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38-597: 268756 ENSG00000234770 ENSMUSG00000034450 n a P58710 n/a NM_178747 n/a NP_848862 L -Gulonolactone oxidase ( EC 1.1.3.8 ) is an enzyme that produces vitamin C . It is expressed in most mammals, but is non-functional in Haplorrhini (a suborder of primates, including humans), in some bats , and in guinea pigs . It catalyzes the reaction of L -gulono-1,4-lactone with oxygen to form L -xylo-hex-3-gulonolactone (2-keto-gulono-γ-lactone) and hydrogen peroxide . It uses FAD as
76-447: A cofactor . The L -xylo-hex-3-gulonolactone then converts to ascorbic acid spontaneously, without enzymatic action. The structure of L-gulonolactone oxidase in rats helps identify characteristics of this enzyme. The non-functional gulonolactone oxidase pseudogene ( GULOP ) was mapped to human chromosome 8p21 , which corresponds to an evolutionarily conserved segment on either porcine chromosome 4 (SSC4) or 14 (SSC14). GULO produces
114-438: A starch indicator . Iodine is reduced by ascorbic acid, and when all the ascorbic acid has reacted, the iodine is in excess, forming a blue-black complex with the starch indicator. This indicates the end-point of the titration. As an alternative, ascorbic acid can be treated with iodine in excess, followed by back titration with sodium thiosulfate using starch as an indicator. This iodometric method has been revised to exploit
152-403: A 1,3-diketone: The ascorbate ion is the predominant species at typical biological pH values. It is a mild reducing agent and antioxidant . It is oxidized with loss of one electron to form a radical cation and then with loss of a second electron to form dehydroascorbic acid . It typically reacts with oxidants of the reactive oxygen species , such as the hydroxyl radical . Ascorbic acid
190-550: A potentially dangerous pro-oxidative compound in certain metabolic contexts. Ascorbic acid and its sodium, potassium, and calcium salts are commonly used as antioxidant food additives . These compounds are water-soluble and, thus, cannot protect fats from oxidation: For this purpose, the fat- soluble esters of ascorbic acid with long-chain fatty acids (ascorbyl palmitate or ascorbyl stearate) can be used as antioxidant food additives. It creates volatile compounds when mixed with glucose and amino acids at 90 °C. It
228-623: A progressively finer classification of the enzyme. Preliminary EC numbers exist and have an 'n' as part of the fourth (serial) digit (e.g. EC 3.5.1.n3). For example, the tripeptide aminopeptidases have the code "EC 3.4.11.4", whose components indicate the following groups of enzymes: NB:The enzyme classification number is different from the 'FORMAT NUMBER' Oxidation /reduction reactions; transfer of H and O atoms or electrons from one substance to another Similarity between enzymatic reactions can be calculated by using bond changes, reaction centres or substructure metrics (formerly EC-BLAST], now
266-448: Is a furan -based lactone of 2-ketogluconic acid . It contains an adjacent enediol adjacent to the carbonyl . This −C(OH)=C(OH)−C(=O)− structural pattern is characteristic of reductones , and increases the acidity of one of the enol hydroxyl groups . The deprotonated conjugate base is the ascorbate anion, which is stabilized by electron delocalization that results from resonance between two forms: For this reason, ascorbic acid
304-421: Is a numerical classification scheme for enzymes , based on the chemical reactions they catalyze . As a system of enzyme nomenclature , every EC number is associated with a recommended name for the corresponding enzyme-catalyzed reaction. EC numbers do not specify enzymes but enzyme-catalyzed reactions. If different enzymes (for instance from different organisms) catalyze the same reaction, then they receive
342-670: Is a cofactor in tyrosine oxidation . The main use of l -ascorbic acid and its salts is as food additives, mostly to combat oxidation. It is approved for this purpose in the EU with E number E300, the US, Australia, and New Zealand. Another major use of l -ascorbic acid is as a dietary supplement . It is on the World Health Organization's List of Essential Medicines . Natural biosynthesis of vitamin C occurs through various processes in many plants and animals. Seventy percent of
380-448: Is a mild reducing agent . Ascorbic acid exists as two enantiomers (mirror-image isomers ), commonly denoted " l " (for "levo") and " d " (for "dextro"). The l isomer is the one most often encountered: it occurs naturally in many foods, and is one form (" vitamer ") of vitamin C , an essential nutrient for humans and many animals. Deficiency of vitamin C causes scurvy , formerly a major disease of sailors in long sea voyages. It
