Folate exists in a pool of interconvertible intermediates each carrying a
1-carbon fragment in several different oxidation states (Figure 4-2). The total
body stores of folate is approximately 110 mg/70 kg and approximately
g/70 kg is lost each day via the urine and feces.
Two different forms
of folate are required for different aspects of nucleotide biosynthesis.
N10-formyl THF
provides the
C-2 and C-8 carbons
for the de novo synthe-
sis of
purine rings,
and thus is critical for DNA metabolism.
methylene form, N5,N10-methylene THF,
is required for the production
dTMP from dUMP.
This reaction involves the transfer of a CH2 group and
a hydrogen from N5,N10-methylene THF. In this process, THF is oxidized to
dihydrofolate (DHF). For subsequent dTMP production, THF must be regen-
erated. THF is produced from DHF by the enzyme DHF reductase (DHFR)
in a reaction requiring NADPH. DHFR is the target of methotrexate, an antifo-
late cancer chemotherapeutic, which by limiting the available pool of N5,
N10-methylene THF, inhibits DNA synthesis in rapidly dividing cancer cells.
Methotrexate therapy can produce side effects resembling folate deficiency.
Additionally, bacterial DHFR is a target for antimicrobials.
Outside of DNA synthesis,
folate plays a role in methylation metabolism.
The major
methyl donor is S-adenosyl methionine (SAM),
which is required
for many reactions. For example, SAM is needed for the
production of nor-
epinephrine from epinephrine and for DNA methylation,
which can influ-
gene transcription.
After methyl group transfer, SAM is converted to
S-adenosyl homocysteine (SAH),
which is hydrolyzed to
homocysteine and
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