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104-403: Citric acid is an organic compound with the skeletal formula H O C (CO 2 H)(CH 2 CO 2 H) 2 . It is a colorless weak organic acid . It occurs naturally in citrus fruits . In biochemistry , it is an intermediate in the citric acid cycle , which occurs in the metabolism of all aerobic organisms . More than two million tons of citric acid are manufactured every year. It

208-428: A monohydrate . The anhydrous form crystallizes from hot water, while the monohydrate forms when citric acid is crystallized from cold water. The monohydrate can be converted to the anhydrous form at about 78 °C. Citric acid also dissolves in absolute (anhydrous) ethanol (76 parts of citric acid per 100 parts of ethanol) at 15 °C. It decomposes with loss of carbon dioxide above about 175 °C. Citric acid

312-497: A chelate complex is formed using all three carboxylate groups, the chelate rings have 7 and 8 members, which are generally less stable thermodynamically than smaller chelate rings. In consequence, the hydroxyl group can be deprotonated, forming part of a more stable 5-membered ring, as in ammonium ferric citrate , [NH + 4 ] 5 Fe(C 6 H 4 O 4− 7 ) 2 ·2H 2 O . Citric acid can be esterified at one or more of its three carboxylic acid groups to form any of

416-418: A dry powdered form is commonly sold in markets and groceries as "sour salt", due to its physical resemblance to table salt. It has use in culinary applications, as an alternative to vinegar or lemon juice, where a pure acid is needed. Citric acid can be used in food coloring to balance the pH level of a normally basic dye. Citric acid is an excellent chelating agent , binding metals by making them soluble. It

520-448: A ferredoxin-dependent 2-oxoglutarate synthase ( EC 1.2.7.3 ). Other organisms, including obligately autotrophic and methanotrophic bacteria and archaea, bypass succinyl-CoA entirely, and convert 2-oxoglutarate to succinate via succinate semialdehyde , using EC 4.1.1.71 , 2-oxoglutarate decarboxylase, and EC 1.2.1.79 , succinate-semialdehyde dehydrogenase. In cancer , there are substantial metabolic derangements that occur to ensure

624-701: A food additive are defined by the Food Chemicals Codex , which is published by the United States Pharmacopoeia (USP). Citric acid can be added to ice cream as an emulsifying agent to keep fats from separating, to caramel to prevent sucrose crystallization, or in recipes in place of fresh lemon juice. Citric acid is used with sodium bicarbonate in a wide range of effervescent formulae, both for ingestion (e.g., powders and tablets) and for personal care ( e.g. , bath salts , bath bombs , and cleaning of grease ). Citric acid sold in

728-500: 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. In cancer, 2-hydroxyglutarate serves as a competitive inhibitor for a number of enzymes that facilitate reactions via alpha-ketoglutarate in alpha-ketoglutarate-dependent dioxygenases . This mutation results in several important changes to

832-408: A lower pH. Acid salts of citric acid can be prepared by careful adjustment of the pH before crystallizing the compound. See, for example, sodium citrate . The citrate ion forms complexes with metallic cations. The stability constants for the formation of these complexes are quite large because of the chelate effect . Consequently, it forms complexes even with alkali metal cations. However, when

936-448: A mild acid is used to neutralize and stop their action quickly, but commonly used acetic acid leaves a strong vinegar odor in the darkroom. Citric acid/potassium-sodium citrate can be used as a blood acid regulator. The citric acid is included to improve palatability Citric acid is an excellent soldering flux , either dry or as a concentrated solution in water. It should be removed after soldering, especially with fine wires, as it

1040-470: 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 ,

1144-474: A regulative force must exist within living bodies. Berzelius also contended that compounds could be distinguished by whether they required any organisms in their synthesis (organic compounds) or whether they did not ( inorganic compounds ). Vitalism taught that formation of these "organic" compounds were fundamentally different from the "inorganic" compounds that could be obtained from the elements by chemical manipulations in laboratories. Vitalism survived for

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1248-525: A reverse, non-enzymatic Krebs cycle reaction . Global production was in excess of 2,000,000 tons in 2018. More than 50% of this volume was produced in China. More than 50% was used as an acidity regulator in beverages, some 20% in other food applications, 20% for detergent applications, and 10% for applications other than food, such as cosmetics, pharmaceuticals, and in the chemical industry. Citric acid can be obtained as an anhydrous (water-free) form or as

