Jump to content

L-gulonolactone oxidase

From Wikipedia, the free encyclopedia
(Redirected from Gulonolactone oxidase)
"GULO" redirects here. For other uses, see Gulo (disambiguation).
GULOP
Identifiers
AliasesGULOP, GULO, SCURVY, gulonolactone (L-) oxidase, pseudogene
External IDsMGI: 1353434; GeneCards: GULOP; OMA:GULOP - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2989

268756

Ensembl

ENSG00000234770

ENSMUSG00000034450

UniProt

n
a

P58710

RefSeq (mRNA)

n/a

NM_178747

RefSeq (protein)

n/a

NP_848862

Location (UCSC)n/aChr 14: 66.22 – 66.25 Mb
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse
L-gulonolactone oxidase
Identifiers
EC no.1.1.3.8
CAS no.9028-78-8
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins

L-Gulonolactone oxidase (EC 1.1.3.8) is an enzyme that produces vitamin C. It is expressed in most mammals, but is non-functional in Haplorrhini (a suborder of primates, 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. The structure of L-gulonolactone oxidase in rats helps identify characteristics of this enzyme.

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 ("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.[10]

L-Gulonolactone oxidase deficiency has been called "hypoascorbemia"[11] and is described by OMIM (Online Mendelian Inheritance in Man)[12] 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.[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–/– 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]

L-gulonolactone oxidase in rats

[edit]
L-gulonolactone oxidase protein of a rat. The magenta color shows the B-sheets that are present in the protein. The blue color represents the alpha helices that make up the structure of  L-gulonolactone oxidase. Lime green is showing the N-terminus. Red is displaying the C-terminus end of the protein.

L-gulonolactone oxidase (GULO) is an enzyme that helps catalyze the production of ascorbic acid aka vitamin C. Mammals such as humans and guinea pigs do not express this gene due to multiple mutations in a specific exon.[29] These mutations correlate to nucleotide substitution.[30] Rats are a species that do express L-gulonolactone oxidase with a specific gene transcript. The protein coding region of the gene 645 base-pairs long, with eight exons and seven introns.[29] The amino acid sequence of this protein has suggested that rat L-Gulonolactone oxidase is located in the membrane portion of the endoplasmic reticulum due to its multiple B-sheet structure which contains hydrophobic areas.[31] It has been determined that rat GULO has a prosthetic domain in the N-terminus, flavian adenine dinucleotide.[31] The only substrates that can make this rat enzyme function are L-GalL and L-GulL.[31]

[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.[32] 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.[33]

See also

[edit]

