SYNTHESIS OF PYRIMIDINE RIBONUCLEOTIDES

See p. 795 for biosynthetic origins of pyrimidine ring atoms.

General Synthetic Strategy

1. First, synthesis of the pyrimidine ring.

2. Next, attachment of ribose-phosphate to the ring.

3. Further modification of the pyrimidine ring

Important Initial Finding

· Mutants of bread mold Neurospora crassa, which require cytosine and uracil for growth, can grow normally in the presence of orotic acid (see Fig. 22-5 for structure).

The Pathway for the Biosynthesis of UMP

· See Fig. 22-5.

Conversion of UMP to UDP and UTP

1. Nucleoside Monophosphate Kinase:

NMP + ATP ⇌ NDP + ADP

2. Nucleoside Diphosphate Kinase:

NDP + ATP ⇌ NTP + ADP

Conversion of UTP to CTP

· See Fig. 22-7.

REGULATION OF PYRIMIDINE NUCLEOTIDE BIOSYNTHESIS

· See Fig. 22-8.

FORMATION OF DEOXYRIBONUCLEOTIDES

· NDPs are converted to dNDPs by ribonucleotide reductases. (p. 799)

· Must be at the diphosphate level.

Conversion of dNDP to dNTP

· Nucleoside Diphosphate Kinase: (The same one for the phosphorylation of NDP.)

dNDP + ATP ⇌ dNTP + ADP

Conversion of dUTP to dTMP

· dUTP is not involved in DNA synthesis and must be converted to dTTP by way of dTMP.

· dUTP diphosphohydrolase

dUTP + H₂O → dUMP + PPi

· Thymidylate Synthase (p. 805)

dUMP + N⁵,N¹⁰-MethyleneTFH → dTMP + Dihydrofolate

Must be at the monophosphate level.

5-Fluorodeoxyuridylate (FdUMP) is a “Mechanism-Based” irreversible (Suicide) inhibitor for thymidylate synthase and a potent antitumor agent. (see p. 808 and Fig. 22-15)

· Dihydrofolate Reductase

DHF + NADPH + H⁺ → NADP⁺ + THF

Conversion of dTMP to dTTP

· Nucleoside Monophosphate Kinase:

dTMP + ATP ⇌ dTDP + ADP

· Nucleoside Diphosphate Kinase:

dTDP + ATP ⇌ dTTP + ADP

PYRIMIDNE DEGRADATION

· See Fig. 22-23.

· Animals: Pyrimidine nucleotides → component bases uracil or thymine.

· The resulting uracil and thymine → degradation through Reduction.

· Uracil → β-alanine → malonyl-CoA

· Thymine → β-aminoisobutyrate → methylmalonyl-CoA