Vitamin C
Robert B. Rucker and Francene Steinberg
University of California, Davis, California, USA
One of the most important redox cofactors in plant and animal
systems is ascorbic acid or vitamin C. Although most animals
make sufficient ascorbic acid, for some animals, ascorbic acid
is a true vitamin because of their inability to carry out
synthesis. For example, in humans, ascorbic acid deficiency can
resulst in the nutritional disease scurvy, which causes a range of
pathologic symptoms, because of defects in ascorbic-acid-
specific enzymatic steps and processes.
In most plants and animals, ascorbic acid is derived as a
product from the direct oxidation of glucose, galactose, and
mannose (in plants), e.g., glucose or galactose ! UDP-D-
glucuronic acid ! glucuronic acid/glucuronolactone !
gulono-1, 4-lactone ! ascorbic acid. In animals, a key enzyme
in this process is
L-gulonolactone oxidase (GLO, EC 1.1.3.8),
which catalyzes the terminal step in ascorbic acid synthesis,
i.e., gulono-1, 4-lactone is oxidized to ascorbic acid.
L-gulonolactone oxidase resides in the kidney of most birds
and reptiles, and during the course of evolution was transferred
to the liver of mammals. For reasons that are not clear, the
ability to express sufficient
L-gulonolactone oxidase activity
disappeared from the guinea pig, some fruit-eating bats, and
most primates, including humans. Accordingly, a dietary source
of ascorbic acid is needed in these animals. There is also a
possibility that minor alternative pathways exist in plants and
mammals for ascorbic acid synthesis.
Chemistry
The chemical designation for ascorbic acid is 2-oxo-L-
theo-hexono-4-lactone-2, 3-enediol. Ascorbic acid is a
near planar five-member ring with two chiral centers
that resolves into the four stereoisomers. The oxidized
form of ascorbic acid, dehydroascorbic acid, retains
vitamin C activity and can exist as a hydrated hemi-
ketal. Crystalline dehydro-
L-ascorbic acid can exist as a
dimer. The most important chemical property of
ascorbic acid is the reversible oxidation of ascorbic
acid to semidehydro-
L-ascorbic acid and to dehydroas-
corbic acid (Figure 1).
In addition to facilitating reduction–oxidation
reactions, ascorbic acid has the ability to form
relatively stable free radical intermediates. Ascorbic
acid can act as a free radical scavenger in reactions
involving reactive oxidant species (ROS). In this
regard, the rate constants for the generation of
ascorbate radicals vary considerably, but often dictate
rapid radical formation, e.g., 10
5
–10
10
k
obs
z
/M
21
s
21
.
Once formed, ascorbate (Asc) radicals decay relatively
slowly by a process of disproportionation (2 Asc
z2
þ
H
þ
! AscH
2
þ DHA). The ability to form free radical
intermediates can significantly delay or prevent free
radical-initiated oxidations. Ascorbic acid readily
scavenges reactive oxygen and nitrogen species, such
as superoxide, hydroperoxyl, peroxynitrite, and nitr-
oxide radicals. Asc[H
2z
] donates a hydrogen atom
(H
z
or H
þ
þ e
2
) to an oxidizing radical to produce
the resonance-stabilized tricarbonyl ascorbate free
radical. Asc[H
z
]hasapK
a
of 2 0.86; thus, it is not
protonated. Further, the unpaired electron of Asc [2 ]
resides in the
p
-system that includes the tricarbonyl
moiety of ascorbate. It is a weakly oxidizing and
reducing radical. Due to its
p
-character, Asc [2 ] does
not react with oxygen to form peroxyl radicals capable
of damaging oxidations. It is relatively unreactive with
a one-electron reduction potential of only þ 282 MV,
and as such is considered a terminal, small-molecule
antioxidant.
Ascorbic acid is often associated with the protection
of lipid, DNA, and proteins from oxidants. As examples,
when peroxyl radicals are generated in plasma, vitamin
C is consumed faster than other antioxidants, e.g., uric
acid, bilirubins, and vitamin E. Ascorbic acid is 10
3
times more reactive than a polyunsaturated fatty acid
in reacting with peroxyl radicals. In contrast, ascorbic
acid can be viewed as a pro-oxidant under aerobic
condition when metals capable of redox (Fe
þ2
$ Fe
þ3
;
Cu
þ1
$ Cu
þ2
) are also present. Metals, such as iron
and copper in their reduced states, are effective Fenton
catalysts.
With regard to other chemical properties, the acidity
of ascorbic acid is due to the low pK
a
of the proton on
oxygen-3. In addition, ascorbic acid is not very stable in
aqueous media, wherein it can decay within a few hours
or even minutes at high pH (. 10.0). In contrast,
ascorbic acid is relatively stable in blood (a day or
more), or if stored at acid pH (, 3.0) or below 2 208C
(often weeks to months).
Encyclopedia of Biological Chemistry, Volume 4. q 2004, Elsevier Inc. All Rights Reserved. 367