Tricarboxylic acid cycle
Tricarboxylic acid cycle, (TCA cycle), also called Krebs cycle and citric acid cycle, the second stage of cellular respiration, the three-stage process by which living cells break down organic fuel molecules in the presence of oxygen to harvest the energy they need to grow and divide. This metabolic process occurs in most plants, animals, fungi, and many bacteria. The citric acid cycle is a closed loop; the last part of the pathway reforms the molecule used in the first step. The cycle includes eight major steps. In the first step of the cycle, acetyl combines with a four-carbon acceptor molecule, oxaloacetate, to form a six-carbon molecule called citrate.
Cylce order for ATP to be produced through oxidative whahthee are required so that they can pass down the electron transport chain. In this article we will outline the steps and regulation of this essential part of cellular physiology. Prior to the TCA cycle, glycolysis has occurred. Pyruvate is then decarboxylated to form acetyl-coA by the pyruvate decarboxylase complex. Acetyl-coA is the intermediate that enters the TCA cycle. The TCA cycle is a central pathway that provides a unifying point for many metabolites, which feed in at various points.
It takes place over eight different steps:. The enzyme responsible for catalysing this step is isocitrate dehydrogenase. This is a rate limiting step as isocitrate dehydrogenase is an allosterically controlled enzyme. These enter or exit the cycle at various points depending on demand.
For example, alpha-ketoglutarate can leave the cycle to be converted into amino acids, and succinate can be converted to haem.
Each molecule of glucose produces two molecules of pyruvate, which in turn produce two molecules of acetyl-coA. Therefore, each molecule of glucose produces double this.
The most important thing to note is that there are in fact no known defects of xycle TCA cycle that are compatible with life. This highlights the importance of this step in ATP production for sustaining life. Once you've finished editing, click 'Submit for Review', and your changes will be reviewed by our team before publishing on the site.
It takes place over eight different steps: Step 1: Acetyl CoA two carbon molecule joins with oxaloacetate 4 carbon molecule to form citrate 6 carbon molecule. Step 2: Citrate is converted to isocitrate an isomer of citrate Step 3: Isocitrate is oxidised ahat alpha-ketoglutarate a five carbon molecule which results in the release of carbon dioxide. One NADH molecule is formed. Step 4: Alpha-ketoglutarate is oxidised to form a 4 carbon molecule. This binds what is a moon phase watch coenzyme A forming succinyl CoA.
A second molecule of NADH is produced, cycl a second molecule of carbon dioxide. Step 7: Fumarate is converted to malate another 4 carbon molecule. Step 8: Malate is ls converted into oxaloacetate. The third molecule of NADH is produced. Citrate: Inhibits phosphofructokinase, a key enzyme in glycolysis. This reduces the rate of production of pyruvate and therefore of acetyl-coA. Calcium: Calcium accelerates the TCA cycle by stimulating the tcca reaction.
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The TCA Cycle
The tricarboxylic acid cycle (TCA cycle) is a series of enzyme-catalyzed chemical reactions that form a key part of aerobic respiration in cells. This cycle . Jul 08, · The TCA cycle is a central pathway that provides a unifying point for many metabolites, which feed in at various points. It takes place over eight different steps: Step 1: Acetyl CoA (two carbon molecule) joins with oxaloacetate (4 carbon molecule) to /5. Jan 08, · The citric acid cycle, also known as the Krebs cycle or tricarboxylic acid (TCA) cycle, is a series of chemical reactions in the cell that breaks down food molecules into carbon dioxide, water, and energy. In plants and animals (eukaryotes), these reactions take place in the matrix of the mitochondria of the cell as part of cellular respiration.
The citric acid cycle CAC — also known as the TCA cycle tricarboxylic acid cycle or the Krebs cycle   — is a series of chemical reactions used by all aerobic organisms to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates , fats , and proteins.