418-517: Is an enzyme that helps catalyze the production of ascorbic acid aka vitamin C. Mammals such as humans and guinea pigs do not express this gene due to multiple mutations in a specific exon. These mutations correlate to nucleotide substitution. Rats are a species that do express L-gulonolactone oxidase with a specific gene transcript. The protein coding region of the gene 645 base-pairs long, with eight exons and seven introns. The amino acid sequence of this protein has suggested that rat L-Gulonolactone oxidase
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#1733085052900456-487: Is described by OMIM (Online Mendelian Inheritance in Man) as "a public inborn error of metabolism", as it affects all humans. There exists a wide discrepancy between the amounts of ascorbic acid other primates consume and what are recommended as "reference intakes" for humans. In its patently pathological form, the effects of ascorbate deficiency are manifested as scurvy . It is likely that some level of adaptation occurred after
494-460: Is located in the membrane portion of the endoplasmic reticulum due to its multiple B-sheet structure which contains hydrophobic areas. It has been determined that rat GULO has a prosthetic domain in the N-terminus, flavian adenine dinucleotide. The only substrates that can make this rat enzyme function are L-GalL and L-GulL. GULO belongs to a family of sugar-1,4-lactone oxidases, which also contains
532-413: Is much more acidic than would be expected if the compound contained only isolated hydroxyl groups. The ascorbate anion forms salts , such as sodium ascorbate , calcium ascorbate , and potassium ascorbate . Ascorbic acid can also react with organic acids as an alcohol forming esters such as ascorbyl palmitate and ascorbyl stearate . Nucleophilic attack of ascorbic acid on a proton results in
570-426: Is special because it can transfer a single electron, owing to the resonance-stabilized nature of its own radical ion , called semidehydroascorbate . The net reaction is: On exposure to oxygen , ascorbic acid will undergo further oxidative decomposition to various products including diketogulonic acid , xylonic acid , threonic acid and oxalic acid . Reactive oxygen species are damaging to animals and plants at
608-428: Is used as a food additive and a dietary supplement for its antioxidant properties. The " d " form can be made via chemical synthesis , but has no significant biological role. The antiscorbutic properties of certain foods were demonstrated in the 18th century by James Lind . In 1907, Axel Holst and Theodor Frølich discovered that the antiscorbutic factor was a water-soluble chemical substance, distinct from
646-454: Is used in the predominant process used by the ascorbic acid industry in China, which supplies 70% of the world's ascorbic acid. Researchers are exploring means for one-step fermentation. The traditional way to analyze the ascorbic acid content is by titration with an oxidizing agent , and several procedures have been developed. The popular iodometry approach uses iodine in the presence of
684-562: The EMBL-EBI Enzyme Portal). Before the development of the EC number system, enzymes were named in an arbitrary fashion, and names like old yellow enzyme and malic enzyme that give little or no clue as to what reaction was catalyzed were in common use. Most of these names have fallen into disuse, though a few, especially proteolyic enzymes with very low specificity, such as pepsin and papain , are still used, as rational classification on
722-592: The primate order occurred about 63 million years ago, at about the time it split into the suborders Haplorhini (which lost the enzyme activity) and Strepsirrhini (which retained it). The haplorhine ("simple-nosed") primates, which cannot make vitamin C enzymatically, include the tarsiers and the simians (apes, monkeys and humans). The strepsirrhine ("bent-nosed" or "wet-nosed") primates, which can still make vitamin C enzymatically, include lorises , galagos , pottos , and, to some extent, lemurs . L -Gulonolactone oxidase deficiency has been called " hypoascorbemia " and
760-533: The Enzyme Commission was dissolved at that time, though its name lives on in the term EC Number . The current sixth edition, published by the International Union of Biochemistry and Molecular Biology in 1992 as the last version published as a printed book, contains 3196 different enzymes. Supplements 1-4 were published 1993–1999. Subsequent supplements have been published electronically, at the website of
