[{"@context":"http:\/\/schema.org\/","@type":"BlogPosting","@id":"https:\/\/wiki.edu.vn\/en\/wiki24\/l-gulonolactone-oxidase-wikipedia\/#BlogPosting","mainEntityOfPage":"https:\/\/wiki.edu.vn\/en\/wiki24\/l-gulonolactone-oxidase-wikipedia\/","headline":"L-gulonolactone oxidase &#8211; Wikipedia","name":"L-gulonolactone oxidase &#8211; Wikipedia","description":"before-content-x4 Enzyme involved in the synthesis of vitamin C after-content-x4 L-Gulonolactone oxidase (EC 1.1.3.8) is an enzyme that produces vitamin","datePublished":"2017-07-22","dateModified":"2017-07-22","author":{"@type":"Person","@id":"https:\/\/wiki.edu.vn\/en\/wiki24\/author\/lordneo\/#Person","name":"lordneo","url":"https:\/\/wiki.edu.vn\/en\/wiki24\/author\/lordneo\/","image":{"@type":"ImageObject","@id":"https:\/\/secure.gravatar.com\/avatar\/c9645c498c9701c88b89b8537773dd7c?s=96&d=mm&r=g","url":"https:\/\/secure.gravatar.com\/avatar\/c9645c498c9701c88b89b8537773dd7c?s=96&d=mm&r=g","height":96,"width":96}},"publisher":{"@type":"Organization","name":"Enzyklop\u00e4die","logo":{"@type":"ImageObject","@id":"https:\/\/wiki.edu.vn\/wiki4\/wp-content\/uploads\/2023\/08\/download.jpg","url":"https:\/\/wiki.edu.vn\/wiki4\/wp-content\/uploads\/2023\/08\/download.jpg","width":600,"height":60}},"image":{"@type":"ImageObject","@id":"https:\/\/wiki.edu.vn\/wiki4\/wp-content\/uploads\/2023\/08\/download.jpg","url":"https:\/\/wiki.edu.vn\/wiki4\/wp-content\/uploads\/2023\/08\/download.jpg","width":100,"height":100},"url":"https:\/\/wiki.edu.vn\/en\/wiki24\/l-gulonolactone-oxidase-wikipedia\/","about":["Wiki"],"wordCount":8375,"articleBody":"     (adsbygoogle = window.adsbygoogle || []).push({});before-content-x4Enzyme involved in the synthesis of vitamin C       (adsbygoogle = window.adsbygoogle || []).push({});after-content-x4L-Gulonolactone oxidase (EC 1.1.3.8) is an enzyme that produces vitamin C, but is non-functional in Haplorrhini (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-\u03b3-lactone) and hydrogen peroxide. It uses FAD as a cofactor. The L-xylo-hex-3-gulonolactone then converts to ascorbic acid spontaneously, without enzymatic action.Table of Contents       (adsbygoogle = window.adsbygoogle || []).push({});after-content-x4Gulonolactone oxidase deficiency[edit]Consequences of loss[edit]Animal models[edit]Plant models[edit]Alternative substrates and related enzymes[edit]See also[edit]References[edit]Further reading[edit]Gulonolactone oxidase deficiency[edit]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).[4][5][6] GULO produces 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.[7] 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 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.[8] 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.[9]Loss of GULO activity in 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 (&#8220;simple-nosed&#8221;) primates, which cannot make vitamin C enzymatically, include the tarsiers and the simians (apes, monkeys and humans). The strepsirrhine (&#8220;bent-nosed&#8221; or &#8220;wet-nosed&#8221;) primates, which can still make vitamin C enzymatically, include lorises, galagos, pottos, and, to some extent, lemurs.