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Vitamin C
Biosynthesis, recycling and degradation in mammals
Carole L. Linster and Emile Van Schaftingen
Universite Catholique de Louvain, Christian de Duve Institute of Cellular Pathology, Brussels, Belgium
Keywords
ascorbate; dehydroascorbate;
2,3-diketogulonate; glucuronate;
gulonolactonase; L-gulonolactone oxidase;
semidehydroascorbate; UDPglucuronosyltransferases; vitamin C;
xenobiotics
Correspondence
E. Van Schaftingen, Laboratory of
Physiological Chemistry, UCL-ICP, Avenue
Hippocrate 75, B-1200 Brussels, Belgium
Fax: +32 27647598
Tel: +32 27647564
E-mail: vanschaftingen@bchm.ucl.ac.be
C. L. Linster, The Department of Chemistry
and Biochemistry and the Molecular Biology
Institute, University of California, Los
Angeles, CA 90095-1569, USA
Fax: +1 310 825 1968
Tel: +1 310 825 3137
E-mail: linster@chem.ucla.edu
(Received 12 September 2006, revised
1 November 2006, accepted 21 November
2006)
doi:10.1111/j.1742-4658.2006.05607.x
Vitamin C, a reducing agent and antioxidant, is a cofactor in reactions catalyzed by Cu+-dependent monooxygenases and Fe2+-dependent dioxygenases. It is synthesized, in vertebrates having this capacity, from d-glucuronate.
The latter is formed through direct hydrolysis of uridine diphosphate
(UDP)-glucuronate by enzyme(s) bound to the endoplasmic reticulum membrane, sharing many properties with, and most likely identical to, UDPglucuronosyltransferases. Non-glucuronidable xenobiotics (aminopyrine,
metyrapone, chloretone and others) stimulate the enzymatic hydrolysis of
UDP-glucuronate, accounting for their effect to increase vitamin C formation in vivo. Glucuronate is converted to l-gulonate by aldehyde reductase,
an enzyme of the aldo-keto reductase superfamily. l-Gulonate is converted
to l-gulonolactone by a lactonase identied as SMP30 or regucalcin, whose
absence in mice leads to vitamin C deciency. The last step in the pathway
of vitamin C synthesis is the oxidation of l-gulonolactone to l-ascorbic acid
by l-gulonolactone oxidase, an enzyme associated with the endoplasmic reticulum membrane and decient in man, guinea pig and other species due to
mutations in its gene. Another fate of glucuronate is its conversion to
d-xylulose in a ve-step pathway, the pentose pathway, involving identied
oxidoreductases and an unknown decarboxylase. Semidehydroascorbate, a
major oxidation product of vitamin C, is reconverted to ascorbate in the
cytosol by cytochrome b5 reductase and thioredoxin reductase in reactions
involving NADH and NADPH, respectively. Transmembrane electron
transfer systems using ascorbate or NADH as electron donors serve to
reduce semidehydroascorbate present in neuroendocrine secretory vesicles
and in the extracellular medium. Dehydroascorbate, the fully oxidized form
of vitamin C, is reduced spontaneously by glutathione, as well as enzymatically in reactions using glutathione or NADPH. The degradation of vitamin C in mammals is initiated by the hydrolysis of dehydroascorbate to
2,3-diketo-l-gulonate, which is spontaneously degraded to oxalate, CO2 and
l-erythrulose. This is at variance with bacteria such as Escherichia coli,
which have enzymatic degradation pathways for ascorbate and probably
also dehydroascorbate.
Abbreviations
BSO, L-buthionine-(S,R)-sulfoximine; DHA, dehydroascorbate; 2,3-DKG, 2,3-diketo-L-gulonate; FAD, flavin adenine dinucleotide; GLO,
L-gulonolactone oxidase; GSH, glutathione (reduced form); GST, glutathione S-transferase; GSTO, Omega class glutathione S-transferase;
PDI, protein disulfide isomerase; SDA, semidehydroascorbate; UDP, uridine diphosphate; UGT, UDP-glucuronosyltransferase.
