of the first turn of the cycle are one ATP, thee NADH, one FADH₂, and two CO₂.
• Because two acetyl-CoA molecules are produced from each glucose molecule, two cycles are required per glucose molecule.
• At the end of all cycles, the products are two ATP, six NADH, two FADH₂, four CO₂.

Regulation

Many of the enzymes in the TCA cycle are regulated by negative feedback from ATP when the energy charge of the cell is high. Such enzymes include the pyruvate dehydrogenase complex that synthesizes the acetyl-CoA needed for the first reaction of the TCA cycle. Also the enzymes citrate synthase, isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase, that regulate the first three steps of the TCA cycle, are inhibited by high concentrations of ATP. This regulation ensures that the TCA cycle will not oxidise excessive amounts of pyruvate and acetyl-CoA when ATP in the cell is plentiful. This type of negative regulation by ATP is by an allosteric mechanism.

Several enzymes are also negatively regulated when the level of reducing equivalents in a cell are high (high ratio of NADH/NAD+). This mechanism for regulation is due to substrate inhibition by NADH of the enzymes that use NAD+ as a substrate. This includes both the entry point enzymes pyruvate dehydrogenase and citrate synthase.

Calcium is used as a regulator. It activates pyruvate dehydrogenase, isocitrate dehydrogenase and oxoglutarate dehydrogenase. This increases the reaction rate of many of the steps in the cycle, and therefore increases flux throughout the pathway

Citrate is used for feedback inhibition, as it inhibits the enzyme that makes it. This prevents a constant high rate of flux when there is a build up of citrate and a decrease in substrate for the enzyme.

Major metabolic pathways converging on the TCA cycle

Most of the body's catabolic pathways converge on the TCA cycle, as the diagram shows. Reactions that form intermediates of the cycle are called anaplerotic reactions.

The citric acid cycle is the second step in carbohydrate catabolism (the breakdown of sugars). Glycolysis breaks glucose (a six-carbon-molecule) down into pyruvate (a three-carbon molecule). In eukaryotes, pyruvate moves into the mitochondria. It is converted into acetyl-CoA and enters the citric acid cycle.

In protein catabolism, proteins are broken down by protease enzymes into their constituent amino acids. These amino acids are brought into the cells and can be a source of energy by being funnelled into the citric acid cycle.

In fat catabolism, triglycerides are hydrolyzed to break them into fatty acids and glycerol. In the liver the glycerol can be converted into glucose via dihydroxyacetone phosphate and glyceraldehyde-3-phosphate by way of gluconeogenesis. In many tissues, especially heart tissue, fatty acids are broken down through a process known as beta oxidation which results in acetyl-CoA which can be used in the citric acid cycle. Sometimes beta oxidation can yield propionyl CoA which can result in further glucose production by gluconeogenesis in liver.

The citric acid cycle is always followed by oxidative phosphorylation. This process extracts the energy from NADH and FADH₂, recreating NAD and FAD, so that the cycle can continue. The citric acid cycle itself does not use oxygen, but oxidative phosphorylation does.

The total energy gained from the complete breakdown of one molecule of glucose by glycolysis, the citric acid cycle and oxidative phosphorylation equals about 36 ATP molecules. The citric acid cycle is called an amphibolic pathway because it participates in both catabolism and anabolism.

See also

• Oxidative decarboxylation
• Citric acid
• Glycolysis
• Oxidative phosphorylation
• Reverse (Reductive) Krebs cycle
• Hans Adolf Krebs

v t e Citric acid cycle metabolic pathway
Acetyl-CoA + H2O Oxaloacetate NADH +H NAD Malate   H2O Fumarate FADH2 FAD Succinate CoA + ATP (GTP) Pi + ADP (GDP) Succinyl-CoA NADH + H + CO2 CoA NAD Citrate   H2O cis-Aconitate H2O   Isocitrate NAD(P) NAD(P)H +  H Oxalosuccinate   CO2 2-oxoglutarate

Reference(s)

• Campbell, Reece: Biology (seventh edition). Benjamin Cummings, 2005.
• Solomon, E.P., Berg, L.R., Martin, D.W., Biology, 7th Edition, Thompson Learning, 2005.

External links

• An animation of the citric acid cycle
• A more detailed tutorial animation
• A citric-acid cycle self quiz flash applet
• The chemical logic behind the citric acid cycle

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• Biochemistry
• Cellular respiration
• Exercise physiology
• Metabolism