[10]       (adsbygoogle = window.adsbygoogle || []).push({});after-content-x4L-Gulonolactone oxidase deficiency has been called &#8220;hypoascorbemia&#8221;[11] and is described by OMIM (Online Mendelian Inheritance in Man)[12] as &#8220;a public inborn error of metabolism&#8221;, as it affects all humans. There exists a wide discrepancy between the amounts of ascorbic acid other primates consume and what are recommended as &#8220;reference intakes&#8221; for humans.[13] In its patently pathological form, the effects of ascorbate deficiency are manifested as scurvy.Consequences of loss[edit]It is likely that some level of adaptation occurred after 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.[14] 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.[15]Linus Pauling observed that after 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.[16] Also, only primates share regulation of CAMP gene expression by vitamin D, which occurred after the loss of GULO gene.[17]Johnson et al. have hypothesized that 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.[18]Animal models[edit]Studies of human diseases have benefited from the availability of small laboratory animal models. However, 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.[8]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 the integrity of their vasculature is compromised.[19]GULO\u2013\/\u2013 mice have been used as a human model in multiple subsequent studies.[20]There have been successful attempts to activate lost enzymatic function in different animal species.[21][22][23][24]   Various GULO mutants were also identified.[25][26]Plant models[edit]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.[27][28]Alternative substrates and related enzymes[edit]GULO belongs to a family of sugar-1,4-lactone oxidases, which also contains 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.[29] 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.[30]See also[edit]References[edit]^ a b c GRCm38: Ensembl release 89: ENSMUSG00000034450 &#8211; Ensembl, May 2017^ &#8220;Human PubMed Reference:&#8221;. National Center for Biotechnology Information, U.S. National Library of Medicine.^ &#8220;Mouse PubMed Reference:&#8221;. National Center for Biotechnology Information, U.S. National Library of Medicine.^ GULOP Archived 2007-09-27 at the Wayback Machine \u2013 iHOP^ Nishikimi M, Koshizaka T, Ozawa T, Yagi K (December 1988). &#8220;Occurrence in humans and guinea pigs of the gene related to their missing enzyme L-gulono-gamma-lactone oxidase&#8221;. Archives of Biochemistry and Biophysics. 267 (2): 842\u20136. doi:10.1016\/0003-9861(88)90093-8. PMID\u00a03214183.^ Nishikimi M, Fukuyama R, Minoshima S, Shimizu N, Yagi K (May 1994). &#8220;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&#8221;. The Journal of Biological Chemistry. 269 (18): 13685\u20138. doi:10.1016\/S0021-9258(17)36884-9. PMID\u00a08175804.^ Cui J, Pan YH, Zhang Y, Jones G, Zhang S (February 2011). &#8220;Progressive pseudogenization: vitamin C synthesis and its loss in bats&#8221;. Molecular Biology and Evolution. 28 (2): 1025\u201331. doi:10.1093\/molbev\/msq286. PMID\u00a021037206.^ a b Nishikimi M, Kawai T, Yagi K (October 1992). &#8220;Guinea pigs possess a highly mutated gene for L-gulono-gamma-lactone oxidase, the key enzyme for L-ascorbic acid biosynthesis missing in this species&#8221;. The Journal of Biological Chemistry. 267 (30): 21967\u201372. doi:10.1016\/S0021-9258(19)36707-9. PMID\u00a01400507.^ Martinez del Rio C (1997). &#8220;Can Passerines Synthesize Vitamin C?