798-661: The Nomenclature Committee of the International Union of Biochemistry and Molecular Biology. In August 2018, the IUBMB modified the system by adding the top-level EC 7 category containing translocases. Ascorbic acid Ascorbic acid is an organic compound with formula C 6 H 8 O 6 , originally called hexuronic acid . It is a white solid, but impure samples can appear yellowish. It dissolves freely in water to give mildly acidic solutions. It
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#1733085052900836-584: The basis of specificity has been very difficult. By the 1950s the chaos was becoming intolerable, and after Hoffman-Ostenhof and Dixon and Webb had proposed somewhat similar schemes for classifying enzyme-catalyzed reactions, the International Congress of Biochemistry in Brussels set up the Commission on Enzymes under the chairmanship of Malcolm Dixon in 1955. The first version was published in 1961, and
874-607: The bleaching solution. Acid-catalyzed hydrolysis of this product performs the dual function of removing the two acetal groups and ring-closing lactonization . This step yields ascorbic acid. Each of the five steps has a yield larger than 90%. A biotechnological process, first developed in China in the 1960s but further developed in the 1990s, bypassing acetone-protecting groups. A second genetically modified microbe species, such as mutant Erwinia , among others, oxidises sorbose into 2-ketogluconic acid (2-KGA), which can then undergo ring-closing lactonization via dehydration. This method
912-739: The integrity of their vasculature is compromised. GULO mice have been used as a human model in multiple subsequent studies. There have been successful attempts to activate lost enzymatic function in different animal species. Various GULO mutants were also identified. In plants, the importance of vitamin C in regulating whole plant morphology, cell structure, and plant development has been clearly established via characterization of low vitamin C mutants of Arabidopsis thaliana , potato, tobacco, tomato, and rice. Elevating vitamin C content by overexpressing inositol oxygenase and gulono-1,4-lactone oxidase in A. thaliana leads to enhanced biomass and tolerance to abiotic stresses. L-gulonolactone oxidase (GULO)
950-492: The loss in the haplorrhine suborder of primates, which includes humans. The remnant of this non-functional gene with many mutations is still present in the genomes of guinea pigs and humans. It is unknown if remains of the gene exist in the bats who lack GULO activity. The function of GULO appears to have been lost several times, and possibly re-acquired, in several lines of passerine birds, where ability to make vitamin C varies from species to species. Loss of GULO activity in
988-432: The loss of endogenous ascorbate production, apo(a) and Lp(a) were greatly favored by evolution, acting as ascorbate surrogate, since the frequency of occurrence of elevated Lp(a) plasma levels in species that had lost the ability to synthesize ascorbate is great. Also, only primates share regulation of CAMP gene expression by vitamin D , which occurred after the loss of GULO gene. Johnson et al. have hypothesized that
1026-525: The loss of the GULO gene by primates. Erythrocyte Glut1 and associated dehydroascorbic acid uptake modulated by stomatin switch are unique traits of humans and the few other mammals that have lost the ability to synthesize ascorbic acid from glucose . As GLUT transporters and stomatin are ubiquitously distributed in different human cell types and tissues, similar interactions may occur in human cells other than erythrocytes. Linus Pauling observed that after
1064-489: The molecular level due to their possible interaction with nucleic acids , proteins, and lipids. Sometimes these radicals initiate chain reactions. Ascorbate can terminate these chain radical reactions by electron transfer . The oxidized forms of ascorbate are relatively unreactive and do not cause cellular damage. However, being a good electron donor, excess ascorbate in the presence of free metal ions can not only promote but also initiate free radical reactions, thus making it
1102-447: The mutation of the GULOP pseudogene so that it stopped producing GULO may have been of benefit to early primates by increasing uric acid levels and enhancing fructose effects on weight gain and fat accumulation. With a shortage of food supplies this gave mutants a survival advantage. Studies of human diseases have benefited from the availability of small laboratory animal models. However,
