|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
L-gulonolactone oxidase (EC 22.214.171.124) 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 L-xylo-hex-3-gulonolactone and hydrogen peroxide. It uses FAD as a cofactor. The L-xylo-hex-3-gulonolactone (2-keto-gulono-gamma-lactone) is able to convert to hexuronic acid (ascorbic acid) spontaneously, without enzymatic action.
Gulonolactone oxidase deficiency
The non-functional gulonolactone oxidase pseudogene (GULOP) was mapped to human chromosome 8p21 that corresponds to an evolutionarily conserved segment on either porcine chromosome 4 (SSC4) or 14 (SSC14). GULO produces the precursor to ascorbic acid, which spontaneously converts to the vitamin ("vitamin C").
The loss of activity of the gene for 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 the loss in the haplorrhini suborder of primates, including humans.
The remains of this non-functional gene with many mutations is, however, 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 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 haplorhines ("simple nosed") primates, which cannot make vitamin C enzymatically, include the tarsiers and the simians (apes, monkeys and humans). The strepsirrhines (bent or wet-nosed) primates, which are still able to make vitamin C enzymatically, include lorises, galagos, pottos, and, to some extent, lemurs.
L-gulonolactone oxidase deficiency is called "hypoascorbemia" and 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 is recommended as "reference intakes" for humans. In its patently pathological form, the effects of ascorbate deficiency are manifested as scurvy.
Consequences of loss
It looks 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. As GLUT transporters and stomatin are ubiquitously distributed in different human cell types and tissues, similar interactions can be hypothesized to occur in human cells other than erythrocytes.
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. 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 the mutation of the GULOP (pseudogene that produces L-gulonolactone oxidase) 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 survival advantage.
Grano and De Tullio proposed that organisms that have lost vitamin C biosynthesis have an advantage in that they can finely regulate HIF1α activation on the basis of the dietary intake of vitamin C: with sufficient supply of vitamin C, the HIF transcription factor is less active than in conditions of vitamin C deficiency; the lack of vitamin C biosynthesis may allow our bodies to know more about our nutritional status and consequently set the proper baseline of HIF1α expression acting like a sensitive titration system.
Calabrese proposed that "the loss of an ability to synthesize ascorbic acid in humans...may have been a critical preadaptation which markedly enhanced the survival of early man with a G6PD deficiency living in a malarial infested environment". He based his observation on evidence which indicates that G6PD deficient individuals display enhanced sensitivity to ascorbic acid induced hemolysis.
Studies of the human diseases have benefited from the availability of small laboratory animal models. There is, however, a major handicap for studies involving the endogenous redox systems of primates and other animals – because of the loss of the GULO gene, as a consequence, tissues of other animals generally have high levels of ascorbic acid, which are often only slightly influenced by exogenous vitamin C.
Guinea pigs who also have lost this enzyme function 20 million years ago and depend on dietary vitamin C are often used as a human model.
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. GULO-/- mice was used as a human model in multiple subsequent studies.
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, potato, tobacco, tomato, and rice. Elevating vitamin C content by overexpressing inositol oxygenase and gulono-1,4-lactone oxidase in Arabidopsis leads to enhanced biomass and tolerance to abiotic stresses.
- GULOP – iHOP
- Nishikimi M, Koshizaka T, Ozawa T, Yagi K (December 1988). "Occurrence in humans and guinea pigs of the gene related to their missing enzyme L-gulono-gamma-lactone oxidase". Arch. Biochem. Biophys. 267 (2): 842–6. doi:10.1016/0003-9861(88)90093-8. PMID 3214183.
- Nishikimi M, Fukuyama R, Minoshima S, Shimizu N, Yagi K (May 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.
- Cui J, Pan YH, Zhang Y, Jones G, Zhang S (February 2011). "Progressive pseudogenization: vitamin C synthesis and its loss in bats". Mol. Biol. Evol. 28 (2): 1025–31. doi:10.1093/molbev/msq286. PMID 21037206.
- Nishikimi M, Kawai T, Yagi K (October 1992). "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". J. Biol. Chem. 267 (30): 21967–72. PMID 1400507.
- Martinez del Rio C (1997). "Can Passerines Synthesize Vitamin C?" (PDF). The Auk 114 (3): 513–516. doi:10.2307/4089257.
- Pollock JI, Mullin RJ (May 1987). "Vitamin C biosynthesis in prosimians: evidence for the anthropoid affinity of Tarsius". Am. J. Phys. Anthropol. 73 (1): 65–70. doi:10.1002/ajpa.1330730106. PMID 3113259.
- HYPOASCORBEMIA – NCBI
- OMIM – Online Mendelian Inheritance in Man – NCBI
- Milton K (September 2003). "Micronutrient intakes of wild primates: are humans different?" (PDF). Comp. Biochem. Physiol., Part A Mol. Integr. Physiol. 136 (1): 47–59. doi:10.1016/S1095-6433(03)00084-9. PMID 14527629.
- Montel-Hagen A, Kinet S, Manel N, Mongellaz C, Prohaska R, Battini JL, Delaunay J, Sitbon M, Taylor N (March 2008). "Erythrocyte Glut1 triggers dehydroascorbic acid uptake in mammals unable to synthesize vitamin C". Cell 132 (6): 1039–48. doi:10.1016/j.cell.2008.01.042. PMID 18358815.
- Mandl J, Szarka A, Bánhegyi G (August 2009). "Vitamin C: update on physiology and pharmacology". Br. J. Pharmacol. 157 (7): 1097–1110. doi:10.1111/j.1476-5381.2009.00282.x. PMC 2743829. PMID 19508394.
