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CASE FILES: BIOCHEMISTRY
All cells, especially rapidly growing cells, must synthesize thymidylate
(dTMP) for DNA synthesis. The difference between (T) and (U) is one methyl
group at the carbon-5 position.
Thymidylate is synthesized by the methyla-
tion of uridylate (dUMP)
in a reaction catalyzed by the enzyme
thymidylate
synthase.
This reaction requires a methyl donor and a source of reducing
equivalents, which are both provided by N5,N10-methylene THF (Figure 3-2).
For this reaction to continue, the regeneration of THF from dihydrofolate
(DHF) must occur.
DHF + NADPH + H+ ^ THF + NADPH+
The enzyme
dihydrofolate reductase (DHFR)
catalyzes this reaction,
which is a target of the
anticancer drugs aminopterin and methotrexate.
These drugs are analogs of DHF and act as
competitive inhibitors of DHFR.
Figure 3-2.
Thymidylate synthesized by the methylation of uridylate (dUMP)
in a reaction catalyzed by the enzyme thymidylate synthase.
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