section 38.4
Vitamin-like Substances
927
transport, and metabolism, vitamins must interact with
many biomolecules before they reach the location where
they function. The active cellular form also must interact
with one or more proteins in carrying out its biological
function. This gives many potential sites for genetic dis-
ruption of vitamin metabolism and function. For exam-
ple, because of mutation in an intestinal transport protein,
a vitamin may be inadequately absorbed. Mutation of an
enzyme may increase the
Km
for a cofactor derived from a
vitamin and result in relative deficiency of activity when
the vitamin is present at normal concentration. Although
such diseases cannot yet be cured, their clinical signs and
symptoms can sometimes be relieved by administration
of a very large oral or parenteral dose of the appropriate
vitamin (Table 38-1). Megadose vitamin therapy in these
patients has a basis in human biochemistry and differs from
indiscriminate self-medication for diseases (real or imag-
ined) that have no established relationship to the vitamins
used.
Some inherited disorders respond to megadoses of
a vitamin that is not directly related to the defective
protein. Pyruvate carboxylase deficiency leads to en-
cephalomyelopathy in which there is lactic and pyruvic
acidemia. Pyruvate carboxylase requires biotin and con-
verts pyruvate to oxaloacetate for the tricarboxylic acid
cycle or for gluconeogenesis. A major metabolic path-
way for pyruvate is oxidative decarboxylation to acetyl-
CoA, catalyzed by the pyruvate dehydrogenase complex.
Some patients have shown clinical improvement when
treated with lipoic acid. Others have responded to thiamine
(Table 38-1). Thiamine and lipoic acid participate in the
pyruvate dehydrogenase complex. They presumably re-
duce the concentrations of pyruvate and lactate by increas-
ing the flux through the pyruvate dehydrogenase complex.
Other examples include the use of vitamin E to reduce
hemolysis in some patients with deficiency of glutathione
synthetase or glucose-
6
-phosphate dehydrogenase; folic
acid, choline, or betaine in some cases of homocystin-
uria due to cystathionine /3-synthase deficiency; and pyri-
doxine in some cases of primary hyperoxaluria due to
deficiency of soluble glyoxalate-a-ketoglutarate carboli-
gase. As in the case of pyruvate carboxylase deficiency,
the effect is probably due to enhancement of alternative
metabolic pathways that bypass the defective enzyme.
Not all patients who present the same clinical pic-
ture respond to vitamin therapy. Thus, if the structural
gene for an apoenzyme or transport molecule is com-
pletely absent because of a gene deletion, no amount of
vitamin or cofactor will correct the defect. If the mutation
affects substrate rather than cofactor binding, the pathway
is blocked just as effectively and cannot be relieved by
increased concentration of cofactor. Thus, six mutations
have been identified that cause methylmalonic aciduria,
but not all respond to large doses of vitamin B
1 2
. Similarly,
only some patients with homocystinuria due to N
5
,N10-
methylenetetrahydrofolate reductase deficiency respond
to treatment with folic acid.
About two dozen inherited diseases respond to phar-
macological doses of a vitamin (Table 38-1). Many have
been mentioned elsewhere in this book in conjunction with
the affected metabolic pathways. Although most are very
rare, their study has contributed much to acknowledge of
metabolism in the human body. Some are heterogeneous
in symptoms and in responsiveness to therapy, suggesting
genetic heterogeneity, as discussed above.
38.4 Vitamin-like Substances
Several compounds, e.g., vitamin D and niacin, are appar-
ently required in the diet even though pathways for their
synthesis occur in the body. Such a situation may arise
if a pathway does not provide an adequate supply for the
body’s needs or if the material cannot be readily trans-
ported from the site of synthesis to the place of action.
The compounds discussed below are essential dietary nu-
trients in one or more nonhuman species, but such a status
in humans is not supported by evidence.
Choline
(N,N,N-trimcthyl-/3-hydroxyethylamine) is an
important constituent of phospholipids (lecithin is phos-
phatidylcholine) and of acetylcholine. It can be com-
pletely synthesized from serine (Chapter 19), but only
in the form of phosphatidylserine and then only when
the dietary supply of amino acids is adequate. Betaine
(N,N,N-trimethylglycine) readily replaces dietary choline
for all species. Choline is conserved by a salvage pathway.
In the lung, this salvage route is the principal route for the
synthesis of the phosphatidylcholine needed as a surfac-
tant (see Chapter 19).
Inositol
(hexahydroxycyclohexane) occurs in several
isomeric forms. Myoinositol (or me.voinositol) is an im-
portant constituent of phospholipids and is the only isomer
with biological activity. Inositol hexaphosphate (phytic
acid) is found in avian erythrocytes, where it binds to
hemoglobin, thereby regulating the oxygen capacity of the
blood. It is also important as an intracellular messenger in
a number of pathways.
Lipoic acid
(thioctic acid) functions as an intermediate
in the oxidation-reduction reaction of the oxidative decar-
boxylation of certain ketoacids.
Ubiquinone
(coenzyme Q) is involved in the mi-
tochondrial electron transport. Although coenzyme Q
supplements have been recommended as preventative
measures for coronary artery disease and cancer, scientific
studies do not confirm their effectiveness in preventing
these diseases.
