If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Synonyms: vitamin C biosynthesis, L-ascorbic acid biosynthesis IV
|Superclasses:||Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → Vitamins Biosynthesis → Ascorbate Biosynthesis|
Expected Taxonomic Range:
Vitamin C (L-ascorbate), a reducing agent and antioxidant, is a cofactor in reactions catalyzed by copper-dependent monooxygenases and iron-dependent dioxygenases. It is synthesized, in vertebrates having this capacity, from D-glucuronate. This compound is formed through direct hydrolysis of UDP-α-D-glucuronate by enzyme(s) bound to the endoplasmic reticulum membrane. They share many properties with, and are most likely identical to, UDP-glucuronosyltransferases [Linster07].
L-ascorbate can be biosynthesized by plants (see L-ascorbate biosynthesis I (L-galactose pathway)), some bacteria (see L-ascorbate biosynthesis III) and many vertebrates. It is used in the pharmaceutical industry for the production of vitamin supplements, cosmetics and therapeutic preparations. It is also used in the food, beverage and animal feed industries.
L-ascorbate is an essential vitamin in the diet of humans, non-human primates and certain other vertebrates that cannot biosynthesize it (some fish and birds, bats and guinea pigs). These species rely on mechanisms for efficient uptake and recycling of this vitamin (see pathway ascorbate recycling (cytosolic)). It is taken up in the intestine, transported in plasma and delivered to tissues. Its recycling in erythrocytes has been described (reviewed in [May98]). It has roles in collagen biosynthesis, as an antioxidant, as a cofactor in reactions catalyzed by some metal-dependent mono- and dioxygenases, and may be involved in cell signaling reactions and transcription factor activation. A deficiency of vitamin C leads to the disorder scurvy (reviewed in [Bremus06, Linster07]). Yeasts are known to biosynthesize D-erythroascorbate, a 5-carbon analog of ascorbate. It functions as an antioxidant, but it lacks antiscorbutic activity (prevention of scurvy) (reviewed in [Bremus06]).
The mammalian liver pathway for L-ascorbate biosynthesis is shown here. D-glucuronate is formed from hydrolysis of UDP-α-D-glucuronate by a membrane-bound enzyme(s) of the endoplasmic reticulum, probably UDP-glucuronidase(s) (reviewed in [Linster07]. The ultimate precursor of UDP-α-D-glucuronate is D-glucose (see pathway UDP-D-xylose biosynthesis). D-glucuronate is reduced to L-gulonate by a NADP+-dependent aldehyde reductase. A broad specificity lactonase then forms L-gulono-1,4-lactone. The L-gulono-1,4-lactone is oxidized to L-ascorbate by L-gulonolactone oxidase via an intermediate lactone which spontaneously isomerizes to L-ascorbate. The production of hydrogen peroxide by this endoplasmic reticulum enzyme is unusual and transfer of electrons to another acceptor might occur in intact cells, as has been shown for plant homologues of this enzyme. L-Gulonolactone oxidase is deficient in humans and other animals unable to biosynthesize L-ascorbate due to mutations in the gene encoding it [Nishikimi94]. Reviewed in [Linster07, May98]).