In addition, the cycle provides precursors of certain amino acids , as well as the reducing agent NADH , that are used in numerous other reactions. Its central importance to many biochemical pathways suggests that it was one of the earliest components of metabolism and may have originated abiogenically. The name of this metabolic pathway is derived from the citric acid a tricarboxylic acid , often called citrate, as the ionized form predominates at biological pH  that is consumed and then regenerated by this sequence of reactions to complete the cycle.
The NADH generated by the citric acid cycle is fed into the oxidative phosphorylation electron transport pathway. The net result of these two closely linked pathways is the oxidation of nutrients to produce usable chemical energy in the form of ATP. In eukaryotic cells, the citric acid cycle occurs in the matrix of the mitochondrion.
In prokaryotic cells, such as bacteria, which lack mitochondria, the citric acid cycle reaction sequence is performed in the cytosol with the proton gradient for ATP production being across the cell's surface plasma membrane rather than the inner membrane of the mitochondrion. Because this tissue maintains its oxidative capacity well after breaking down in the "Latapie" mill and releasing in aqueous solutions, breast muscle of the pigeon was very well qualified for the study of oxidative reactions.
The citric acid cycle is a key metabolic pathway that connects carbohydrate , fat , and protein metabolism. The reactions of the cycle are carried out by eight enzymes that completely oxidize acetate a two carbon molecule , in the form of acetyl-CoA , into two molecules each of carbon dioxide and water.
Through catabolism of sugars, fats, and proteins, the two-carbon organic product acetyl-CoA a form of acetate is produced which enters the citric acid cycle. One of the primary sources of acetyl-CoA is from the breakdown of sugars by glycolysis which yield pyruvate that in turn is decarboxylated by the pyruvate dehydrogenase complex generating acetyl-CoA according to the following reaction scheme:.
The product of this reaction, acetyl-CoA, is the starting point for the citric acid cycle. Acetyl-CoA may also be obtained from the oxidation of fatty acids.
Below is a schematic outline of the cycle:. There are ten basic steps in the citric acid cycle, as outlined below. The cycle is continuously supplied with new carbon in the form of acetyl-CoA , entering at step 0 in the table. The NADH generated in the citric acid cycle may later be oxidized donate its electrons to drive ATP synthesis in a type of process called oxidative phosphorylation.
FADH 2 , therefore, facilitates transfer of electrons to coenzyme Q , which is the final electron acceptor of the reaction catalyzed by the succinate:ubiquinone oxidoreductase complex, also acting as an intermediate in the electron transport chain. Because two acetyl-CoA molecules are produced from each glucose molecule, two cycles are required per glucose molecule. The total number of ATP molecules obtained after complete oxidation of one glucose in glycolysis, citric acid cycle, and oxidative phosphorylation is estimated to be between 30 and While the citric acid cycle is in general highly conserved, there is significant variability in the enzymes found in different taxa  note that the diagrams on this page are specific to the mammalian pathway variant.
Some differences exist between eukaryotes and prokaryotes. A step with significant variability is the conversion of succinyl-CoA to succinate. Most organisms utilize EC 6. The level of utilization of each isoform is tissue dependent. This specialized enzyme links the TCA cycle with acetate metabolism in these organisms. Some variability also exists at the previous step — the conversion of 2-oxoglutarate to succinyl-CoA. In cancer , there are substantial metabolic derangements that occur to ensure the proliferation of tumor cells, and consequently metabolites can accumulate which serve to facilitate tumorigenesis , dubbed oncometabolites.
Under physiological conditions, 2-hydroxyglutarate is a minor product of several metabolic pathways as an error but readily converted to alpha-ketoglutarate via hydroxyglutarate dehydrogenase enzymes L2HGDH and D2HGDH  but does not have a known physiologic role in mammalian cells; of note, in cancer, 2-hydroxyglutarate is likely a terminal metabolite as isotope labelling experiments of colorectal cancer cell lines show that its conversion back to alpha-ketoglutarate is too low to measure.