References

[edit]
  1. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000034450 – Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ GULOP Archived 2007-09-27 at the Wayback Machine – iHOP
  5. ^ 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". Archives of Biochemistry and Biophysics. 267 (2): 842–6. doi:10.1016/0003-9861(88)90093-8. PMID 3214183.
  6. ^ 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". The Journal of Biological Chemistry. 269 (18): 13685–8. doi:10.1016/S0021-9258(17)36884-9. PMID 8175804.
  7. ^ Cui J, Pan YH, Zhang Y, Jones G, Zhang S (February 2011). "Progressive pseudogenization: vitamin C synthesis and its loss in bats". Molecular Biology and Evolution. 28 (2): 1025–31. doi:10.1093/molbev/msq286. PMID 21037206.
  8. ^ a b 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". The Journal of Biological Chemistry. 267 (30): 21967–72. doi:10.1016/S0021-9258(19)36707-9. PMID 1400507.
  9. ^ Martinez del Rio C (1997). "Can Passerines Synthesize Vitamin C?" (PDF). The Auk. 114 (3): 513–516. doi:10.2307/4089257. JSTOR 4089257.
  10. ^ Pollock JI, Mullin RJ (May 1987). "Vitamin C biosynthesis in prosimians: evidence for the anthropoid affinity of Tarsius". American Journal of Physical Anthropology. 73 (1): 65–70. doi:10.1002/ajpa.1330730106. PMID 3113259.
  11. ^ HYPOASCORBEMIA – NCBI
  12. ^ OMIM – Online Mendelian Inheritance in Man – NCBI
  13. ^ Milton K (September 2003). "Micronutrient intakes of wild primates: are humans different?" (PDF). Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology. 136 (1): 47–59. doi:10.1016/S1095-6433(03)00084-9. PMID 14527629.
  14. ^ 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.
  15. ^ Mandl J, Szarka A, Bánhegyi G (August 2009). "Vitamin C: update on physiology and pharmacology". British Journal of Pharmacology. 157 (7): 1097–110. doi:10.1111/j.1476-5381.2009.00282.x. PMC 2743829. PMID 19508394.
  16. ^ Pauling L, Rath (1992). "A Unified Theory of Human Cardiovascular Disease" (PDF). Journal of Orthomolecular Medicine. 7 (1).
  17. ^ Gombart AF (November 2009). "The vitamin D-antimicrobial peptide pathway and its role in protection against infection". Future Microbiology. 4 (9): 1151–65. doi:10.2217/fmb.09.87. PMC 2821804. PMID 19895218.
  18. ^ Johnson RJ, Andrews P, Benner SA, Oliver W (2010). "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. PMC 2917125. PMID 20697570.
  19. ^ Maeda N, Hagihara H, Nakata Y, Hiller S, Wilder J, Reddick R (January 2000). "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. Bibcode:2000PNAS...97..841M. doi:10.1073/pnas.97.2.841. PMC 15418. PMID 10639167.
  20. ^ Li Y, Schellhorn HE (October 2007). "New developments and novel therapeutic perspectives for vitamin C". The Journal of Nutrition. 137 (10): 2171–84. doi:10.1093/jn/137.10.2171. PMID 17884994.
  21. ^ 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". Biochemical and Biophysical Research Communications. 223 (3): 650–3. doi:10.1006/bbrc.1996.0949. PMID 8687450.
  22. ^ 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". Human Gene Therapy. 19 (12): 1349–58. doi:10.1089/hgt.2008.106. PMID 18764764.
  23. ^ 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.
  24. ^ Yu, Rosemary. "DEVELOPMENT OF ROBUST ANIMAL MODELS FOR VITAMIN C FUNCTION". Open Access Dissertations and Theses. McMaster University Library. Archived from the original on 13 May 2013. Retrieved 8 February 2013.
  25. ^ 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" (PDF). Mammalian Genome. 15 (4): 323–33. doi:10.1007/s00335-003-2324-6. hdl:20.500.11850/422871. PMID 15112110. S2CID 23479620.
  26. ^ 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". Journal of Bone and Mineral Research. 20 (9): 1597–610. doi:10.1359/JBMR.050406. PMID 16059632. S2CID 28699531.
  27. ^ Lisko KA, Torres R, Harris RS, Belisle M, Vaughan MM, Jullian B, Chevone BI, Mendes P, Nessler CL, Lorence A (December 2013). "Arabidopsis 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. PMC 4354779. PMID 25767369.
  28. ^ Radzio JA, Lorence A, Chevone BI, Nessler CL (December 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. S2CID 37821860.
  29. ^ a b Yue, Xiaojing; Rao, Anjana (2020-09-17). "TET family dioxygenases and the TET activator vitamin C in immune responses and cancer". Blood. 136 (12): 1394–1401. doi:10.1182/blood.2019004158. ISSN 0006-4971. PMC 7498365. PMID 32730592.
  30. ^ Aboobucker, Siddique I.; Lorence, Argelia (2016-01-01). "Recent progress on the characterization of aldonolactone oxidoreductases". Plant Physiology and Biochemistry. 98: 171–185. Bibcode:2016PlPB...98..171A. doi:10.1016/j.plaphy.2015.11.017. ISSN 0981-9428. PMC 4725720. PMID 26696130.
  31. ^ a b c Paciolla, Costantino; Fortunato, Stefania; Dipierro, Nunzio; Paradiso, Annalisa; De Leonardis, Silvana; Mastropasqua, Linda; de Pinto, Maria Concetta (November 2019). "Vitamin C in Plants: From Functions to Biofortification". Antioxidants. 8 (11): 519. doi:10.3390/antiox8110519. ISSN 2076-3921. PMC 6912510. PMID 31671820.
  32. ^ "L-gulonolactone/D-arabinono-1,4-lactone oxidase (IPR010031)". InterPro. Retrieved 3 February 2020.
  33. ^ Aboobucker, SI; Lorence, A (January 2016). "Recent progress on the characterization of aldonolactone oxidoreductases". Plant Physiology and Biochemistry. 98: 171–85. Bibcode:2016PlPB...98..171A. doi:10.1016/j.plaphy.2015.11.017. PMC 4725720. PMID 26696130.

Further reading

[edit]
Retrieved from "https://en.wikipedia.org/w/index.php?title=L-gulonolactone_oxidase&oldid=1265115365"