Citric acid cycle

From New World Encyclopedia

The citric acid cycle (also known as the tricarboxylic acid cycle, the TCA cycle, and the Krebs cycle is a series of chemical reactions of central importance in all living cells that utilize oxygen to generate useful energy by cellular respiration. This cycle the "power plant" that energizes all metabolism and thus life. The enzymes that run this cycle were established very early in God's plan of creation. This set of enzymes is essentially the same in all bacteria, fungi, plants and animals that 'burn' their food using oxygen.

In essence, the cycle run by these enzymes very simple. Food is first broken down to a small, but high-energy carbohydrate fragment that is combined with the first molecule in the cycle. This fragment is chipped off atom by atom until the first molecule results. The first molecule then picks up another fragment to burn and the cycle continues, thousands of times a second. The chemical and reducing potential of each atom being chipped off is captured along the way to drive the rest of metabolism. One turn of the cycle turns the high-energy fragment into carbon dioxide and water, just as if it had burnt in a flame.

In oxygen using aerobic organisms, the citric acid cycle is the final step in the breakdown of carbohydrates, fats and proteins into carbon dioxide and water in order to generate energy. Lacking oxygen, cells can survive, usually for a short time, using two other metabolic pathways called glycolysis and oxidative phosphorylation. These are very inefficient compared to the cycle. 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 such fermentation reactions in the absence of oxygen.

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.

The reactions of TCAC as they happen in a human cell.
The color scheme is as follows: enzymes, coenzymes, substrate names, metal ions, inorganic molecules, inhibition, stimulation .
* - FAD/FADH2 is covalently attached to SDH

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.

Molecule Enzyme Reaction type Reactants/
Coenzymes
Products/
Coenzymes
I. Citrate 1. Aconitase Dehydration H2O
II. cis-Aconitate 2. Aconitase Hydration H2O
III. Isocitrate 3. Isocitrate dehydrogenase Oxidation NAD+ NADH + H+
IV. Oxalosuccinate 4. Isocitrate dehydrogenase Decarboxylation
V. α-Ketoglutarate 5. α-Ketoglutarate
dehydrogenase
Oxidative
decarboxylation
NAD+ +
CoA-SH
NADH + H+
+ CO2
VI. Succinyl-CoA 6. Succinyl-CoA synthetase Hydrolysis GDP
+ Pi
GTP +
CoA-SH
VII. Succinate 7. Succinate dehydrogenase Oxidation FAD FADH2
VIII. Fumarate 8. Fumarase Addition (H2O) H2O
IX. L-Malate 9. Malate dehydrogenase Oxidation NAD+ NADH + H+
X. Oxaloacetate 10. Citrate synthase Condensation
XI. Acetyl-CoA

To a biochemist, this intricate assembly is as much a testament to God's genius as a beautiful rose.

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 pyruvate, producing one CO2, then one CoA. It begins with the six carbon sugar, glucose. It produces 2 CO2 and consumes 3 NAD+ producing 3NADH and 3H+. It consumes 3 H2O and consumes one FAD, producing one FADH+.

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.

See also

  • Oxidative decarboxylation
  • Citric acid
  • Glycolysis
  • Oxidative phosphorylation
  • Reverse (reductive) Krebs cycle

External links


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