This mutation results in several important changes to the metabolism of the cell. For one thing, because there is an extra NADPH-catalyzed reduction, this can contribute to depletion of cellular stores of NADPH and also reduce levels of alpha-ketoglutarate available to the cell. It is produced largely via the pentose phosphate pathway in the cytoplasm. There are also changes on the genetic and epigenetic level through the function of histone lysine demethylases KDMs and ten-eleven translocation TET enzymes; ordinarily TETs hydroxylate 5-methylcytosines to prime them for demethylation.
However, in the absence of alpha-ketoglutarate this cannot be done and there is hence hypermethylation of the cell's DNA, serving to promote epithelial-mesenchymal transition EMT and inhibit cellular differentiation.
A similar phenomenon is observed for the Jumonji C family of KDMs which require a hydroxylation to perform demethylation at the epsilon-amino methyl group. This results in a pseudohypoxic phenotype in the cancer cell that promotes angiogenesis , metabolic reprogramming , cell growth , and migration. Allosteric regulation by metabolites. The regulation of the citric acid cycle is largely determined by product inhibition and substrate availability. If the cycle were permitted to run unchecked, large amounts of metabolic energy could be wasted in overproduction of reduced coenzyme such as NADH and ATP.
Acetyl-coA inhibits pyruvate dehydrogenase , while succinyl-CoA inhibits alpha-ketoglutarate dehydrogenase and citrate synthase. Citrate is used for feedback inhibition, as it inhibits phosphofructokinase , an enzyme involved in glycolysis that catalyses formation of fructose 1,6-bisphosphate , a precursor of pyruvate.
This prevents a constant high rate of flux when there is an accumulation of citrate and a decrease in substrate for the enzyme. Regulation by calcium. Calcium is also used as a regulator in the citric acid cycle. Calcium levels in the mitochondrial matrix can reach up to the tens of micromolar levels during cellular activation. Transcriptional regulation. Recent work has demonstrated an important link between intermediates of the citric acid cycle and the regulation of hypoxia-inducible factors HIF.
HIF plays a role in the regulation of oxygen homeostasis , and is a transcription factor that targets angiogenesis , vascular remodeling , glucose utilization, iron transport and apoptosis. HIF is synthesized constitutively, and hydroxylation of at least one of two critical proline residues mediates their interaction with the von Hippel Lindau E3 ubiquitin ligase complex, which targets them for rapid degradation. This reaction is catalysed by prolyl 4-hydroxylases.
Fumarate and succinate have been identified as potent inhibitors of prolyl hydroxylases, thus leading to the stabilisation of HIF. Several catabolic pathways converge on the citric acid cycle. Most of these reactions add intermediates to the citric acid cycle, and are therefore known as anaplerotic reactions , from the Greek meaning to "fill up". These increase the amount of acetyl CoA that the cycle is able to carry, increasing the mitochondrion's capability to carry out respiration if this is otherwise a limiting factor.
Processes that remove intermediates from the cycle are termed "cataplerotic" reactions. In this section and in the next, the citric acid cycle intermediates are indicated in italics to distinguish them from other substrates and end-products. Pyruvate molecules produced by glycolysis are actively transported across the inner mitochondrial membrane, and into the matrix.
However, it is also possible for pyruvate to be carboxylated by pyruvate carboxylase to form oxaloacetate. This latter reaction "fills up" the amount of oxaloacetate in the citric acid cycle, and is therefore an anaplerotic reaction, increasing the cycle's capacity to metabolize acetyl-CoA when the tissue's energy needs e.
In the citric acid cycle all the intermediates e. Adding more of any of these intermediates to the mitochondrion therefore means that that additional amount is retained within the cycle, increasing all the other intermediates as one is converted into the other. Hence the addition of any one of them to the cycle has an anaplerotic effect, and its removal has a cataplerotic effect. These anaplerotic and cataplerotic reactions will, during the course of the cycle, increase or decrease the amount of oxaloacetate available to combine with acetyl-CoA to form citric acid.
This in turn increases or decreases the rate of ATP production by the mitochondrion, and thus the availability of ATP to the cell. Acetyl-CoA , on the other hand, derived from pyruvate oxidation, or from the beta-oxidation of fatty acids , is the only fuel to enter the citric acid cycle.