1352-452: A short period after the formulation of modern ideas about the atomic theory and chemical elements . It first came under question in 1824, when Friedrich Wöhler synthesized oxalic acid , a compound known to occur only in living organisms, from cyanogen . A further experiment was Wöhler's 1828 synthesis of urea from the inorganic salts potassium cyanate and ammonium sulfate . Urea had long been considered an "organic" compound, as it

1456-404: A single element and so not generally considered chemical compounds . The word "organic" in this context does not mean "natural". Vitalism was a widespread conception that substances found in organic nature are formed from the chemical elements by the action of a "vital force" or "life-force" ( vis vitalis ) that only living organisms possess. In the 1810s, Jöns Jacob Berzelius argued that

1560-474: A six percent concentration of citric acid will remove hard water stains from glass without scrubbing. Citric acid can be used in shampoo to wash out wax and coloring from the hair. Illustrative of its chelating abilities, citric acid was the first successful eluant used for total ion-exchange separation of the lanthanides , during the Manhattan Project in the 1940s. In the 1950s, it was replaced by

1664-634: A small percentage of Earth's crust , they are of central importance because all known life is based on organic compounds. Living things incorporate inorganic carbon compounds into organic compounds through a network of processes ( the carbon cycle ) that begins with the conversion of carbon dioxide and a hydrogen source like water into simple sugars and other organic molecules by autotrophic organisms using light ( photosynthesis ) or other sources of energy. Most synthetically-produced organic compounds are ultimately derived from petrochemicals consisting mainly of hydrocarbons , which are themselves formed from

1768-421: A transition metal and to oxygen, and are often prepared directly from metal and carbon monoxide . Nickel tetracarbonyl is typically classified as an organometallic compound as it satisfies the broad definition that organometallic chemistry covers all compounds that contain at least one carbon to metal covalent bond; it is unknown whether organometallic compounds form a subset of organic compounds. For example,

1872-516: A variety of mono-, di-, tri-, and mixed esters. Citrate is an intermediate in the citric acid cycle , also known as the TCA ( T ri C arboxylic A cid) cycle or the Krebs cycle, a central metabolic pathway for animals, plants, and bacteria. In the Krebs cycle, citrate synthase catalyzes the condensation of oxaloacetate with acetyl CoA to form citrate. Citrate then acts as the substrate for aconitase and

1976-1692: A variety of ways. One major distinction is between natural and synthetic compounds. Organic compounds can also be classified or subdivided by the presence of heteroatoms , e.g., organometallic compounds , which feature bonds between carbon and a metal , and organophosphorus compounds , which feature bonds between carbon and a phosphorus . Another distinction, based on the size of organic compounds, distinguishes between small molecules and polymers . Natural compounds refer to those that are produced by plants or animals. Many of these are still extracted from natural sources because they would be more expensive to produce artificially. Examples include most sugars , some alkaloids and terpenoids , certain nutrients such as vitamin B 12 , and, in general, those natural products with large or stereoisometrically complicated molecules present in reasonable concentrations in living organisms. Further compounds of prime importance in biochemistry are antigens , carbohydrates , enzymes , hormones , lipids and fatty acids , neurotransmitters , nucleic acids , proteins , peptides and amino acids , lectins , vitamins , and fats and oils . Compounds that are prepared by reaction of other compounds are known as " synthetic ". They may be either compounds that are already found in plants/animals or those artificial compounds that do not occur naturally . Most polymers (a category that includes all plastics and rubbers ) are organic synthetic or semi-synthetic compounds. Many organic compounds—two examples are ethanol and insulin —are manufactured industrially using organisms such as bacteria and yeast. Typically,

2080-450: Is 38 (assuming 3 molar equivalents of ATP per equivalent NADH and 2 ATP per FADH 2 ). In eukaryotes, two equivalents of NADH and two equivalents of ATP are generated in glycolysis , which takes place in the cytoplasm . If transported using the glycerol phosphate shuttle rather than the malate–aspartate shuttle , transport of two of these equivalents of NADH into the mitochondria effectively consumes two equivalents of ATP, thus reducing

