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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.
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.
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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 3 NADH and 3 H+.
* It consumes one H2O and consumes one FAD, producing one FADH+.
* 1st turn end= 1 GTP, 3 NADH, 1 FADH2, 2 CO2
* Since there are two molecules of Pyruvic acid to deal with, the cycle turns once more.
* The complete end result= 2 GTP, 6 NADH, 2 FADH2, 4 CO2
[edit] 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.
[edit] 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.
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Glycolysis is a metabolic pathway by which a molecule of glucose (Glc) is oxidized to two molecules of pyruvic acid (Pyr). The word glycolysis is derived from Greek glyk (sweet) and lysis (dissolving). It is the initial process of most carbohydrate catabolism, and it serves three principal functions:
* The generation of high-energy molecules (ATP and NADH) as cellular energy sources as part of anaerobic respiration.
* Production of pyruvate for the citric acid cycle as part of aerobic respiration.
* The production of a variety of six- and three-carbon intermediate compounds, which may be removed at various steps in the process for other cellular purposes.
As the foundation of both aerobic and anaerobic respiration, glycolysis is one of the most universal metabolic processes known and occurs (with variations) in many types of cells in nearly all organisms. Glycolysis, through anaerobic respiration, is the main energy source in many prokaryotes, eukaryotic cells devoid of mitochondria (e.g. mature erythrocytes) and eukaryotic cells under low oxygen conditions (e.g. heavily exercising muscle or fermenting yeast).
In eukaryotes and prokaryotes, glycolysis takes place within the cytosol of the cell. In plant cells some of the glycolytic reactions are also found in the Calvin cycle which functions inside the chloroplasts. This wide conservation supports the fact that glycolysis has great antiquity; it may have originated in the first prokaryotes, 3.5 billion years ago or more.
The most common and well-known type of glycolysis is the Embden-Meyerhof pathway, initially elucidated by Gustav Embden and Otto Meyerhof. The term can be taken to include alternative pathways, such as the Entner-Doudoroff Pathway. However, glycolysis will be used here as a synonym for the Embden-Meyerhof pathway.
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The products all have vital cellular uses:
* ATP provides an energy source for many cellular functions.
* NADH + H+ provides reducing power for other metabolic pathways or further ATP synthesis.
* Pyruvate is used in the citric acid cycle in aerobic respiration to produce more ATP, or are converted to other small carbon molecules in anaerobic respiration.
For simple anaerobic fermentations, the metabolism of one molecule of glucose to two molecules of pyruvate has a net yield of two molecules of ATP. Most cells will then carry out further reactions to 'repay' the used NAD+ and produce a final product of ethanol or lactic acid. Many bacteria use inorganic compounds as hydrogen acceptors to regenerate the NAD+.
Cells performing aerobic respiration synthesize much more ATP, but not as part of glycolysis. These further aerobic reactions use pyruvate and NADH + H+ from glycolysis. Eukaryotic aerobic respiration produces approximately 34 additional molecules of ATP for each glucose molecule, however most of these are produced by a vastly different mechanism to the substrate-level phosphorylation in glycolysis.
The lower energy production, per glucose, of anaerobic respiration relative to aerobic respiration results in greater flux through the pathway under hypoxic (low oxygen) conditions, unless alternative sources of anerobically oxidizable substrates, such as fatty acids, are found.
[edit] Discovery of glycolysis
The first indications of the glycolitc process were in 1860 when Louis Pasteur discovered that microorganisms were responsible for fermentation, and in 1897 when Eduard Buchner found certain cell extracts could cause fermentation. The next major contribution was from Arthur Harden and William Young in 1905 who determined that a heat sensitive high molecular weight (the enzymes) and a heat insensitive low molecular weight cytoplasm fraction (ADP, ATP and NAD+ and other cofactors) were both required for fermentation. The pathway itself was eventually determined in 1940, with a major input from Otto Meyerhof. The biggest difficulties in determining the pathway was due to the very short lifetime and low concentration of the many intermediates of the fast glycolitic reactions.
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[edit] Sequence of reactions
These are the major reactions, through which most glucose will pass. There are additional alternative pathways and regulatory products which are not shown here.
[edit] Preparatory phase
The first five steps are regarded as a preparatory phase since they consume energy to convert the glucose into two three-carbon sugar phosphates (G3P).
The first step in glycolysis is phosphorylation of glucose by a family of enzymes called hexokinases to form glucose 6-phosphate. This reaction consumes ATP, but it acts to keep the glucose concentration low, promoting continuous transport of glucose into the cell through the plasma membrane transporters. In addition it blocks the glucose leaking out - the cell lacks transporters for glucose 6-phosphate. Glucose may alternatively be from the hydrolysis of intracellular starch or glycogen.
In animals an isozyme of hexokinase called glucokinase is also used in the liver, which differs primarily in regulatory properties. The alternate regulation of this enzyme is due to the role of the liver in maintaining blood sugar levels.
Cofactors: Mg2+
D-Glucose (Glc) Hexokinase (HK)
a transferase -D-Glucose-6-phosphate (G6P)
image:Glucose_wpmp.png image:Glucose-6-phosphate_wpmp.png
ATP ADP
G6P is then rearranged into fructose 6-phosphate by glucose phosphate isomerase. fructose can also enter the glycolytic pathway by phosphorylation at this point. ATP is used again at this step.
The change in structure is a redox reaction, in which the aldehyde has been reduced to an alcohol, and the adjacent carbon has been oxidized to form a ketone. While this reaction is not normally favorable, it is driven by a low concentration of fructose 6-phosphate, which is constantly consumed during the next step of glycolysis. Under conditions of high fructose 6-phosphate concentration this reaction readily runs in reverse. This phenomenon can be explained through Le Chatelier's Principle.
The energy expenditure of another ATP in this step is justified in 2 ways: the glycolytic process (up to this step) is now irreversible, and the energy supplied destabilizes the molecule. This reaction is a key regulatory point, see below. [During fasting the concentration of fructose 2,6-bisphosphate (an allosteric activator of PFK1) is low such that PFK1 activity is reduced. This leads to an increase of flux through the gluconeogenesis pathway.]
Cofactors: Mg2+
-D-Fructose 6-phosphate (F6P) phosphofructokinase (PFK-1)
a transferase -D-Fructose 1,6-bisphosphate (F1,6BP)
image:Fructose-6-phosphate_wpmp.png image:beta-D-fructose-1,6-bisphosphate_wpmp.png
ATP ADP
Pi H2O
phosphofructokinase (PFK-1)
Destablising the molecule in the previous reaction allows the hexose ring to be split by aldolase into two triose sugars, dihydroxyacetone phosphate and glyceraldehyde 3-phosphate.
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