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why it plays the role of a cofactor in reactions catalyzed by a number of metal-dependent oxygenases.
The Cu+-dependent monooxygenases peptidylglycine
a-amidating monooxygenase and dopamine b-hydroxylase convert two ascorbate molecules to two SDAs per
catalytic cycle [4]. In the case of Fe2+ a-ketoglutaratedependent dioxygenases (e.g. collagen prolyl and lysyl
hydroxylases, the two hydroxylases involved in carnitine biosynthesis [5], the asparaginyl hydroxylase
that modies hypoxia-inducible factor 1 (HIF-1) [6]),
ascorbate most probably serves to reconvert inactive,
Fe3+-containing enzyme (which results from abortive
catalytic cycles) to the active, Fe2+-containing form
[5]. Because of these important roles, it is not surprising that vitamin C deciency leads to a debilitating
disorder, scurvy, in man and in animals unable to synthesize the vitamin.
Important progress has been made recently in our
understanding of the synthesis and the recycling of
vitamin C, and a novel pathway has been described
for the degradation of vitamin C in bacteria. This
forms the subject of this review. Vitamin C transport,
which has also witnessed important developments
lately, is only briey alluded to in the following paragraph, as other recent reviews are available [79].
Ascorbate entry into mammalian cells is energydependent, being effected by two distinct Na+-dependent cotransporters, SVCT1 and SVCT2, which show
distinct tissue distributions. Interestingly, targeted deletion of the widely distributed SVCT2 is lethal in mice
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Fig. 2. Vitamin C synthesis pathway and pentose pathway in animals. The reactions are catalyzed by the following enzymes: 1, UDP-glucose
pyrophosphorylase; 2, UDP-glucose dehydrogenase; 3, nucleotide pyrophosphatase; 4, UDP-glucuronosyltransferase; 5, UDP-glucuronidase;
6, phosphatase; 7, b-glucuronidase; 8, glucuronate reductase; 9, gulonolactonase; 10, L-gulonolactone oxidase; 11, L-gulonate 3-dehydrogenase; 12, decarboxylase; 13, L-xylulose reductase; 14, xylitol dehydrogenase; 15, D-xylulokinase. Three possible mechanisms for glucuronate
formation (a, b and c) are shown (see text). For the sake of clarity, the linear form of glucuronate is represented. SMP30 KO mice, senescence marker protein 30 knockout mice; ODS rats, osteogenic disorder Shionogi rats; od od pigs, mutant pigs deficient in L-gulonolactone
oxidase; GLO KO mice, L-gulonolactone oxidase knockout mice.
of the UGT2 family are involved in ascorbate biosynthesis, possibly by forming a glucuronidated intermediate that would be hydrolyzed by microsomal
b-glucuronidase or, as suggested below, by catalyzing
the hydrolysis of UDP-glucuronate to UDP and
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oxidase
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Recycling of vitamin C
As described in the introduction, ascorbate plays
major roles as a water-soluble antioxidant and as a
cofactor of several enzymes, which lead to its oneelectron oxidation to SDA. Disproportionation of
SDA (2 SDA ascorbate + DHA), in turn, results
in the formation of DHA. Both SDA and DHA are
reduced back to ascorbate by several enzymatic systems that are briey reviewed below and schematized
in Fig. 3.
Reduction of semidehydroascorbate
The reduction of SDA in the cytosol has been assigned
to enzymes using NADH (NADH-cytochrome b5
reductase) or NADPH (thioredoxin reductase). SDA
can also be reduced in the lumen of neuroendocrine
secretory vesicles or in the external medium by transmembrane electron transfer systems.