2184-404: Is a tribasic acid , with pK a values, extrapolated to zero ionic strength, of 3.128, 4.761, and 6.396 at 25 °C. The pK a of the hydroxyl group has been found, by means of C NMR spectroscopy , to be 14.4. The speciation diagram shows that solutions of citric acid are buffer solutions between about pH 2 and pH 8. In biological systems around pH 7, the two species present are

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2288-496: 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. It activates pyruvate dehydrogenase phosphatase which in turn activates the pyruvate dehydrogenase complex . Calcium also activates isocitrate dehydrogenase and α-ketoglutarate dehydrogenase . This increases

2392-972: Is any compound that contains a significant amount of carbon—even though many of the organic compounds known today have no connection to any substance found in living organisms. The term carbogenic has been proposed by E. J. Corey as a modern alternative to organic , but this neologism remains relatively obscure. The organic compound L -isoleucine molecule presents some features typical of organic compounds: carbon–carbon bonds , carbon–hydrogen bonds , as well as covalent bonds from carbon to oxygen and to nitrogen. As described in detail below, any definition of organic compound that uses simple, broadly-applicable criteria turns out to be unsatisfactory, to varying degrees. The modern, commonly accepted definition of organic compound essentially amounts to any carbon-containing compound, excluding several classes of substances traditionally considered "inorganic". The list of substances so excluded varies from author to author. Still, it

2496-597: Is catalyzed in eukaryotes by the NAD -dependent EC 1.1.1.41 , while prokaryotes employ the NADP -dependent EC 1.1.1.42 . Similarly, the conversion of ( S )-malate to oxaloacetate is catalyzed in eukaryotes by the NAD -dependent EC 1.1.1.37 , while most prokaryotes utilize a quinone-dependent enzyme, EC 1.1.5.4 . A step with significant variability is the conversion of succinyl-CoA to succinate. Most organisms utilize EC 6.2.1.5 , succinate–CoA ligase (ADP-forming) (despite its name,

2600-477: Is converted into aconitic acid . The cycle ends with regeneration of oxaloacetate. This series of chemical reactions is the source of two-thirds of the food-derived energy in higher organisms. The chemical energy released is available under the form of Adenosine triphosphate (ATP). Hans Adolf Krebs received the 1953 Nobel Prize in Physiology or Medicine for the discovery. Citrate can be transported out of

2704-710: Is generally agreed upon that there are (at least) a few carbon-containing compounds that should not be considered organic. For instance, almost all authorities would require the exclusion of alloys that contain carbon, including steel (which contains cementite , Fe 3 C ), as well as other metal and semimetal carbides (including "ionic" carbides, e.g, Al 4 C 3 and CaC 2 and "covalent" carbides, e.g. B 4 C and SiC , and graphite intercalation compounds, e.g. KC 8 ). Other compounds and materials that are considered 'inorganic' by most authorities include: metal carbonates , simple oxides of carbon ( CO , CO 2 , and arguably, C 3 O 2 ),

2808-412: Is hydrated to malate. Lastly, beta-hydroxyacyl-CoA is oxidized to beta-ketoacyl-CoA while NAD+ is reduced to NADH, which follows the same process as the oxidation of malate to oxaloacetate . In the liver, the carboxylation of cytosolic pyruvate into intra-mitochondrial oxaloacetate is an early step in the gluconeogenic pathway which converts lactate and de-aminated alanine into glucose, under

2912-541: Is mildly corrosive. It dissolves and rinses quickly in hot water. Alkali citrate can be used as an inhibitor of kidney stones by increasing urine citrate levels, useful for prevention of calcium stones, and increasing urine pH, useful for preventing uric acid and cystine stones. Citric acid is a versatile precursor to many other organic compounds. Dehydration routes give itaconic acid and its anhydride. Citraconic acid can be produced via thermal isomerization of itaconic acid anhydride. The required itaconic acid anhydride

3016-449: Is necessary to promote degradation of the latter (as under conditions of low oxygen there will not be adequate substrate for hydroxylation). 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

3120-412: Is no known allosteric mechanism that can account for large changes in reaction rate from an allosteric effector whose concentration changes less than 10%. 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

3224-407: Is no need for phosphofructokinase to continue to send molecules of its substrate, fructose 6-phosphate , into glycolysis. Citrate acts by augmenting the inhibitory effect of high concentrations of ATP , another sign that there is no need to carry out glycolysis. Citrate is a vital component of bone, helping to regulate the size of apatite crystals. Because it is one of the stronger edible acids,

