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.

Here they can be oxidized and combined with coenzyme A to form CO 2 , acetyl-CoA , and NADH , as in the normal cycle. 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 muscle are suddenly increased by activity. In the citric acid cycle all the intermediates e. citrate , iso-citrate , alpha-ketoglutarate , succinate , fumarate , malate , and oxaloacetate are regenerated during each turn of the cycle.

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 thus released captured in the form of ATP.

Acyl-CoA is oxidized to trans-Enoyl-CoA while FAD is reduced to FADH 2 , which is similar to the oxidation of succinate to fumarate. 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. the de-aminated amino acids may either enter the citric acid cycle as intermediates e. alpha-ketoglutarate derived from glutamate or glutamine , having an anaplerotic effect on the cycle, or, in the case of leucine , isoleucine , lysine , phenylalanine , tryptophan , and tyrosine , they are converted into acetyl-CoA which can be burned to CO 2 and water, or used to form ketone bodies , which too can only be burned in tissues other than the liver where they are formed, or excreted via the urine or breath.

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 skeletal muscle, glycerol is used in glycolysis by converting glycerol into glycerolphosphate , then into dihydroxyacetone phosphate DHAP , then into glyceraldehydephosphate. 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.

There it is cleaved by ATP citrate lyase into acetyl-CoA and oxaloacetate. 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.

Of these amino acids, aspartate and glutamine are used, together with carbon and nitrogen atoms from other sources, to form the purines that are used as the bases in DNA and RNA , as well as in ATP , AMP , GTP , NAD , FAD and CoA. The pyrimidines are partly assembled from aspartate derived from oxaloacetate.

The pyrimidines, thymine , cytosine and uracil , form the complementary bases to the purine bases in DNA and RNA, and are also components of CTP , UMP , UDP and UTP. 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 , mitochondrial cytopathies such as DPH Cytopathy , and the scientific field of oncology tumors.

In the classical Cori cycle , muscles produce lactate which is then taken up by the liver for gluconeogenesis. New studies suggest that lactate can be used as a source of carbon for the TCA cycle. It is believed that components of the citric acid cycle were derived from anaerobic bacteria , and that the TCA cycle itself may have evolved more than once.

If several TCA alternatives had evolved independently, they all appear to have converged to the TCA cycle. cis- Aconitate. Contents move to sidebar hide. Article Talk. Read Edit View history. Tools Tools. What links here Related changes Upload file Special pages Permanent link Page information Cite this page Get shortened URL Download QR code Wikidata item.

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Methods in Enzymology, Volume Citric Acid Cycle. Boston: Academic Press. ISBN Krebs' citric acid cycle: half a century and still turning.

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Bulletin of Mathematical Biology. Scholia has a profile for TCA cycle aka Krebs or citric acid cycle Q Metabolism , catabolism , anabolism. Metabolic pathway Metabolic network Primary nutritional groups. Purine metabolism Nucleotide salvage Pyrimidine metabolism Purine nucleotide cycle. Pentose phosphate pathway Fructolysis Polyol pathway Galactolysis Leloir pathway.

Glycosylation N-linked O-linked. Photosynthesis Anoxygenic photosynthesis Chemosynthesis Carbon fixation DeLey-Doudoroff pathway Entner-Doudoroff pathway. Xylose metabolism Radiotrophism. Fatty acid degradation Beta oxidation Fatty acid synthesis. Symptoms vary with this deficiency; these symptoms can include neonatal-onset, hypotonicity, lethargy, neurodegeneration, muscle spasticity, and early death.

Early, acute thiamine vitamin B1 deficiency is referred to as dry beriberi while chronic deficiency is referred to as wet beriberi, resulting in cardiac symptoms such as dilated cardiomyopathy. Like with PDC deficiency pyruvate is shunted to lactate dehydrogenase and converted to lactate.

This chronic shunting of pyruvate can result in a fatal metabolic acidosis. Isocitrate dehydrogenase 2 IDH2 , an isoform of isocitrate dehydrogenase, mitigates oxidative damage.

IDH2 is also frequently mutated in adult patients with acute myeloid leukemia. This mutation causes IDH2 to catalyze its reaction to a final product of 2-hydroxyglutarate instead of the correct alpha-ketoglutarate.

Disclosure: Aida Haddad declares no relevant financial relationships with ineligible companies. Disclosure: Shamim Mohiuddin declares no relevant financial relationships with ineligible companies.

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StatPearls [Internet]. Treasure Island FL : StatPearls Publishing; Jan-. Show details Treasure Island FL : StatPearls Publishing ; Jan-. Search term. Biochemistry, Citric Acid Cycle Aida Haddad ; Shamim S. Author Information and Affiliations Authors Aida Haddad 1 ; Shamim S. Affiliations 1 Indiana University School of Medicine.

Introduction The citric acid cycle serves as the mitochondrial hub for the final steps in carbon skeleton oxidative catabolism for carbohydrates, amino acids, and fatty acids. Fundamentals Acetyl-CoA, a significant carbon input into the citric acid cycle, can be derived from glucose or fatty acids; however, a substantial portion of acetyl-CoA comes from glucose or more specifically, pyruvate.

Cellular Level Three separate mechanisms regulate the pyruvate dehydrogenase complex: covalent modification the primary form of regulation , allosteric regulation, and transcriptional regulation.

Molecular Level The Pyruvate Dehydrogenase Complex's Reactions [1] : Pyruvate decarboxylase which is made up of 20 or 30 protein chains, is the first enzyme E1 complex in the PDC.

Function Cataplerotic Processes Citric acid intermediates may leave the cycle to biosynthesize other compounds. Clinical Significance Pyruvate Dehydrogenase Complex Deficiency A pyruvate dehydrogenase complex deficiency diagnosis most often results from a defective pyruvate decarboxylase subunit due to a mutated X-linked PDHAD gene.

Review Questions Access free multiple choice questions on this topic. Comment on this article. References 1. Sheeran FL, Angerosa J, Liaw NY, Cheung MM, Pepe S.

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