Vitamin C, a
reducing agent and
antioxidant, is a cofactor in reactions catalyzed by Cu(+)-dependent
monooxygenases and Fe(2+)-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,
UDP-glucuronosyltransferases. 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 identified as SMP30 or regucalcin, whose absence in mice leads to
vitamin C deficiency. 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 deficient 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 five-step pathway, the
pentose pathway, involving identified
oxidoreductases and an unknown
decarboxylase.
Semidehydroascorbate, a major oxidation product of
vitamin C, is reconverted to ascorbate in the cytosol by
cytochrome b(5)
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, CO(2) and l-
erythrulose. This is at variance with bacteria such as Escherichia coli, which have enzymatic degradation pathways for ascorbate and probably also dehydroascorbate.