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3328-762: Is obtained by dry distillation of citric acid. Aconitic acid can be synthesized by dehydration of citric acid using sulfuric acid : Acetonedicarboxylic acid can also be prepared by decarboxylation of citric acid in fuming sulfuric acid. Although a weak acid, exposure to pure citric acid can cause adverse effects. Inhalation may cause cough, shortness of breath, or sore throat. Over-ingestion may cause abdominal pain and sore throat. Exposure of concentrated solutions to skin and eyes can cause redness and pain. Long-term or repeated consumption may cause erosion of tooth enamel . Organic compound Due to carbon's ability to catenate (form chains with other carbon atoms ), millions of organic compounds are known. The study of

3432-479: Is on a carbon atom. For historical reasons discussed below, a few types of carbon-containing compounds, such as carbides , carbonates (excluding carbonate esters ), simple oxides of carbon (for example, CO and CO 2 ) and cyanides are generally considered inorganic compounds . Different forms ( allotropes ) of pure carbon, such as diamond , graphite , fullerenes and carbon nanotubes are also excluded because they are simple substances composed of

3536-401: 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 . For each pyruvate molecule (from glycolysis ), the overall yield of energy-containing compounds from the citric acid cycle is three NADH, one FADH 2 , and one GTP . Several of the components and reactions of

3640-458: 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

3744-399: 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. Two carbon atoms are oxidized to CO 2 ,

3848-539: 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.W.Duo Click on genes, proteins and metabolites below to link to respective articles. The metabolic role of lactate

3952-478: Is used as an odorless alternative to white vinegar for fabric dyeing with acid dyes . Sodium citrate is a component of Benedict's reagent , used for both qualitative and quantitative identification of reducing sugars. Citric acid can be used as an alternative to nitric acid in passivation of stainless steel . Citric acid can be used as a lower-odor stop bath as part of the process for developing photographic film . Photographic developers are alkaline, so

4056-435: Is used to remove and discourage the buildup of limescale from boilers and evaporators. It can be used to treat water, which makes it useful in improving the effectiveness of soaps and laundry detergents. By chelating the metals in hard water , it lets these cleaners produce foam and work better without need for water softening. Citric acid is the active ingredient in some bathroom and kitchen cleaning solutions. A solution with

4160-400: Is used widely as acidifier , flavoring , preservative , and chelating agent . A citrate is a derivative of citric acid; that is, the salts , esters , and the polyatomic anion found in solutions and salts of citric acid. An example of the former, a salt is trisodium citrate ; an ester is triethyl citrate . When citrate trianion is part of a salt, the formula of the citrate trianion

4264-457: 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

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4368-549: Is written as C 6 H 5 O 7 or C 3 H 5 O(COO) 3 . Citric acid occurs in a variety of fruits and vegetables, most notably citrus fruits . Lemons and limes have particularly high concentrations of the acid; it can constitute as much as 8% of the dry weight of these fruits (about 47 g/L in the juices). The concentrations of citric acid in citrus fruits range from 0.005  mol/L for oranges and grapefruits to 0.30 mol/L in lemons and limes; these values vary within species depending upon

4472-557: The DNA of an organism is altered to express compounds not ordinarily produced by the organism. Many such biotechnology -engineered compounds did not previously exist in nature. A great number of more specialized databases exist for diverse branches of organic chemistry. The main tools are proton and carbon-13 NMR spectroscopy , IR Spectroscopy , Mass spectrometry , UV/Vis Spectroscopy and X-ray crystallography . Krebs cycle reaction The citric acid cycle —also known as

4576-586: The Krebs cycle , Szent–Györgyi–Krebs cycle , or TCA cycle ( tricarboxylic acid cycle ) —is a series of biochemical reactions to release the energy stored in nutrients through the oxidation of acetyl-CoA derived from carbohydrates , fats , proteins , and alcohol . The chemical energy released is available in the form of ATP . The Krebs cycle is used by organisms that respire (as opposed to organisms that ferment ) to generate energy, either by anaerobic respiration or aerobic respiration . In addition,