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Fig. 3. Recycling of vitamin C. Vitamin C is transported into the cell under its reduced (ascorbate) and oxidized (DHA) forms by active and
facilitative transport systems (shown in blue), respectively. The utilization of ascorbate as an antioxidant or enzyme cofactor leads to the formation of SDA in the cytosol, neuroendocrine secretory vesicles and the extracellular medium. Various enzymatic systems (represented in
green) reconvert SDA to ascorbate. Intracellular DHA, arising through disproportionation of SDA or import from external sources, can also be
reduced back to ascorbate by several enzymes (shown in red) or through spontaneous reaction with GSH (not shown). DHA, dehydroascorbate; GSTO, Omega class glutathione S-transferase; 3a-hydroxysteroid DH, 3a-hydroxysteroid dehydrogenase; PDI, protein disulfide isomerase; SDA, semidehydroascorbate.
NADH-cytochrome b5 reductase
Early studies showed that oxidation of NADH by liver
microsomes was stimulated in the presence of SDA,
and microsomal NADH-cytochrome b5 reductase was
proposed to participate in the electron transfer system,
since the puried enzyme itself was able to reduce
SDA in the presence of NADH [89]. Ito et al. [90]
showed that, in rat liver, most of the NADH-dependent SDA reductase activity is localized in the outer
mitochondrial membrane. Some activity could be
detected in the nuclear and microsomal fractions. Inhibition of the mitochondrial SDA reductase activity
with specic antibodies suggested participation of
NADH-cytochrome b5 reductase and of a cytochrome b5-like protein of the outer mitochondrial
membrane [90].
NADH-cytochrome b5 reductase is an FAD-containing enzyme [91,92], which exists as a 300 amino
acid membrane-bound form and a 275 amino acid
soluble form [93]. The membrane-bound protein is
located mainly in the endoplasmic reticulum and the
outer mitochondrial membranes, but a small fraction
of the enzyme is apparently also associated with
the plasma membrane [94]. Its C-terminal catalytic
domain (275 amino acid residues) is oriented
10
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11
the data reported by Winkler et al. [121], it can be calculated that at 5 mm GSH and 0.1 mm DHA (pH 7.0;
2022 C), this reaction would be half-complete after
10 min, which compares with a half-life of 100 min
for the spontaneous hydrolysis of DHA to 2,3-diketogulonate at the same temperature [122]. However, as
described in the next section, the hydrolysis of DHA is
enhanced by bicarbonate and by an intracellular lactonase. These considerations lead to the conclusion that
an important (irreversible) loss of vitamin C would
occur if the spontaneous reaction with GSH were
solely responsible for the reduction of DHA to ascorbate. However, as detailed below, several enzymes
facilitate this reaction with GSH. Furthermore,
NADPH-dependent reductases appear also to be
involved in DHA reduction.
Glutaredoxin and protein disulfide isomerase
Highly puried preparations of glutaredoxin (also
known as thioltransferase) from pig liver, beef thymus
and human placenta, as well as of bovine liver protein
disulde isomerase (PDI) display DHA reductase activity [123]. Glutaredoxin and PDI are thiol-disulde
oxidoreductases, which both possess active-site cysteine
residues. Glutaredoxins are small (12 kDa) cytosolic
enzymes that physiologically use GSH as a reductant,
whereas PDI is a larger (57 kDa) protein, bound to the
endoplasmic reticulum membrane, which serves to create and rearrange disulde bonds [123]. Kinetic analysis
of their DHA reductase activity revealed Km values in
the range of 0.22.2 mm and 1.68.7 mm for DHA and
GSH, respectively. Based on the subcellular localization
of these two types of enzymes, it was proposed that
glutaredoxin could contribute to ascorbate recycling
from DHA in the cytosol, whereas PDI might catalyze
this reaction in the endoplasmic reticulum. The nding
that PDI can act on DHA led to the proposal that the
latter could be implicated as an oxidant in protein
disulde formation catalyzed by PDI [124,125].
