The biochemical function of biotin-requiring enzymes is the
insertion of carboxyl groups to allow modification of metabolic
intermediates. The catabolism of the amino acid leucine is a highflux
process that offers a biochemical marker of biotin deficiency.
The product formed after the first three steps of the pathway, ?-
methylcrotonyl-CoA, requires a biotin-dependent carboxylation to
allow the flow to continue.
This compound accumulates if biotin
is deficient, and its hydrated product, ?-hydroxyisovalerate, spills
in urine. ?-Hydroxyisovaleric aciduria appears early in people who
are made biotin deficient by consuming the biotin-binding protein,
avidin. After starting avidin administration, elevated ?-hydroxyisovalerate
appears at the third day while serum biotin concentrations
remain in the normal range until the tenth day (Figure 6-8). The
effects are completely reversible.
Heritable disorders of biotin metabolism lead to the condition
called multiple carboxylase deficiency, in which the activities of
enzymes that have absolute requirements for biotin to carry out
carboxylation reactions are deficient [61]. ?-Hydroxyisovalerate
is a compound that is elevated in biotin deficiency and multiple
carboxylase insufficiency [62].
Biotin deficiencies of various degrees
have been shown to develop in normal pregnancies [63] and
in patients on long-term anticonvulsant therapy [64]. When ?-
hydroxyisovalerate was used to assess biotin in pregnant women,
biotin status was found to decrease during pregnancy, and out of
13 women studied were biotin depleted even in early pregnancy [65].
Symptoms of biotin deficiency include alopecia, skin rash, Candida
dermatitis, unusual odor to the urine, immune deficiencies, and
muscle weakness.
The enzymes that use biotin as a cofactor are called carboxylases,
because they use carbon dioxide to insert carboxyl groups into
substrates. Biotin from food or from intestinal microbial synthesis
is absorbed in the upper small intestine and transported to tissues
bound to several blood proteins. Cellular biotin must be incorporated
into the carboxylase enzymes by the action of other enzymes called
synthases (Figure 6-9). If these enzymes are not fully active, higher
biotin concentrations can increase enzymatic activity and enhance
the reaction rate.
The carboxylase enzymes have critical roles in
major pathways for the utilization of energy from amino acids (where
?-hydroxyisovalerate is formed), the synthesis of fatty acids for cell
membrane replacement, and the maintenance of blood glucose via
gluconeogenesis. At cell death, the biotin may be recovered if there
is sufficient activity of the enzyme biotinidase, which acts on the
biotin-peptide fragments called biocytin. All five of the major
factors (boxed text) in Figure 6-9 contribute to the maintenance of
active carboxylase enzymes.
Biotin deficiency can be caused by lack
of biotin-rich foods or genetic variations in the enzymes shown in
Figure 6-8. Antibiotic overuse can contribute to biotin insufficiency
by lowering the population of biotin-producing organisms and
favoring the overgrowth of non-biotin producing species.
avid