4680-781: The allotropes of carbon, cyanide derivatives not containing an organic residue (e.g., KCN , (CN) 2 , BrCN , cyanate anion OCN , etc.), and heavier analogs thereof (e.g., cyaphide anion CP , CSe 2 , COS ; although carbon disulfide CS 2 is often classed as an organic solvent). Halides of carbon without hydrogen (e.g., CF 4 and CClF 3 ), phosgene ( COCl 2 ), carboranes , metal carbonyls (e.g., nickel tetracarbonyl ), mellitic anhydride ( C 12 O 9 ), and other exotic oxocarbons are also considered inorganic by some authorities. Nickel tetracarbonyl ( Ni(CO) 4 ) and other metal carbonyls are often volatile liquids, like many organic compounds, yet they contain only carbon bonded to

4784-669: 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

4888-459: The cultivar and the circumstances under which the fruit was grown. Citric acid was first isolated in 1784 by the chemist Carl Wilhelm Scheele , who crystallized it from lemon juice. Industrial-scale citric acid production first began in 1890 based on the Italian citrus fruit industry, where the juice was treated with hydrated lime ( calcium hydroxide ) to precipitate calcium citrate , which

4992-416: The mitochondria and into the cytoplasm, then broken down into acetyl-CoA for fatty acid synthesis , and into oxaloacetate. Citrate is a positive modulator of this conversion, and allosterically regulates the enzyme acetyl-CoA carboxylase , which is the regulating enzyme in the conversion of acetyl-CoA into malonyl-CoA (the commitment step in fatty acid synthesis). In short, citrate is transported into

5096-562: The oxidation of isocitrate to oxalosuccinate , which then spontaneously decarboxylates to alpha-ketoglutarate , as discussed above; in this case an additional reduction step occurs after the formation of alpha-ketoglutarate via NADPH to yield 2-hydroxyglutarate), and hence IDH is considered an oncogene . 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

5200-545: The pentose phosphate pathway in the cytoplasm. The depletion of NADPH results in increased oxidative stress within the cell as it is a required cofactor in the production of GSH , and this oxidative stress can result in DNA damage. 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

5304-450: 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

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5408-530: The ADP and GDP ions, respectively, and ATP and GTP the ATP and GTP ions, respectively. 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 38. The theoretical maximum yield of ATP through oxidation of one molecule of glucose in glycolysis, citric acid cycle, and oxidative phosphorylation

5512-406: The TCA cycle itself may have evolved more than once. It may even predate biosis: the substrates appear to undergo most of the reactions spontaneously in the presence of persulfate radicals. Theoretically, several alternatives to the TCA cycle exist; however, the TCA cycle appears to be the most efficient. If several TCA alternatives had evolved independently, they all appear to have converged to

5616-436: The TCA cycle with acetate metabolism in these organisms. Some bacteria, such as Helicobacter pylori , employ yet another enzyme for this conversion – succinyl-CoA:acetoacetate CoA-transferase ( EC 2.8.3.5 ). Some variability also exists at the previous step – the conversion of 2-oxoglutarate to succinyl-CoA. While most organisms utilize the ubiquitous NAD -dependent 2-oxoglutarate dehydrogenase, some bacteria utilize

5720-412: 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. Acetyl-CoA cannot be transported out of the mitochondrion. To obtain cytosolic acetyl-CoA, citrate is removed from the citric acid cycle and carried across the inner mitochondrial membrane into

5824-561: 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. Additionally, the inability of prolyl hydroxylases to catalyze reactions results in stabilization of hypoxia-inducible factor alpha , which

5928-469: 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

6032-434: 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

6136-408: The citrate ion and mono-hydrogen citrate ion. The SSC 20X hybridization buffer is an example in common use. Tables compiled for biochemical studies are available. Conversely, the pH of a 1 mM solution of citric acid will be about 3.2. The pH of fruit juices from citrus fruits like oranges and lemons depends on the citric acid concentration, with a higher concentration of citric acid resulting in

6240-413: The citric acid cycle all the intermediates (e.g. 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

6344-525: The citric acid cycle and the mitochondrial electron transport chain in 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 . Mitochondria in animals, including humans, possess two succinyl-CoA synthetases: one that produces GTP from GDP, and another that produces ATP from ADP. Plants have

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6448-407: The citric acid cycle are, in turn, used by the oxidative phosphorylation pathway to generate energy-rich ATP. 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,