More recently, experiments with cultured human
lens epithelial cells in which thioltransferase (glutaredoxin) was overexpressed or knocked down, indicated
that this enzyme plays a major role in ascorbate recycling in these cells [126]. Other studies have shown that
PDI is intrinsically much poorer (250-fold lower
catalytic efciency) as a DHA reductase than glutaredoxin [127].
Omega class glutathione transferase
Maellaro et al. [128] puried a cytosolic rat liver DHA
reductase, which was clearly different from glutaredox12
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Catabolism of vitamin C
In mammals, the degradation of ascorbate appears to
proceed via DHA, an unstable molecule, and to
involve spontaneous and possibly enzyme-catalyzed
reactions. A specic pathway for the degradation of
vitamin C has only been fully described in bacteria.
Spontaneous breakdown of dehydroascorbate
Ascorbate is oxidized to DHA in a variety of enzymatic and nonenzymatic reactions (see Introduction).
DHA can be reduced back to ascorbate (see previous
section), but can also be hydrolyzed to 2,3-diketo-lgulonate (2,3-DKG). The latter reaction is irreversible
and 2,3-DKG, unlike DHA, is therefore devoid of
antiscorbutic activity. DHA is unstable and nonenzymatic hydrolysis occurs rather rapidly at neutral pH,
the half-time of decay being about 515 min at 37 C
[122]. Incubation of DHA or 2,3-DKG in the presence
of phosphate buffer (pH 7) for several hours at 37 C
leads to the formation of l-erythrulose and oxalate
[139], indicating cleavage between the second and the
third carbon (Fig. 4). When the incubation is performed in the presence of H2O2 (which may be formed
FEBS Journal 274 (2007) 122 2006 The Authors Journal compilation 2006 FEBS
13
Fig. 4. Spontaneous breakdown of dehydroascorbate (oxidation product of ascorbate) in the absence or in the presence of hydrogen peroxide.
FEBS Journal 274 (2007) 122 2006 The Authors Journal compilation 2006 FEBS
other lactones and shares many properties with gulonolactonase, from which it could not be separated
[143]. Lower activities of both dehydroascorbatase
[145] and gulonolactonase (aldonolactonase) [45,146]
are present in tissues of primates compared to other
mammals. Assuming that both activities are contributed by the same enzyme, this lower activity may be
benecial in primates because it would slow down the
irreversible loss of DHA while not having any detrimental effect on ascorbate formation (which is absent).
It would be interesting to know if the bone loss
observed in transgenic rats overexpressing regucalcin
[147,148] (which, as noted above, has recently been
identied as the aldonolactonase involved in ascorbate
synthesis [47]) is related to vitamin C deciency.
As for the formation of oxalate, which is one of
the major excretion products of ascorbate in
humans, no enzyme has yet been described that catalyzes the cleavage of 2,3-DKG between the second
and the third carbon. It is therefore likely that this
reaction takes place spontaneously. The metabolic
fate of the other product (most probably l-erythrulose, since H2O2 levels are kept low) is unknown.
The nding that addition of ascorbate or DHA to
glycogen-depleted mouse hepatocytes causes an
increase in the formation of glucose and in the concentration of d-xylulose 5-phosphate [149] suggests
that they can be converted to a metabolizable sugar
or sugar derivative.
Utilization of vitamin C by Escherichia coli
E. coli can ferment ascorbate and the operon responsible for ascorbate utilization has recently been identied [150]. This identication was based on the
hypothesis that the catabolic pathway of ascorbate
could lead to the formation of the pentose phosphate intermediate d-xylulose 5-phosphate, via 4-epimerization of l-ribulose 5-phosphate. The latter
