Citric acid cycle

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.

History
The citric acid cycle is also known as the Krebs cycle after Sir Hans Adolf Krebs (1900-1981), who proposed the key elements of this pathway in 1937 and was awarded the Nobel Prize in Medicine for its discovery in 1953. It is correctly written without a possessive apostrophe.

Location of cycle and inputs and outputs
The citric acid cycle takes place within the mitochondrial matrix in eukaryotes, and within the cytoplasm in prokaryotes.



Fuel molecule catabolism (including glycolysis) produces acetyl-CoA, a two-carbon acetyl group bound to coenzyme A. Acetyl-CoA is the main input to the citric acid cycle. Citrate is both the first and the last product of the cycle (Fig 1), and is regenerated by the condensation of oxaloacetate and acetyl-CoA.

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


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

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 process begins with the oxidation of pyruvate, producing one CO2, and one acetyl-CoA.
 * Acetyl-CoA reacts with the four carbon carboxylic acid, oxaloacetate--to form the six carbon carboxylic acid, citrate.
 * Through a series of reactions citrate is converted back to oxaloacetate. This cycle produces 2 CO2 and consumes 3 NAD+, producing 3NADH and 3H+.
 * It consumes 3 H2O and consumes one FAD, producing one FADH+.
 * 1st turn end= 1 ATP, 3 NADH, 1 FADH2
 * Since there are two molecules of Pyruvic acid to deal with, the cycle turns once more.
 * The complete end result= 2 ATP, 6 NADH, 2 FADH2

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 synthesises 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 amount 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.

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.