section 38 2
H C— CH
. - A .
C H - ( C H ,) ,-( C ^
O H /'
Biotin is bound to carboxylase
enzym es by a n am ide bond
betw een this carboxyl group
and the e -am ino group
of a lysine
F IG U R E 3 8-21
Structure of biotin.
The structure of biotin consists of fused imidazole
and tetrahydrothiophene rings and a carboxyl-containing
side chain (Figure 38-21). In oxybiotin, which can
substitute for biotin in most species, the sulfur of the
tetrahydrothiophene ring is replaced by oxygen, making
it a tetrahydrofuran ring.
Biotin is a coenzyme for the carbon dioxide fix-
ation reactions catalyzed by acetyl-CoA carboxylase
(Chapter 19), propionyl-CoA carboxylase, pyruvate car-
boxylase, and /1-methylcrotonyl-CoA carboxylase. Car-
boxylation reactions that do not require biotin are the
addition of C
to the purine ring (Chapter 27), the for-
mation of carbamoyl phosphate (Chapter 17), and the
y-carboxylation of glutamyl residues of several of the clot-
ting factors, which requires vitamin K (Chapter 36).
Biotin is bound to an apoenzyme by an amide link-
age to a lysyl e-amino group (Figure 38-21). This bind-
ing occurs in two steps, catalyzed by holocarboxylase
Biotin + ATP -> biotinyl 5'-adenylate + PP;
Biotinyl 5'-adenylate + apocarboxylase
holocarboxylase + AMP
Most dietary biotin is bound to protein, the amide link-
age being broken prior to absorption. At least eight chil-
dren have been described who have multiple carboxylase
deficiency with low activities of several of the biotin-
requiring carboxylases, i.e., multiple carboxylase defi-
ciency (Table 38-1). Pharmacological doses of biotin re-
stored the activities of the carboxylases in these patients,
indicating that the defect was not in the apocarboxylases.
Thus, the defect is presumably in the intestinal transport
system, in holocarboxylase synthetase, or in some step in
cellular uptake or intracellular transport of biotin.
s-biotinyllysine, or biocytin. Biotinidase cleaves biocytin
and biotinylated peptides, resulting from degradation of
endogenous carboxylases, to biotin and lysine. Thus,
biotin is recycled. Deficiency of biotinidase may cause
biotin deficiency, manifested clinically by neurological
problems, cutaneous findings, and developmental delay.
These defects can be corrected by pharmacological doses
of biotin. Toxicity due to excessive consumption of biotin
is not known.
is an autosomal recessive disor-
der with an estimated incidence of 1 in 72,000-126,000.
Many newborn-screening programs of genetic diseases in-
clude testing for this enzyme. Prompt treatment with oral
biotin administration of 5-20 mg/d in affected infants will
prevent clinical consequences. If the treatment is delayed,
neurological manifestations (e.g., hearing loss and optic
atrophy) and developmental delay occur and may not re-
vert to normal.
Ascorbic Acid (Vitamin C)
Humans and guinea pigs lack the enzyme that converts
L-gulonolactone to 2-keto-L-gulonolactone required for
biosynthesis of ascorbic acid (Chapter 15), L-ascorbic
acid, and L-dehydroascorbic acid (Figure 38-22) are
biologically equivalent in humans, presumably because
of the ready reduction of dehydroascorbate to ascorbate
in the body. Ascorbic acid (M.W. 176.1) is a six-carbon
enediol lactone (ketolactone) having a configuration
analogous to that of glucose. The enolic hydroxyl groups
dissociate with pK', =4.17 and pK) = 11.57. It is one of
the strongest naturally occurring reducing agents known.
Ascorbate is a specific electron donor for eight enzymes
and also may participate in several nonenzymatic reac-
tions as a reductant (Table 38-2). However, it should be
the role of ascorbate as a reductant
in nonenzymatic reactions (based on its redox potential)
is not established. Other reductants may participate or
substitute for ascorbate in nonenzymatic reactions.
The RDA for ascorbate (Appendix IV) is the amount
needed to cure or prevent scurvy while allowing ade-
quate body reserves. However, rates of ascorbate synthe-
sis in animals and the amounts needed to maintain serum
F I G U R E 3 8 -2 2
Structures of L-ascorbic acid (a) and L-dehydroascorbic acid (b).