6552-443: The citric acid cycle have been recognized. 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 cycle consumes acetate (in the form of acetyl-CoA) and water , reduces NAD to NADH, releasing carbon dioxide. The NADH generated by

6656-434: 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

6760-573: The citric acid cycle were established in the 1930s by the research of Albert Szent-Györgyi , who received the Nobel Prize in Physiology or Medicine in 1937 specifically for his discoveries pertaining to fumaric acid , a component of the cycle. He made this discovery by studying pigeon breast muscle. Because this tissue maintains its oxidative capacity well after breaking down in the Latapie mincer and releasing in aqueous solutions, breast muscle of

6864-454: 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

6968-750: 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 is produced which enters the citric acid cycle. The reactions of the cycle also convert three equivalents of nicotinamide adenine dinucleotide (NAD ) into three equivalents of reduced NAD (NADH), one equivalent of flavin adenine dinucleotide (FAD) into one equivalent of FADH 2 , and one equivalent each of guanosine diphosphate (GDP) and inorganic phosphate (P i ) into one equivalent of guanosine triphosphate (GTP). The NADH and FADH 2 generated by

7072-410: The cycle are one GTP (or ATP ), three NADH , one FADH 2 and two CO 2 . Because two acetyl-CoA molecules are produced from each glucose molecule, two cycles are required per glucose molecule. Therefore, at the end of two cycles, the products are: two GTP, six NADH, two FADH 2 , and four CO 2 . The above reactions are balanced if P i represents the H 2 PO 4 ion, ADP and GDP

7176-454: 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

7280-417: 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 . Even though it is branded as a "cycle", it is not necessary for metabolites to follow only one specific route; at least three alternative segments of

7384-409: 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. The major eventual substrate of the cycle is ADP which gets converted to ATP. A reduced amount of ADP causes accumulation of precursor NADH which in turn can inhibit a number of enzymes. NADH, a product of all dehydrogenases in the citric acid cycle with

7488-431: The cytoplasm, converted into acetyl-CoA, which is then converted into malonyl-CoA by acetyl-CoA carboxylase, which is allosterically modulated by citrate. High concentrations of cytosolic citrate can inhibit phosphofructokinase , the catalyst of a rate-limiting step of glycolysis . This effect is advantageous: high concentrations of citrate indicate that there is a large supply of biosynthetic precursor molecules, so there

7592-590: 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). The cytosolic acetyl-CoA is used for fatty acid synthesis and the production of cholesterol . 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

7696-457: The de-aminated amino acids) may either enter the citric acid cycle as intermediates (e.g. 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

7800-556: The dominant use of citric acid is as a flavoring and preservative in food and beverages, especially soft drinks and candies. Within the European Union it is denoted by E number E330 . Citrate salts of various metals are used to deliver those minerals in a biologically available form in many dietary supplements . Citric acid has 247 kcal per 100 g. In the United States the purity requirements for citric acid as

7904-462: The energy from these reactions is transferred to other metabolic processes through GTP (or ATP), and as electrons in NADH and QH 2 . 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 is covalently attached to succinate dehydrogenase , an enzyme which functions both in

8008-428: The energy thus released captured in the form of ATP. The three steps of beta-oxidation resemble the steps that occur in the production of oxaloacetate from succinate in the TCA cycle. 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

8112-441: The enzyme operates in the pathway in the direction of ATP formation). In mammals a GTP-forming enzyme, succinate–CoA ligase (GDP-forming) ( EC 6.2.1.4 ) also operates. The level of utilization of each isoform is tissue dependent. In some acetate-producing bacteria, such as Acetobacter aceti , an entirely different enzyme catalyzes this conversion – EC 2.8.3.18 , succinyl-CoA:acetate CoA-transferase. This specialized enzyme links

8216-938: The evidence of covalent Fe-C bonding in cementite , a major component of steel, places it within this broad definition of organometallic, yet steel and other carbon-containing alloys are seldom regarded as organic compounds. Thus, it is unclear whether the definition of organometallic should be narrowed, whether these considerations imply that organometallic compounds are not necessarily organic, or both. Metal complexes with organic ligands but no carbon-metal bonds (e.g., (CH 3 CO 2 ) 2 Cu ) are not considered organometallic; instead, they are called metal-organic compounds (and might be considered organic). The relatively narrow definition of organic compounds as those containing C-H bonds excludes compounds that are (historically and practically) considered organic. Neither urea CO(NH 2 ) 2 nor oxalic acid (COOH) 2 are organic by this definition, yet they were two key compounds in

