CLINICAL CASES
37
D efinitions
S-Adenosyl methionine:
An important carrier of activated methyl groups.
It is formed by the condensation of ATP with the amino acid methionine
catalyzed by the enzyme methionine adenosyltransferase in a reaction
that releases triphosphate.
Dihydrofolate reductase:
The enzyme that reduces folic acid (folate) first
to dihydrofolate and then to the active tetrahydrofolate. Dihydrofolate
reductase uses NADPH as the source of the reducing equivalents for the
reaction.
Folic acid:
An essential vitamin composed of a pteridine ring bound to
p-aminobenzoate, which is in an amide linkage to one or more glutamate
residues. The active form of the enzyme is tetrahydrofolate (THF, FH4),
which is an important carrier of 1-carbon units in a variety of oxidation
states.
Megaloblastic anemia:
An anemia characterized by macrocytic erythro-
cytes produced by abnormal proliferation of erythroid precursors in the
bone marrow due to a limitation in normal DNA synthesis.
Methotrexate:
One of a number of antifolate drugs. Methotrexate is an
analog of folate which competitively inhibits dihydrofolate reductase.
Since a plentiful supply of THF is required for ongoing synthesis of the
pyrimidine nucleotide thymidylate, synthesis of this nucleotide is inhib-
ited resulting in decreased DNA synthesis.
Methyl trap:
The sequestering of tetrahydrofolate as N5-methyl THF because
of decreased conversion of homocysteine to methionine as a result of a
deficiency of methionine synthase or its cofactor, cobalamin (vitamin B12).
D ISC U SSIO N
Folate (folic acid) is an essential vitamin
which, in its
active form of tetrahy-
drofolate
(
THF,
Figure 4-1),
transfers 1-carbon groups to intermediates in
metabolism.
Folate plays an important role in
DNA synthesis.
It is required
for the de novo synthesis of
purines
and for the
conversion of deoxyuridine
5-monophosphate (dUMP) to deoxythymidine 5'
-
monophosphate (dTMP).
Additionally, folate derivatives participate in the biosynthesis of choline, serine,
glycine, and methionine. However, in situations of folate deficiency, symptoms
are not observed from the lack of these products as adequate levels of choline
and amino acids are obtained from the diet. (See also Case 3.)
Folate deficiency
results in
megaloblastic anemia.
Megaloblastic anemia
is characterized by
macrocytic erythrocytes
produced by
abnormal prolif-
eration of erythroid precursors in the bone marrow.
Folate deficiency
encumbers the maturation of these cells by
inhibition of DNA synthesis.
Without an adequate supply of folate, DNA synthesis is limited by
decreased
purine and dTMP levels.
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