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MetaCyc Pathway: L-ascorbate biosynthesis IV
Traceable author statement to experimental support

Enzyme View:

Pathway diagram: L-ascorbate biosynthesis IV

This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. 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: BiosynthesisCofactors, Prosthetic Groups, Electron Carriers BiosynthesisVitamins BiosynthesisAscorbate Biosynthesis

Some taxa known to possess this pathway include : Bos taurus, Capra hircus, Mesocricetus auratus, Mus musculus, Rattus norvegicus, Sus scrofa

Expected Taxonomic Range: Vertebrata

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)

Created 14-May-2007 by Evsikov A, The Jackson Laboratory
Revised 24-Sep-2008 by Fulcher CA, SRI International


Bremus06: Bremus C, Herrmann U, Bringer-Meyer S, Sahm H (2006). "The use of microorganisms in L-ascorbic acid production." J Biotechnol 124(1);196-205. PMID: 16516325

Linster07: Linster CL, Van Schaftingen E (2007). "Vitamin C. Biosynthesis, recycling and degradation in mammals." FEBS J 274(1);1-22. PMID: 17222174

May98: May JM (1998). "Ascorbate function and metabolism in the human erythrocyte." Front Biosci 3;d1-10. PMID: 9405334

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

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Allan00: Allan D, Lohnes D (2000). "Cloning and developmental expression of mouse aldehyde reductase (AKR1A4)." Mech Dev 94(1-2);271-5. PMID: 10842086

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

elKabbani95: el-Kabbani O, Judge K, Ginell SL, Myles DA, DeLucas LJ, Flynn TG (1995). "Structure of porcine aldehyde reductase holoenzyme." Nat Struct Biol 2(8);687-92. PMID: 7552731

Green05: Green MA, Fry SC (2005). "Vitamin C degradation in plant cells via enzymatic hydrolysis of 4-O-oxalyl-L-threonate." Nature 433(7021);83-7. PMID: 15608627

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

IsherwoodD60: IsherwoodD FA, MapsonLW, Chen YT (1960). "Synthesis of L-ascorbic acid in rat-liver homogenates. Conversion of L-gulono- and L-galactono-gamma-lactone and the respective acids into L-ascorbic acid." Biochem J 76;157-71. PMID: 14405898

Kaufman81: Kaufman EE, Nelson T (1981). "Kinetics of coupled gamma-hydroxybutyrate oxidation and D-glucuronate reduction by an NADP+-dependent oxidoreductase." J Biol Chem 256(13);6890-4. PMID: 7240249

Kiuchi82: Kiuchi K, Nishikimi M, Yagi K (1982). "Purification and characterization of L-gulonolactone oxidase from chicken kidney microsomes." Biochemistry 21(20);5076-82. PMID: 7138847

Kondo06: Kondo Y, Inai Y, Sato Y, Handa S, Kubo S, Shimokado K, Goto S, Nishikimi M, Maruyama N, Ishigami A (2006). "Senescence marker protein 30 functions as gluconolactonase in L-ascorbic acid biosynthesis, and its knockout mice are prone to scurvy." Proc Natl Acad Sci U S A 103(15);5723-8. PMID: 16585534

Koshizaka88: Koshizaka T, Nishikimi M, Ozawa T, Yagi K (1988). "Isolation and sequence analysis of a complementary DNA encoding rat liver L-gulono-gamma-lactone oxidase, a key enzyme for L-ascorbic acid biosynthesis." J Biol Chem 263(4);1619-21. PMID: 3338984

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Linster06: Linster CL, Van Schaftingen E (2006). "Glucuronate, the precursor of vitamin C, is directly formed from UDP-glucuronate in liver." FEBS J 273(7);1516-27. PMID: 16689937

Nishikimi79: Nishikimi M (1979). "L-Gulono-gamma-lactone oxidase (rat and goat liver)." Methods Enzymol 62;24-30. PMID: 440104

Simpson00: Simpson GL, Ortwerth BJ (2000). "The non-oxidative degradation of ascorbic acid at physiological conditions." Biochim Biophys Acta 1501(1);12-24. PMID: 10727845

Son06: Son TG, Zou Y, Jung KJ, Yu BP, Ishigami A, Maruyama N, Lee J (2006). "SMP30 deficiency causes increased oxidative stress in brain." Mech Ageing Dev 127(5);451-7. PMID: 16500693

Tulsiani77: Tulsiani DR, Touster (1977). "Resolution and partial characterization of two aldehyde reductases of mammalian liver." J Biol Chem 252(8);2545-50. PMID: 15991

Yagi97: Yagi K, Nishikimi M (1997). "Expression of recombinant L-gulono-gamma-lactone oxidase." Methods Enzymol 279;24-9. PMID: 9211253

Yamaguchi05: Yamaguchi M (2005). "Role of regucalcin in maintaining cell homeostasis and function (review)." Int J Mol Med 15(3);371-89. PMID: 15702226

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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