&#8221; (PDF). The Auk. 114 (3): 513\u2013516. doi:10.2307\/4089257. JSTOR\u00a04089257.^ Pollock JI, Mullin RJ (May 1987). &#8220;Vitamin C biosynthesis in prosimians: evidence for the anthropoid affinity of Tarsius&#8221;. American Journal of Physical Anthropology. 73 (1): 65\u201370. doi:10.1002\/ajpa.1330730106. PMID\u00a03113259.^ HYPOASCORBEMIA \u2013 NCBI^ OMIM \u2013 Online Mendelian Inheritance in Man \u2013 NCBI^ Milton K (September 2003). &#8220;Micronutrient intakes of wild primates: are humans different?&#8221; (PDF). Comparative Biochemistry and Physiology. Part A, Molecular &#038; Integrative Physiology. 136 (1): 47\u201359. doi:10.1016\/S1095-6433(03)00084-9. PMID\u00a014527629.^ Montel-Hagen A, Kinet S, Manel N, Mongellaz C, Prohaska R, Battini JL, Delaunay J, Sitbon M, Taylor N (March 2008). &#8220;Erythrocyte Glut1 triggers dehydroascorbic acid uptake in mammals unable to synthesize vitamin C&#8221;. Cell. 132 (6): 1039\u201348. doi:10.1016\/j.cell.2008.01.042. PMID\u00a018358815.^ Mandl J, Szarka A, B\u00e1nhegyi G (August 2009). &#8220;Vitamin C: update on physiology and pharmacology&#8221;. British Journal of Pharmacology. 157 (7): 1097\u2013110. doi:10.1111\/j.1476-5381.2009.00282.x. PMC\u00a02743829. PMID\u00a019508394.^ Pauling L, Rath (1992). &#8220;A Unified Theory of Human Cardiovascular Disease&#8221; (PDF). Journal of Orthomolecular Medicine. 7 (1).^ Gombart AF (November 2009). &#8220;The vitamin D-antimicrobial peptide pathway and its role in protection against infection&#8221;. Future Microbiology. 4 (9): 1151\u201365. doi:10.2217\/fmb.09.87. PMC\u00a02821804. PMID\u00a019895218.^ Johnson RJ, Andrews P, Benner SA, Oliver W (2010). &#8220;Theodore E. Woodward award. The evolution of obesity: insights from the mid-Miocene&#8221;. Transactions of the American Clinical and Climatological Association. 121: 295\u2013305, discussion 305\u20138. PMC\u00a02917125. PMID\u00a020697570.^ Maeda N, Hagihara H, Nakata Y, Hiller S, Wilder J, Reddick R (January 2000). &#8220;Aortic wall damage in mice unable to synthesize ascorbic acid&#8221;. Proceedings of the National Academy of Sciences of the United States of America. 97 (2): 841\u20136. Bibcode:2000PNAS&#8230;97..841M. doi:10.1073\/pnas.97.2.841. PMC\u00a015418. PMID\u00a010639167.^ Li Y, Schellhorn HE (October 2007). &#8220;New developments and novel therapeutic perspectives for vitamin C&#8221;. The Journal of Nutrition. 137 (10): 2171\u201384. doi:10.1093\/jn\/137.10.2171. PMID\u00a017884994.^ Toyohara H, Nakata T, Touhata K, Hashimoto H, Kinoshita M, Sakaguchi M, Nishikimi M, Yagi K, Wakamatsu Y, Ozato K (June 1996). &#8220;Transgenic expression of L-gulono-gamma-lactone oxidase in medaka (Oryzias latipes), a teleost fish that lacks this enzyme necessary for L-ascorbic acid biosynthesis&#8221;. Biochemical and Biophysical Research Communications. 223 (3): 650\u20133. doi:10.1006\/bbrc.1996.0949. PMID\u00a08687450.^ Li Y, Shi CX, Mossman KL, Rosenfeld J, Boo YC, Schellhorn HE (December 2008). &#8220;Restoration of vitamin C synthesis in transgenic Gulo-\/- mice by helper-dependent adenovirus-based expression of gulonolactone oxidase&#8221;. Human Gene Therapy. 19 (12): 1349\u201358. doi:10.1089\/hgt.2008.106. PMID\u00a018764764.^ Ha MN, Graham FL, D&#8217;Souza CK, Muller WJ, Igdoura SA, Schellhorn HE (March 2004). &#8220;Functional rescue of vitamin C synthesis deficiency in human cells using adenoviral-based expression of murine l-gulono-gamma-lactone oxidase&#8221;. Genomics. 