reaction is also involved in the catabolic pathway of
l-arabinose, where it is catalyzed by AraD. Two
multigene operons of unknown function were found
to comprise an AraD homologue in the genome of
E. coli K-12.
The deletion of one of these operons generated
mutants that failed to ferment ascorbate [150]. The
utilization of L-ascorbate operon (ula operon) thus
identied contains six genes (designated ulaA, B, C, D,
E and F) (Fig. 5A). UlaA, UlaB and UlaC are components of a PTS system involved in the uptake of
ascorbate and its phosphorylation to l-ascorbate
6-phosphate [151]. The proteins encoded by ulaD,
ulaE and ulaF were functionally characterized as
3-keto-l-gulonate 6-phosphate decarboxylase, l-xylulose 5-phosphate 3-epimerase and l-ribulose 5-phosphate 4-epimerase, respectively [150]. A gene located
upstream of the ula operon, ulaG, encodes a distant
homologue of a metal-dependent hydrolase that is
essential for ascorbate utilization [151]. It was proposed
to encode a cytoplasmic ascorbate 6-phosphate lactonase catalyzing the conversion of ascorbate 6-phosphate to 3-keto-l-gulonate 6-phosphate.
All together the divergently transcribed operons
ulaABCDEF and ulaG encode proteins allowing the
uptake of ascorbate and its conversion to d-xylulose
5-phosphate and CO2 (Fig. 5C). They are both regulated by the nearby ulaR gene and together constitute a
regulon [152]. ulaR encodes a repressor belonging to
the DeoR family of bacterial regulatory proteins and
inactivation of this gene leads to constitutive expression of the ula operons. A detailed study of the regulation of expression of the ula operons by UlaR and
other factors has been reported [153].
Disruption of the other operon (yia) containing an
AraD homologue (Fig. 5B) did not affect the fermentation of ascorbate [150]. This operon encodes nine
different proteins, ve of which have been overexpressed and characterized [150]. On this basis, it
has been proposed that the yia operon allows the
metabolism of 2,3-diketo-l-gulonate through a pathway in which it is successively reduced to 3-ketol-gulonate by YiaK (a dehydrogenase belonging to a
novel family of pyridine nucleotide-linked oxidoreductases [154]) and phosphorylated to 3-keto-l-gulonate
6-phosphate by an ATP-dependent kinase (YiaP)
(Fig. 5C). 3-Keto-l-gulonate 6-phosphate would then
be converted to d-xylulose 5-phosphate in a sequence
of reactions similar to that described above for the
ula operon. The gene products involved are YiaQ
(3-keto-l-gulonate 6-phosphate decarboxylase), YiaR
(l-xylulose 5-phosphate 3-epimerase) and YiaS (l-ribulose 5-phosphate 4-epimerase). It should be noted
that no enzymatic activity could be detected in the
case of YiaR despite its high degree of identity with
UlaE (l-xylulose 5-phosphate 3-epimerase) [150]. The
operon also encodes three proteins of a putative ABC
transport system (YiaM, YiaN and YiaO), possibly
involved in the transport of 2,3-DKG [150]. However,
the denitive proof that this operon is involved in the
utilization of the hydrolyzed form of DHA is still
lacking.
A search for similar operons in other bacterial genomes using the SEED database (http://theseed.uchicago.
edu) indicates that the rst (ula) occurs not only in
Enterobacteriae (E. coli, Shigella dysenteriae, Shigella
sonnei, Shigella exneri, Salmonella enterica, Salmonella
FEBS Journal 274 (2007) 122 2006 The Authors Journal compilation 2006 FEBS
15
Fig. 5. Degradation of vitamin C in bacteria. Operons in the E. coli K-12 genome encoding proteins involved in the utilization of ascorbate
(ula) (A) and, hypothetically, 2,3-diketo-L-gulonate (yia) (B). The reactions catalyzed by the gene products of these operons are shown in (C).
Acknowledgements
This work was supported by the Concerted Research
Action Program of the Communaute Francaise de Belgique; the Interuniversity Attraction Poles Program,
Belgian Science Policy; and the Fonds de la Recherche
Scientique Medicale. CLL was a fellow of the Fonds
National de la Recherche Scientique (FNRS).
FEBS Journal 274 (2007) 122 2006 The Authors Journal compilation 2006 FEBS
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