1140-451: The one that prevented beriberi . Between 1928 and 1932, Albert Szent-Györgyi isolated a candidate for this substance, which he called it "hexuronic acid", first from plants and later from animal adrenal glands. In 1932 Charles Glen King confirmed that it was indeed the antiscorbutic factor. In 1933, sugar chemist Walter Norman Haworth , working with samples of "hexuronic acid" that Szent-Györgyi had isolated from paprika and sent him in
1178-464: The precursor to ascorbic acid , which spontaneously converts to the vitamin itself. The loss of activity of the gene encoding L -gulonolactone oxidase (GULO) has occurred separately in the history of several species. GULO activity has been lost in some species of bats, but others retain it. The loss of this enzyme activity is responsible for the inability of guinea pigs to enzymatically synthesize vitamin C. Both these events happened independently of
L-gulonolactone oxidase - Misplaced Pages Continue
1216-595: The previous year, deduced the correct structure and optical-isomeric nature of the compound, and in 1934 reported its first synthesis. In reference to the compound's antiscorbutic properties, Haworth and Szent-Györgyi proposed to rename it "a-scorbic acid" for the compound, and later specifically l -ascorbic acid. Because of their work, in 1937 two Nobel Prizes : in Chemistry and in Physiology or Medicine were awarded to Haworth and Szent-Györgyi, respectively. Ascorbic acid
1254-469: The product with acetone in the presence of an acid catalyst converts four of the remaining hydroxyl groups to acetals . The unprotected hydroxyl group is oxidized to the carboxylic acid by reaction with the catalytic oxidant TEMPO (regenerated by sodium hypochlorite – bleaching solution). Historically, industrial preparation via the Reichstein process used potassium permanganate as
1292-416: The reaction of ascorbic acid with iodate and iodide in acid solution. Electrolyzing the potassium iodide solution produces iodine, which reacts with ascorbic acid. The end of the process is determined by potentiometric titration like Karl Fischer titration . The amount of ascorbic acid can be calculated by Faraday's law . Another alternative uses N -bromosuccinimide (NBS) as the oxidizing agent in
1330-470: The same EC number. Furthermore, through convergent evolution , completely different protein folds can catalyze an identical reaction (these are sometimes called non-homologous isofunctional enzymes ) and therefore would be assigned the same EC number. By contrast, UniProt identifiers uniquely specify a protein by its amino acid sequence. Every enzyme code consists of the letters "EC" followed by four numbers separated by periods. Those numbers represent
1368-568: The tissues of animal models with a GULO gene generally have high levels of ascorbic acid and so are often only slightly influenced by exogenous vitamin C. This is a major handicap for studies involving the endogenous redox systems of primates and other animals that lack this gene. Guinea pigs are a popular human model. They lost the ability to make GULO 20 million years ago. In 1999, Maeda et al. genetically engineered mice with inactivated GULO gene. The mutant mice, like humans, entirely depend on dietary vitamin C, and they show changes indicating that
1406-481: The world's supply of ascorbic acid is produced in China. Ascorbic acid is prepared in industry from glucose in a method based on the historical Reichstein process . In the first of a five-step process, glucose is catalytically hydrogenated to sorbitol , which is then oxidized by the microorganism Acetobacter suboxydans to sorbose . Only one of the six hydroxy groups is oxidized by this enzymatic reaction. From this point, two routes are available. Treatment of
1444-570: The yeast enzyme D -arabinono-1,4-lactone oxidase (ALO). ALO produces erythorbic acid when acting on its canonical substrate. This family is in turn a subfamily under more sugar-1,4-lactone oxidases, which also includes the bacterial L -gulono-1,4-lactone dehydrogenase and the plant galactonolactone dehydrogenase . All these aldonolactone oxidoreductases play a role in some form of vitamin C synthesis, and some (including GULO and ALO) accept substrates of other members. Enzyme Commission number The Enzyme Commission number ( EC number )
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