83 (3): 482\u201392. doi:10.1016\/j.ygeno.2003.08.018. PMID\u00a014962674.^ Yu, Rosemary. &#8220;DEVELOPMENT OF ROBUST ANIMAL MODELS FOR VITAMIN C FUNCTION&#8221;. Open Access Dissertations and Theses. McMaster University Library. Retrieved 8 February 2013.^ Hasan L, V\u00f6geli P, Stoll P, Kramer SS, Stranzinger G, Neuenschwander S (April 2004). &#8220;Intragenic deletion in the gene encoding L-gulonolactone oxidase causes vitamin C deficiency in pigs&#8221; (PDF). Mammalian Genome. 15 (4): 323\u201333. doi:10.1007\/s00335-003-2324-6. hdl:20.500.11850\/422871. PMID\u00a015112110. S2CID\u00a023479620.^ Mohan S, Kapoor A, Singgih A, Zhang Z, Taylor T, Yu H, Chadwick RB, Chung YS, Chung YS, Donahue LR, Rosen C, Crawford GC, Wergedal J, Baylink DJ (September 2005). &#8220;Spontaneous fractures in the mouse mutant sfx are caused by deletion of the gulonolactone oxidase gene, causing vitamin C deficiency&#8221;. Journal of Bone and Mineral Research. 20 (9): 1597\u2013610. doi:10.1359\/JBMR.050406. PMID\u00a016059632. S2CID\u00a028699531.^ Lisko KA, Torres R, Harris RS, Belisle M, Vaughan MM, Jullian B, Chevone BI, Mendes P, Nessler CL, Lorence A (December 2013). &#8220;Arabidopsis leads to enhanced biomass and tolerance to abiotic stresses&#8221;. In Vitro Cellular &#038; Developmental Biology. Plant. 49 (6): 643\u2013655. doi:10.1007\/s11627-013-9568-y. PMC\u00a04354779. PMID\u00a025767369.^ Radzio JA, Lorence A, Chevone BI, Nessler CL (December 2003). &#8220;L-Gulono-1,4-lactone oxidase expression rescues vitamin C-deficient Arabidopsis (vtc) mutants&#8221;. Plant Molecular Biology. 53 (6): 837\u201344. doi:10.1023\/B:PLAN.0000023671.99451.1d. PMID\u00a015082929. S2CID\u00a037821860.^ &#8220;L-gulonolactone\/D-arabinono-1,4-lactone oxidase (IPR010031)&#8221;. InterPro. Retrieved 3 February 2020.^ Aboobucker, SI; Lorence, A (January 2016). &#8220;Recent progress on the characterization of aldonolactone oxidoreductases&#8221;. Plant Physiology and Biochemistry. 98: 171\u201385. doi:10.1016\/j.plaphy.2015.11.017. PMC\u00a04725720. PMID\u00a026696130.Further reading[edit]Zhang ZD, Frankish A, Hunt T, Harrow J, Gerstein M (2010). &#8220;Identification and analysis of unitary pseudogenes: historic and contemporary gene losses in humans and other primates&#8221;. Genome Biology. 11 (3): R26. doi:10.1186\/gb-2010-11-3-r26. PMC\u00a02864566. PMID\u00a020210993.Inai Y, Ohta Y, Nishikimi M (October 2003). &#8220;The whole structure of the human nonfunctional L-gulono-gamma-lactone oxidase gene&#8211;the gene responsible for scurvy&#8211;and the evolution of repetitive sequences thereon&#8221;. Journal of Nutritional Science and Vitaminology. 49 (5): 315\u20139. doi:10.3177\/jnsv.49.315. PMID\u00a014703305.Otowa T, Yoshida E, Sugaya N, Yasuda S, Nishimura Y, Inoue K, Tochigi M, Umekage T, Miyagawa T, Nishida N, Tokunaga K, Tanii H, Sasaki T, Kaiya H, Okazaki Y (February 2009). &#8220;Genome-wide association study of panic disorder in the Japanese population&#8221;. Journal of Human Genetics. 54 (2): 122\u20136. doi:10.1038\/jhg.2008.17. PMID\u00a019165232.De Tullio M (2010). &#8220;The Mystery of Vitamin C&#8221;. Nature Education. 9. 3 (48). Retrieved 5 November 2012.     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