- Pauling L, Rath (1992). "A Unified Theory of Human Cardiovascular Disease" (PDF). Journal of Orthomolecular Medicine 7 (1).
- Gombart AF (November 2009). "The vitamin D-antimicrobial peptide pathway and its role in protection against infection". Future Microbiol 4 (9): 1151–65. doi:10.2217/fmb.09.87. PMC 2821804. PMID 19895218.
- Johnson RJ, Andrews P, Benner SA, Oliver W (2010). "Theodore E. Woodward award. The evolution of obesity: insights from the mid-Miocene". Trans. Am. Clin. Climatol. Assoc. 121: 295–305; discussion 305–8. PMC 2917125. PMID 20697570.
- Grano A, De Tullio MC (2007). "Ascorbic acid as a sensor of oxidative stress and a regulator of gene expression: the Yin and Yang of vitamin C". Med. Hypotheses 69 (4): 953–4. doi:10.1016/j.mehy.2007.02.008. PMID 17376607.
- Calabrese EJ (February 1982). "Evolutionary loss of ascorbic acid synthesis: how it may have enhanced the survival interests of man". Med. Hypotheses 8 (2): 173–5. doi:10.1016/0306-9877(82)90100-1. PMID 7087819.
- Maeda N, Hagihara H, Nakata Y, Hiller S, Wilder J, Reddick R (January 2000). "Aortic wall damage in mice unable to synthesize ascorbic acid". Proc. Natl. Acad. Sci. U.S.A. 97 (2): 841–6. doi:10.1073/pnas.97.2.841. PMC 15418. PMID 10639167.
- Li Y, Schellhorn HE (October 2007). "New developments and novel therapeutic perspectives for vitamin C". J. Nutr. 137 (10): 2171–84. PMID 17884994.
- Toyohara H, Nakata T, Touhata K, Hashimoto H, Kinoshita M, Sakaguchi M, Nishikimi M, Yagi K, Wakamatsu Y, Ozato K (June 1996). "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". Biochem. Biophys. Res. Commun. 223 (3): 650–3. doi:10.1006/bbrc.1996.0949. PMID 8687450.
- Li Y, Shi CX, Mossman KL, Rosenfeld J, Boo YC, Schellhorn HE (December 2008). "Restoration of vitamin C synthesis in transgenic Gulo-/- mice by helper-dependent adenovirus-based expression of gulonolactone oxidase". Hum. Gene Ther. 19 (12): 1349–58. doi:10.1089/hgt.2008.106. PMID 18764764.
- Ha MN, Graham FL, D'Souza CK, Muller WJ, Igdoura SA, Schellhorn HE (March 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. doi:10.1016/j.ygeno.2003.08.018. PMID 14962674.
- Yu, Rosemary. "DEVELOPMENT OF ROBUST ANIMAL MODELS FOR VITAMIN C FUNCTION". Open Access Dissertations and Theses. McMaster University Library. Retrieved 8 February 2013.
- Hasan L, Vögeli P, Stoll P, Kramer SS, Stranzinger G, Neuenschwander S (April 2004). "Intragenic deletion in the gene encoding L-gulonolactone oxidase causes vitamin C deficiency in pigs". Mamm. Genome 15 (4): 323–33. doi:10.1007/s00335-003-2324-6. PMID 15112110.
- 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). "Spontaneous fractures in the mouse mutant sfx are caused by deletion of the gulonolactone oxidase gene, causing vitamin C deficiency". J. Bone Miner. Res. 20 (9): 1597–610. doi:10.1359/JBMR.050406. PMID 16059632.
- Lisko, Katherine; Raquel Torres; Rodney S. Harris; Melinda Belisle; Martha M. Vaughan; Berangère Jullian; Boris I. Chevone; Pedro Mendes; Craig L. Nessler; Argelia Lorence (2013). "Elevating vitamin C content overexpression of-inositol oxygenase and-gulono-1, 4-lactone oxidase in leads to enhanced biomass and tolerance to abiotic stresses". In Vitro Cellular & Developmental Biology - Plant 49 (6): 643–655. doi:10.1007/s11627-013-9568-y. Retrieved 30 May 2014.
- Radzio, JA; Lorence, A; Chevone, BI; Nessler, CL (Dec 2003). "L-Gulono-1,4-lactone oxidase expression rescues vitamin C-deficient Arabidopsis (vtc) mutants.". Plant molecular biology 53 (6): 837–44. doi:10.1023/B:PLAN.0000023671.99451.1d. PMID 15082929.
- Zhang ZD, Frankish A, Hunt T, Harrow J, Gerstein M (2010). "Identification and analysis of unitary pseudogenes: historic and contemporary gene losses in humans and other primates". Genome Biol. 11 (3): R26. doi:10.1186/gb-2010-11-3-r26. PMC 2864566. PMID 20210993.
- Inai Y, Ohta Y, Nishikimi M (October 2003). "The whole structure of the human nonfunctional L-gulono-gamma-lactone oxidase gene—the gene responsible for scurvy—and the evolution of repetitive sequences thereon". J. Nutr. Sci. Vitaminol. 49 (5): 315–9. doi:10.3177/jnsv.49.315. PMID 14703305.
- 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). "Genome-wide association study of panic disorder in the Japanese population". J. Hum. Genet. 54 (2): 122–6. doi:10.1038/jhg.2008.17. PMID 19165232.
- De Tullio M (2010). "The Mystery of Vitamin C". Nature Education. 9 3 (48). Retrieved 5 November 2012.