1066 CHAPTER 25 The Organic Mechanisms of the Coenzymes • Metabolism
Tutorial:
Mechanism for catalysis by
thymidylate synthaseNotice that the coenzyme initially transfers a methylene group to the substrate.
The methylene group is subsequently reduced to a methyl group. Because the coen-
zyme is the reducing agent, it is simultaneously oxidized. The oxidized coenzyme is
dihydrofolate.
When the reaction is over, dihydrofolate must be converted back to
so that the coenzyme can undergo another catalytic cycle. Dihydro-
folate is first reduced to tetrahydrofolate. Then serine hydroxymethyl transferase—the
PLP-requiring enzyme that cleaves the bond of serine to form glycine and
formaldehyde—transfers formaldehyde to the coenzyme (Section 25.6). In other
words, the formaldehyde that is cleaved off serine is immediately transferred to THF
to form which is fortunate because formaldehyde is cyto-
toxic. (It kills cells.)Cancer Chemotherapy
Cancer is associated with rapidly growing and proliferating cells. Because cells cannot
multiply if they cannot synthesize DNA, several cancer chemotherapeutic agents have
been developed to inhibit thymidylate synthase and dihydrofolate reductase. If a cell
cannot make thymidine, it cannot synthesize DNA. Inhibiting dihydrofolate reductase
also prevents the synthesis of thymidine because cells have a limited amount of
tetrahydrofolate. If they cannot convert dihydrofolate back to tetrahydrofolate, they
cannot continue to synthesize thymidine.N^5 ,N^10 -methylene-THF,Ca¬Cbmethylene-THFN^5 ,N^10 -OO− O O−S ES EBBH 2 CNRO NNHNNRH 2 NH
NNONHNHNRH 2 NH
NN
OHNHNHNRH 2 NH
NN_RHNOO N
RHNHNOOS EB−S ES EBHHCH 2CH 3OO N
RHNCH 2O NNHNHNRH 2 NH
NNRHN+mechanism for catalysis by thymidylate synthaseoxidized
coenzymeHBHBB–BHBB–+dihydrofolate
reductase
dihydrofolate + + NADPH H+ tetrahydrofolate + NADP+serine hydroxymethyl
transferase
tetrahydrofolate + HOCH 2 CHCOO− N^5 ,N^10 -methylene-THF + CH 2 COO−
+NH
3+NH
3PLPserine glycine