Variants: L-ascorbate biosynthesis I (L-galactose pathway) , L-ascorbate biosynthesis II (L-gulose pathway) , L-ascorbate biosynthesis III , L-ascorbate biosynthesis V , L-ascorbate biosynthesis VI (engineered pathway)
Nishikimi94: Nishikimi M, Fukuyama R, Minoshima S, Shimizu N, Yagi K (1994). "Cloning and chromosomal mapping of the human nonfunctional gene for L-gulono-gamma-lactone oxidase, the enzyme for L-ascorbic acid biosynthesis missing in man." J Biol Chem 269(18);13685-8. PMID: 8175804
Accorsi89: Accorsi A, Piatti E, Piacentini MP, Gini S, Fazi A (1989). "Isoenzymes of phosphoglucomutase from human red blood cells: isolation and kinetic properties." Prep Biochem 19(3);251-71. PMID: 2533352
Arrecubieta94: Arrecubieta C, Lopez R, Garcia E (1994). "Molecular characterization of cap3A, a gene from the operon required for the synthesis of the capsule of Streptococcus pneumoniae type 3: sequencing of mutations responsible for the unencapsulated phenotype and localization of the capsular cluster on the pneumococcal chromosome." J Bacteriol 176(20);6375-83. PMID: 7929009
Bindschedler05: Bindschedler LV, Wheatley E, Gay E, Cole J, Cottage A, Bolwell GP (2005). "Characterisation and expression of the pathway from UDP-glucose to UDP-xylose in differentiating tobacco tissue." Plant Mol Biol 57(2);285-301. PMID: 15821883
Csutora05: Csutora P, Strassz A, Boldizsar F, Nemeth P, Sipos K, Aiello DP, Bedwell DM, Miseta A (2005). "Inhibition of phosphoglucomutase activity by lithium alters cellular calcium homeostasis and signaling in Saccharomyces cerevisiae." Am J Physiol Cell Physiol 289(1);C58-67. PMID: 15703203
Dai06: Dai N, Petreikov M, Portnoy V, Katzir N, Pharr DM, Schaffer AA (2006). "Cloning and expression analysis of a UDP-galactose/glucose pyrophosphorylase from melon fruit provides evidence for the major metabolic pathway of galactose metabolism in raffinose oligosaccharide metabolizing plants." Plant Physiol 142(1);294-304. PMID: 16829585
Daran95: Daran JM, Dallies N, Thines-Sempoux D, Paquet V, Francois J (1995). "Genetic and biochemical characterization of the UGP1 gene encoding the UDP-glucose pyrophosphorylase from Saccharomyces cerevisiae." Eur J Biochem 233(2);520-30. PMID: 7588797
Duggleby96: Duggleby RG, Chao YC, Huang JG, Peng HL, Chang HY (1996). "Sequence differences between human muscle and liver cDNAs for UDPglucose pyrophosphorylase and kinetic properties of the recombinant enzymes expressed in Escherichia coli." Eur J Biochem 235(1-2);173-9. PMID: 8631325
ElKabbani94: El-Kabbani O, Green NC, Lin G, Carson M, Narayana SV, Moore KM, Flynn TG, DeLucas LJ (1994). "Structures of human and porcine aldehyde reductase: an enzyme implicated in diabetic complications." Acta Crystallogr D Biol Crystallogr 50(Pt 6);859-68. PMID: 15299353
Fu95: Fu L, Bounelis P, Dey N, Browne BL, Marchase RB, Bedwell DM (1995). "The posttranslational modification of phosphoglucomutase is regulated by galactose induction and glucose repression in Saccharomyces cerevisiae." J Bacteriol 177(11);3087-94. PMID: 7768805
Garcia93: Garcia E, Garcia P, Lopez R (1993). "Cloning and sequencing of a gene involved in the synthesis of the capsular polysaccharide of Streptococcus pneumoniae type 3." Mol Gen Genet 239(1-2);188-95. PMID: 8510646
Graille06: Graille M, Baltaze JP, Leulliot N, Liger D, Quevillon-Cheruel S, van Tilbeurgh H (2006). "Structure-based functional annotation: yeast ymr099c codes for a D-hexose-6-phosphate mutarotase." J Biol Chem 281(40);30175-85. PMID: 16857670
Grangeasse03: Grangeasse C, Obadia B, Mijakovic I, Deutscher J, Cozzone AJ, Doublet P (2003). "Autophosphorylation of the Escherichia coli protein kinase Wzc regulates tyrosine phosphorylation of Ugd, a UDP-glucose dehydrogenase." J Biol Chem 278(41);39323-9. PMID: 12851388
Ha04: Ha MN, Graham FL, D'Souza CK, Muller WJ, Igdoura SA, Schellhorn HE (2004). "Functional rescue of vitamin C synthesis deficiency in human cells using adenoviral-based expression of murine l-gulono-gamma-lactone oxidase." Genomics 83(3);482-92. PMID: 14962674
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