L-gulonolactone oxidase

GULOP
Identifiers
Aliases	GULOP, GULO, SCURVY, gulonolactone (L-) oxidase, pseudogene
External IDs	MGI: 1353434; GeneCards: GULOP; OMA:GULOP - orthologs
Gene location (Mouse) Chr. Chromosome 14 (mouse)[1] Band 14|14 D1 Start 66,224,235 bp[1] End 66,246,656 bp[1]
Orthologs Species Human Mouse 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/a Chr 14: 66.22 – 66.25 Mb PubMed search [2] [3]
Wikidata
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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.

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.

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]

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]

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 (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]

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]

• Vitamin C (ascorbic acid)
• Oxidoreductase
• Scurvy