With each turn of the cycle one molecule of acetyl-CoA is consumed for every molecule of oxaloacetate present in the mitochondrial matrix, and is never regenerated. It is the oxidation of the acetate portion of acetyl-CoA that produces CO 2 and water, with the energy of O 2  thus released captured in the form of ATP. Following , trans-Enoyl-CoA is hydrated across the double bond to beta-hydroxyacyl-CoA, just like fumarate is hydrated to malate.
In protein catabolism , proteins are broken down by proteases into their constituent amino acids. Their carbon skeletons i. These are the so-called "glucogenic" amino acids. De-aminated alanine, cysteine, glycine, serine, and threonine are converted to pyruvate and can consequently either enter the citric acid cycle as oxaloacetate an anaplerotic reaction or as acetyl-CoA to be disposed of as CO 2 and water.
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 glyceraldehydephosphate by way of gluconeogenesis.
In many tissues, especially heart and skeletal muscle tissue , fatty acids are broken down through a process known as beta oxidation , which results in the production of mitochondrial acetyl-CoA , which can be used in the citric acid cycle. Beta oxidation of fatty acids with an odd number of methylene bridges produces propionyl-CoA , which is then converted into succinyl-CoA and fed into the citric acid cycle as an anaplerotic intermediate.
The total energy gained from the complete breakdown of one six-carbon molecule of glucose by glycolysis , the formation of 2 acetyl-CoA molecules, their catabolism in the citric acid cycle, and oxidative phosphorylation equals about 30 ATP molecules , in eukaryotes.
The number of ATP molecules derived from the beta oxidation of a 6 carbon segment of a fatty acid chain, and the subsequent oxidation of the resulting 3 molecules of acetyl-CoA is In this subheading, as in the previous one, the TCA intermediates are identified by italics. Several of the citric acid cycle intermediates are used for the synthesis of important compounds, which will have significant cataplerotic effects on the cycle.
To obtain cytosolic acetyl-CoA, citrate is removed from the citric acid cycle and carried across the inner mitochondrial membrane into the cytosol. The oxaloacetate is returned to mitochondrion as malate and then converted back into oxaloacetate to transfer more acetyl-CoA out of the mitochondrion. Cholesterol can, in turn, be used to synthesize the steroid hormones , bile salts , and vitamin D. The carbon skeletons of many non-essential amino acids are made from citric acid cycle intermediates.
To turn them into amino acids the alpha keto-acids formed from the citric acid cycle intermediates have to acquire their amino groups from glutamate in a transamination reaction, in which pyridoxal phosphate is a cofactor. In this reaction the glutamate is converted into alpha-ketoglutarate , which is a citric acid cycle intermediate.
The intermediates that can provide the carbon skeletons for amino acid synthesis are oxaloacetate which forms aspartate and asparagine ; and alpha-ketoglutarate which forms glutamine , proline , and arginine.
The pyrimidines are partly assembled from aspartate derived from oxaloacetate. The majority of the carbon atoms in the porphyrins come from the citric acid cycle intermediate, succinyl-CoA.
These molecules are an important component of the hemoproteins , such as hemoglobin , myoglobin and various cytochromes. During gluconeogenesis mitochondrial oxaloacetate is reduced to malate which is then transported out of the mitochondrion, to be oxidized back to oxaloacetate in the cytosol. Cytosolic oxaloacetate is then decarboxylated to phosphoenolpyruvate by phosphoenolpyruvate carboxykinase , which is the rate limiting step in the conversion of nearly all the gluconeogenic precursors such as the glucogenic amino acids and lactate into glucose by the liver and kidney.
Because the citric acid cycle is involved in both catabolic and anabolic processes, it is known as an amphibolic pathway. Evan M. Duo Click on genes, proteins and metabolites below to link to respective articles.
The metabolic role of lactate is well recognized as a fuel for tissues and tumors. In the classical Cori cycle , muscles produce lactate which is then taken up by the liver for gluconeogenesis.