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chapter 27

Nucleotide Metabolism

'0 ,P 0 H ,C

/

Senne

hydroxymethyl

transterase

NADP

HjN — CH,— COO

CH,OH

♦

J

H,N — CH — COO

CH,-----N

dUMP

N ,N -Methylenetetrahydro-

fo la te

Thymidylate

Inhibited by

synthase

fluorodeoxyundylate

Tetrahydrofolate

Dihydrotolate

Inhibited

by methotrexate

OjPOHgC

N A D P H ♦ H

H C

7,8-Dihydrotolate

IMP

FIG U R E 27-28

Synthesis of thymidylic acid (TMP). Fluorodeoxyuridylate inhibits conversion of dUMP to TMP, and methotrexate

inhibits regeneration of the tetrahydrofolate coenzyme.

Synthesis of Cytidine Nucleotides

CTP is synthesized from UTP by transfer of the amide

nitrogen of glutamine to C-4 of the pyrimidine ring of

UTP. This reaction requires ATP as an energy source.

The deoxycytidine phosphates result from reduction of

CDP to dCDP by a mechanism analogous to that described

for the purine nucleotides. Then dCDP is converted to

dCTP by nucleoside diphosphate kinase.

Synthesis of Thymidine Nucleotides

De novo

synthesis of thymidilic acid (TMP) oc-

curs exclusively by methylation of the C-5 of dUMP

(Figure 27-28) by thymidylate synthase. The methylene

group of N

5

,NI0-methylene FH

4

is the source of the methyl

group, and FH

4

is oxidized to FH2. For sustained synthesis,

FH

4

must be regenerated by dihydrofolate reductase. Re-

call that deoxynucleotides are formed at the diphosphate

level by ribonucleotide reductase; thus, UDP is converted

to dUDP, then to dUTP, dUMP is then generated mainly

by dUTPase.

dUTPase

dUTP------►

dUMP + PPi

The dUTPase reaction is very important because the

DNA polymerases cannot distinguish dUTP from TTP

and catalyze significant incorporation of dUMP into DNA

when dUTP is present. Incorporation of the base U into

DNA is not deleterious because all cells contain a uracil