HOME

TheInfoList



OR:

L-Gulonolactone oxidase ( ECbr>1.1.3.8
is an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
that produces
vitamin C Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits and vegetables, also sold as a dietary supplement and as a topical 'serum' ingredient to treat melasma (dark pigment spots) ...
, but is non-functional in
Haplorrhini Haplorhini (), the haplorhines ( Greek for "simple-nosed") or the "dry-nosed" primates, is a suborder of primates containing the tarsiers and the simians (Simiiformes or anthropoids), as sister of the Strepsirrhini ("moist-nosed"). The name is ...
(including humans), in some
bat Bats are mammals of the order Chiroptera.''cheir'', "hand" and πτερόν''pteron'', "wing". With their forelimbs adapted as wings, they are the only mammals capable of true and sustained flight. Bats are more agile in flight than most ...
s, and in
guinea pig The guinea pig or domestic guinea pig (''Cavia porcellus''), also known as the cavy or domestic cavy (), is a species of rodent belonging to the genus '' Cavia'' in the family Caviidae. Breeders tend to use the word ''cavy'' to describe the ...
s. It
catalyze Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
s the
reaction Reaction may refer to a process or to a response to an action, event, or exposure: Physics and chemistry *Chemical reaction *Nuclear reaction * Reaction (physics), as defined by Newton's third law *Chain reaction (disambiguation). Biology and m ...
of L-gulono-1,4-lactone with
oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as ...
to form L-xylo-hex-3-gulonolactone (2-keto-gulono-γ-lactone) and
hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3% ...
. It uses
FAD A fad or trend is any form of collective behavior that develops within a culture, a generation or social group in which a group of people enthusiastically follow an impulse for a short period. Fads are objects or behaviors that achieve short- ...
as a cofactor. The L-xylo-hex-3-gulonolactone then converts to hexuronic acid ( ascorbic acid) spontaneously, without enzymatic action.


Gulonolactone oxidase deficiency

The non-functional gulonolactone oxidase pseudogene (''GULOP'') was mapped to human
chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
8p21, which 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 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. The loss of this enzyme activity is responsible for the inability of
guinea pig The guinea pig or domestic guinea pig (''Cavia porcellus''), also known as the cavy or domestic cavy (), is a species of rodent belonging to the genus '' Cavia'' in the family Caviidae. Breeders tend to use the word ''cavy'' to describe the ...
s 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. 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 A passerine () is any bird of the order Passeriformes (; from Latin 'sparrow' and '-shaped'), which includes more than half of all bird species. Sometimes known as perching birds, passerines are distinguished from other orders of birds by th ...
birds, where ability to make vitamin C varies from species to species. Loss of GULO activity in the
primate Primates are a diverse order of mammals. They are divided into the strepsirrhines, which include the lemurs, galagos, and lorisids, and the haplorhines, which include the tarsiers and the simians ( monkeys and apes, the latter including ...
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
loris Loris is the common name for the strepsirrhine mammals of the subfamily Lorinae (sometimes spelled Lorisinae) in the family Lorisidae. ''Loris'' is one genus in this subfamily and includes the slender lorises, ''Nycticebus'' is the genus conta ...
es,
galago Galagos , also known as bush babies, or ''nagapies'' (meaning "night monkeys" in Afrikaans), are small nocturnal primates native to continental, sub-Sahara Africa, and make up the family Galagidae (also sometimes called Galagonidae). They are ...
s,
potto The pottos are three species of strepsirrhine primate in the genus ''Perodicticus'' of the family Lorisidae. In some English-speaking parts of Africa, they are called "softly-softlys". Etymology The common name "potto" may be from Wolof (a t ...
s, and, to some extent,
lemur Lemurs ( ) (from Latin ''lemures'' – ghosts or spirits) are wet-nosed primates of the superfamily Lemuroidea (), divided into 8 families and consisting of 15 genera and around 100 existing species. They are endemic to the island of Madagas ...
s. L-Gulonolactone oxidase deficiency has been called "
hypoascorbemia Irwin Stone (1907–1984) was an American biochemist, chemical engineer, and writer. He was the first to use ascorbic acid in the food processing industry as a preservative, and originated and published the hypothesis that humans require muc ...
" and is described by
OMIM Online Mendelian Inheritance in Man (OMIM) is a continuously updated catalog of human genes and genetic disorders and traits, with a particular focus on the gene-phenotype relationship. , approximately 9,000 of the over 25,000 entries in 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 are recommended as "reference intakes" for humans. In its patently pathological form, the effects of ascorbate deficiency are manifested as
scurvy Scurvy is a disease resulting from a lack of vitamin C (ascorbic acid). Early symptoms of deficiency include weakness, feeling tired and sore arms and legs. Without treatment, decreased red blood cells, gum disease, changes to hair, and bleeding ...
.


Consequences of loss

It is likely that some level of adaptation occurred after the loss of the GULO gene by primates.
Erythrocyte Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
Glut1 Glucose transporter 1 (or GLUT1), also known as solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1), is a uniporter protein that in humans is encoded by the ''SLC2A1'' gene. GLUT1 facilitates the transport of glucose across ...
and associated
dehydroascorbic acid Dehydroascorbic acid (DHA) is an oxidized form of ascorbic acid (vitamin C). It is actively imported into the endoplasmic reticulum of cells via glucose transporters. It is trapped therein by reduction back to ascorbate by glutathione and othe ...
uptake modulated by
stomatin Stomatin also known as human erythrocyte integral membrane protein band 7 is a protein that in humans is encoded by the STOM gene. Clinical significance Stomatin is a 31 kDa integral membrane protein, named after the rare human haemolytic ana ...
switch are unique traits of humans and the few other mammals that have lost the ability to synthesize ascorbic acid from
glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...
. 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. 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. Also, only primates share regulation of CAMP gene expression by
vitamin D Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group are vitamin D3 (c ...
, which occurred after the loss of GULO gene. 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 Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the metabolic breakdown ...
levels and enhancing fructose effects on weight gain and fat accumulation. With a shortage of food supplies this gave mutants a survival advantage.


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. 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 have been used as a human model in multiple subsequent studies. There have been 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 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.


Alternative substrates and related enzymes

GULO belongs to a
family Family (from la, familia) is a group of people related either by consanguinity (by recognized birth) or affinity (by marriage or other relationship). The purpose of the family is to maintain the well-being of its members and of society. Idea ...
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. 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.


See also

*
Vitamin C Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits and vegetables, also sold as a dietary supplement and as a topical 'serum' ingredient to treat melasma (dark pigment spots) ...
(ascorbic acid) *
Oxidoreductase In biochemistry, an oxidoreductase is an enzyme that catalyzes the transfer of electrons from one molecule, the reductant, also called the electron donor, to another, the oxidant, also called the electron acceptor. This group of enzymes usually u ...
*
Scurvy Scurvy is a disease resulting from a lack of vitamin C (ascorbic acid). Early symptoms of deficiency include weakness, feeling tired and sore arms and legs. Without treatment, decreased red blood cells, gum disease, changes to hair, and bleeding ...


References


Further reading

* * * * {{DEFAULTSORT:L-Gulonolactone Oxidase EC 1.1.3 Pseudogenes