section 27.1
One-Carbon Metabolism
617
coo
-
N
C H :— C H ,— C O O
M ethotrexate
Dihydrofolate
NADPH + H
Dihydrofolate '
reductase v
j.
^ NADP+
H,N
OH
HN.
Tetrahydrofolate
FIGURE 27-2
Reduction of folate to tetrahydrofolate.
plasma. Within tissue cells, N5-methyltetrahydrofolate
transfers its methyl group to homocysteine with the for-
mation of methionine (Chapter 17). This reaction is cat-
alyzed by homocysteine methyltransferase, a vitamin B
J 2
coenzyme-dependent enzyme, and appears to be the major
site of interdependence of these two vitamins.
In the tissues, tetrahydrofolate is converted to polyg-
lutamyl forms by an ATP-dependent synthetase. In the
liver, the major form is pteroyl pentaglutamate. Reduced
polyglutamyl forms, each substituted with one of sev-
eral one-carbon moieties, are the preferred coenzymes
of folate-dependent enzymes. Reduction of folate (F) to
tetrahydrofolate (FH
4
) occurs in two steps: F is reduced
to 7,8-dihydrofolate (FH2), and FH
2
is reduced to 5,6,7,8-
tetrahydrofolate (FH
4
). Both of these reactions are cat-
alyzed by a single NADPH-linked enzyme, dihydrofolate
reductase (Figure 27-2).
Inhibitors of Dihydrofolate Reductase
Methotrexate (Figure 27-3), a structural analogue of FH2,
is a potent inhibitor of dihydrofolate reductase and is used
FIGURE 27-3
Inhibitors of dihydrofolate reductase. Methotrexate, a structural analogue
of dihydrofolate, is effective against intact mammalian cells but ineffective
against protozoa and some bacteria owing to permeability barriers.
Trimethoprim and pyrimethamine (2,4-diaminopyrimidines) are effective
against microorganisms. The former is antibacterial and antimalarial; the
latter is primarily antimalarial.
in chemotherapy of neoplastic disease. Methotrexate is
not effective against infections from bacteria and pro-
tozoa, since these organisms are impermeable to folate
and its analogues. However, methotrexate inhibits dihy-
drofolate reductase of both bacterial and protozoal origin
in cell-free preparations. Pyrimethamine is extremely ef-
fective against protozoan (e.g., malarial parasite) infec-
tions, is ineffective against bacterial infections., and is a
mild inhibitor of the mammalian enzyme. Trimethoprim
is an effective inhibitor of both bacterial and protozoal
enzymes but has minimal inhibitory action against the
mammalian enzyme. These selective enzyme inhibitors
have been used in the treatment of bacterial and malarial
infections.
Formation of One-Carbon Derivatives of Folate
There are several one-carbon derivatives of folate (of dif-
ferent redox states) that function as one-carbon carriers in
different metabolic processes. In all of these reactions,
the one-carbon moiety is carried in a covalent linkage
to one or both of the nitrogen atoms at the 5- and 10-
positions of the pteroic acid portion of tetrahydrofolate.
Six known forms of carrier are shown in Figure 27-4.
Folinic acid (N5-formyl FH
4
), also called
leucovorin
or
citrovorum factor,
is chemically stable and is used clin-
ically to prevent or reverse the toxic effect of folate
antimetabolites, such as methotrexate and pyrimethamine.
The formation and interconversion of some metabolites of