8320-512: The exception of succinate dehydrogenase , inhibits pyruvate dehydrogenase , isocitrate dehydrogenase , α-ketoglutarate dehydrogenase , and also citrate synthase . Acetyl-coA inhibits pyruvate dehydrogenase , while succinyl-CoA inhibits alpha-ketoglutarate dehydrogenase and citrate synthase . When tested in vitro with TCA enzymes, ATP inhibits citrate synthase and α-ketoglutarate dehydrogenase ; however, ATP levels do not change more than 10% in vivo between rest and vigorous exercise. There

8424-427: The far more efficient EDTA . In industry, it is used to dissolve rust from steel, and to passivate stainless steels . Citric acid is used as an acidulant in creams, gels, and liquids. Used in foods and dietary supplements, it may be classified as a processing aid if it was added for a technical or functional effect (e.g. acidulent, chelator, viscosifier, etc.). If it is still present in insignificant amounts, and

8528-402: 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 40. In this subheading, as in the previous one,

8632-432: The glycerol can be converted into glucose via dihydroxyacetone phosphate and glyceraldehyde-3-phosphate by way of gluconeogenesis . In skeletal muscle, glycerol is used in glycolysis by converting glycerol into glycerol-3-phosphate , then into dihydroxyacetone phosphate (DHAP), then into glyceraldehyde-3-phosphate. In many tissues, especially heart and skeletal muscle tissue , fatty acids are broken down through

8736-404: The high pressure and temperature degradation of organic matter underground over geological timescales. This ultimate derivation notwithstanding, organic compounds are no longer defined as compounds originating in living things, as they were historically. In chemical nomenclature, an organyl group , frequently represented by the letter R, refers to any monovalent substituent whose open valence

8840-555: The influence of high levels of glucagon and/or epinephrine in the blood. Here the addition of oxaloacetate to the mitochondrion does not have a net anaplerotic effect, as another citric acid cycle intermediate ( malate ) is immediately removed from the mitochondrion to be converted into cytosolic oxaloacetate, which is ultimately converted into glucose, in a process that is almost the reverse of glycolysis . In protein catabolism , proteins are broken down by proteases into their constituent amino acids. Their carbon skeletons (i.e.

8944-424: The liver where they are formed, or excreted via the urine or breath. These latter amino acids are therefore termed "ketogenic" amino acids, whereas those that enter the citric acid cycle as intermediates can only be cataplerotically removed by entering the gluconeogenic pathway via malate which is transported out of the mitochondrion to be converted into cytosolic oxaloacetate and ultimately into glucose . These are

9048-409: 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. In particular, the depletion of NADPH is problematic because NADPH is highly compartmentalized and cannot freely diffuse between the organelles in the cell. It is produced largely via

9152-601: The mineral mellite ( Al 2 C 6 (COO) 6 ·16H 2 O ). A slightly broader definition of the organic compound includes all compounds bearing C-H or C-C bonds. This would still exclude urea. Moreover, this definition still leads to somewhat arbitrary divisions in sets of carbon-halogen compounds. For example, CF 4 and CCl 4 would be considered by this rule to be "inorganic", whereas CHF 3 , CHCl 3 , and C 2 Cl 6 would be organic, though these compounds share many physical and chemical properties. Organic compounds may be classified in

9256-576: The mold is filtered out of the resulting suspension , citric acid is isolated by precipitating it with calcium hydroxide to yield calcium citrate salt, from which citric acid is regenerated by treatment with sulfuric acid, as in the direct extraction from citrus fruit juice. In 1977, a patent was granted to Lever Brothers for the chemical synthesis of citric acid starting either from aconitic or isocitrate (also called alloisocitrate) calcium salts under high pressure conditions; this produced citric acid in near quantitative conversion under what appeared to be

9360-411: The net production of ATP to 36. Furthermore, inefficiencies in oxidative phosphorylation due to leakage of protons across the mitochondrial membrane and slippage of the ATP synthase /proton pump commonly reduces the ATP yield from NADH and FADH 2 to less than the theoretical maximum yield. The observed yields are, therefore, closer to ~2.5 ATP per NADH and ~1.5 ATP per FADH 2 , further reducing

