Biology:L-gulonolactone oxidase

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Short description: Enzyme involved in the synthesis of vitamin C


L-gulonolactone oxidase
Identifiers
EC number1.1.3.8
CAS number9028-78-8
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO

L-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-γ-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.

Gulonolactone oxidase deficiency

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).[1][2][3] 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.[4] 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.[5] 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.[6]

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 ("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.[7]

L-Gulonolactone oxidase deficiency has been called "hypoascorbemia"[8] and is described by OMIM (Online Mendelian Inheritance in Man)[9] 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.[10] In its patently pathological form, the effects of ascorbate deficiency are manifested as scurvy.

Consequences of loss

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.[11] 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.[12]

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.[13] Also, only primates share regulation of CAMP gene expression by vitamin D, which occurred after the loss of GULO gene.[14]

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.[15]

Animal models

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.[5]

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.[16] GULO–/– mice have been used as a human model in multiple subsequent studies.[17]

There have been successful attempts to activate lost enzymatic function in different animal species.[18][19][20][21] Various GULO mutants were also identified.[22][23]

Plant models

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.[24][25]

Alternative substrates and related enzymes

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.[26] 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.[27]

See also

References

  1. ↑ GULOP – iHOP
  2. ↑ "Occurrence in humans and guinea pigs of the gene related to their missing enzyme L-gulono-gamma-lactone oxidase". Archives of Biochemistry and Biophysics 267 (2): 842–6. December 1988. doi:10.1016/0003-9861(88)90093-8. PMID 3214183. 
  3. ↑ "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". The Journal of Biological Chemistry 269 (18): 13685–8. May 1994. doi:10.1016/S0021-9258(17)36884-9. PMID 8175804. 
  4. ↑ "Progressive pseudogenization: vitamin C synthesis and its loss in bats". Molecular Biology and Evolution 28 (2): 1025–31. February 2011. doi:10.1093/molbev/msq286. PMID 21037206. 
  5. ↑ 5.0 5.1 "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". The Journal of Biological Chemistry 267 (30): 21967–72. October 1992. doi:10.1016/S0021-9258(19)36707-9. PMID 1400507. 
  6. ↑ "Can Passerines Synthesize Vitamin C?". The Auk 114 (3): 513–516. 1997. doi:10.2307/4089257. http://sora.unm.edu/sites/default/files/journals/auk/v114n03/p0513-p0516.pdf. 
  7. ↑ "Vitamin C biosynthesis in prosimians: evidence for the anthropoid affinity of Tarsius". American Journal of Physical Anthropology 73 (1): 65–70. May 1987. doi:10.1002/ajpa.1330730106. PMID 3113259. 
  8. ↑ HYPOASCORBEMIA – NCBI
  9. ↑ OMIM – Online Mendelian Inheritance in Man – NCBI
  10. ↑ "Micronutrient intakes of wild primates: are humans different?". Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology 136 (1): 47–59. September 2003. doi:10.1016/S1095-6433(03)00084-9. PMID 14527629. http://nature.berkeley.edu/miltonlab/pdfs/kmilton_micronutrient.pdf. 
  11. ↑ "Erythrocyte Glut1 triggers dehydroascorbic acid uptake in mammals unable to synthesize vitamin C". Cell 132 (6): 1039–48. March 2008. doi:10.1016/j.cell.2008.01.042. PMID 18358815. 
  12. ↑ "Vitamin C: update on physiology and pharmacology". British Journal of Pharmacology 157 (7): 1097–110. August 2009. doi:10.1111/j.1476-5381.2009.00282.x. PMID 19508394. 
  13. ↑ Pauling L, Rath (1992). "A Unified Theory of Human Cardiovascular Disease". Journal of Orthomolecular Medicine 7 (1). http://orthomolecular.org/library/jom/1992/pdf/1992-v07n01-p005.pdf. 
  14. ↑ "The vitamin D-antimicrobial peptide pathway and its role in protection against infection". Future Microbiology 4 (9): 1151–65. November 2009. doi:10.2217/fmb.09.87. PMID 19895218. 
  15. ↑ "Theodore E. Woodward award. The evolution of obesity: insights from the mid-Miocene". Transactions of the American Clinical and Climatological Association 121: 295–305; discussion 305–8. 2010. PMID 20697570. 
  16. ↑ "Aortic wall damage in mice unable to synthesize ascorbic acid". Proceedings of the National Academy of Sciences of the United States of America 97 (2): 841–6. January 2000. doi:10.1073/pnas.97.2.841. PMID 10639167. Bibcode: 2000PNAS...97..841M. 
  17. ↑ "New developments and novel therapeutic perspectives for vitamin C". The Journal of Nutrition 137 (10): 2171–84. October 2007. doi:10.1093/jn/137.10.2171. PMID 17884994. 
  18. ↑ "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". Biochemical and Biophysical Research Communications 223 (3): 650–3. June 1996. doi:10.1006/bbrc.1996.0949. PMID 8687450. 
  19. ↑ "Restoration of vitamin C synthesis in transgenic Gulo-/- mice by helper-dependent adenovirus-based expression of gulonolactone oxidase". Human Gene Therapy 19 (12): 1349–58. December 2008. doi:10.1089/hgt.2008.106. PMID 18764764. 
  20. ↑ "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. March 2004. doi:10.1016/j.ygeno.2003.08.018. PMID 14962674. 
  21. ↑ Yu, Rosemary. "DEVELOPMENT OF ROBUST ANIMAL MODELS FOR VITAMIN C FUNCTION". Open Access Dissertations and Theses. McMaster University Library. http://digitalcommons.mcmaster.ca/opendissertations/7309/. 
  22. ↑ "Intragenic deletion in the gene encoding L-gulonolactone oxidase causes vitamin C deficiency in pigs". Mammalian Genome 15 (4): 323–33. April 2004. doi:10.1007/s00335-003-2324-6. PMID 15112110. http://doc.rero.ch/record/317198/files/335_2003_Article_2324.pdf. 
  23. ↑ "Spontaneous fractures in the mouse mutant sfx are caused by deletion of the gulonolactone oxidase gene, causing vitamin C deficiency". Journal of Bone and Mineral Research 20 (9): 1597–610. September 2005. doi:10.1359/JBMR.050406. PMID 16059632. http://repository.ajou.ac.kr/handle/201003/2996. 
  24. ↑ "Arabidopsis leads to enhanced biomass and tolerance to abiotic stresses". In Vitro Cellular & Developmental Biology. Plant 49 (6): 643–655. December 2013. doi:10.1007/s11627-013-9568-y. PMID 25767369. PMC 4354779. http://yadda.icm.edu.pl/yadda/element/bwmeta1.element.springer-955adbe4-a3e1-3d37-a303-812cb3003eb0. 
  25. ↑ "L-Gulono-1,4-lactone oxidase expression rescues vitamin C-deficient Arabidopsis (vtc) mutants". Plant Molecular Biology 53 (6): 837–44. December 2003. doi:10.1023/B:PLAN.0000023671.99451.1d. PMID 15082929. 
  26. ↑ "L-gulonolactone/D-arabinono-1,4-lactone oxidase (IPR010031)". https://www.ebi.ac.uk/interpro/entry/InterPro/IPR010031/. 
  27. ↑ Aboobucker, SI; Lorence, A (January 2016). "Recent progress on the characterization of aldonolactone oxidoreductases.". Plant Physiology and Biochemistry 98: 171–85. doi:10.1016/j.plaphy.2015.11.017. PMID 26696130. 

Further reading



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