L gulonolactone oxidase

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 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. 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.

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. Guinea pigs, for instance, are a popular human model but lost the ability to synthesize L-gulono-gamma-lactone oxidase 20 million years ago. This is a major handicap for studies involving the endogenous redox systems of primates and other animals that lack this gene.

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.

There were number of successful attempts to activate lost enzymatic function in different animal species. Various GULO mutants were also identified.

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, 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.