9464-413: 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.g. in muscle ) are suddenly increased by activity. In

9568-422: 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

9672-489: The pharmaceutical company Pfizer began industrial-level production using this technique two years later, followed by Citrique Belge in 1929. In this production technique, which is still the major industrial route to citric acid used today, cultures of Aspergillus niger are fed on a sucrose or glucose -containing medium to produce citric acid. The source of sugar is corn steep liquor , molasses , hydrolyzed corn starch , or other inexpensive, carbohydrate solution. After

9776-562: The pigeon was very well qualified for the study of oxidative reactions. The citric acid cycle itself was finally identified in 1937 by Hans Adolf Krebs and William Arthur Johnson while at the University of Sheffield , for which the former received the Nobel Prize for Physiology or Medicine in 1953, and for whom the cycle is sometimes named the "Krebs cycle". The citric acid cycle is a metabolic pathway that connects carbohydrate , fat , and protein metabolism . The reactions of

9880-401: The proliferation of tumor cells, and consequently metabolites can accumulate which serve to facilitate tumorigenesis , dubbed onco metabolites . Among the best characterized oncometabolites is 2-hydroxyglutarate which is produced through a heterozygous gain-of-function mutation (specifically a neomorphic one) in isocitrate dehydrogenase (IDH) (which under normal circumstances catalyzes

9984-647: The properties, reactions, and syntheses of organic compounds comprise the discipline known as organic chemistry . For historical reasons, a few classes of carbon-containing compounds (e.g., carbonate salts and cyanide salts ), along with a few other exceptions (e.g., carbon dioxide , and even hydrogen cyanide despite the fact it contains a carbon-hydrogen bond), are generally considered inorganic . Other than those just named, little consensus exists among chemists on precisely which carbon-containing compounds are excluded, making any rigorous definition of an organic compound elusive. Although organic compounds make up only

10088-461: The reaction rate of many of the steps in the cycle, and therefore increases flux throughout the pathway. Transcriptional regulation . There is a 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

10192-405: 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

10296-540: The technical or functional effect is no longer present, it may be exempt from labeling <21 CFR §101.100(c)>. Citric acid is an alpha hydroxy acid and is an active ingredient in chemical skin peels. Citric acid is commonly used as a buffer to increase the solubility of brown heroin . Citric acid is used as one of the active ingredients in the production of facial tissues with antiviral properties. The buffering properties of citrates are used to control pH in household cleaners and pharmaceuticals . Citric acid

10400-525: The total net production of ATP to approximately 30. An assessment of the total ATP yield with newly revised proton-to-ATP ratios provides an estimate of 29.85 ATP per glucose molecule. 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. The conversion of D- threo -isocitrate to 2-oxoglutarate

10504-410: The type that produces ATP (ADP-forming succinyl-CoA synthetase). Several of the enzymes in the cycle may be loosely associated in a multienzyme protein complex within the mitochondrial matrix . The GTP that is formed by GDP-forming succinyl-CoA synthetase may be utilized by nucleoside-diphosphate kinase to form ATP (the catalyzed reaction is GTP + ADP → GDP + ATP). Products of the first turn of

10608-589: The vitalism debate. However, the IUPAC Blue Book on organic nomenclature specifically mentions urea and oxalic acid as organic compounds. Other compounds lacking C-H bonds but traditionally considered organic include benzenehexol , mesoxalic acid , and carbon tetrachloride . Mellitic acid , which contains no C-H bonds, is considered a possible organic compound in Martian soil. Terrestrially, it, and its anhydride, mellitic anhydride , are associated with

10712-460: Was isolated and converted back to the acid using diluted sulfuric acid . In 1893, C. Wehmer discovered Penicillium mold could produce citric acid from sugar. However, microbial production of citric acid did not become industrially important until World War I disrupted Italian citrus exports. In 1917, American food chemist James Currie discovered that certain strains of the mold Aspergillus niger could be efficient citric acid producers, and

10816-445: Was known to occur only in the urine of living organisms. Wöhler's experiments were followed by many others, in which increasingly complex "organic" substances were produced from "inorganic" ones without the involvement of any living organism, thus disproving vitalism. Although vitalism has been discredited, scientific nomenclature retains the distinction between organic and inorganic compounds. The modern meaning of organic compound

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