54. Pyrimidine metabolism

Question 1

Nomenclature of pyrimidines

Answer 1

Base: cytosine, thymine, uracil, orotic acid.
NucleoSIDE: cystidine, uridine, thymidine.
NucleoTIDE: CMP, TMP, UMP.

Question 2

Synthesis of pyrimidine

Answer 2

1) Glu+HCO3+2ATP–>carbamoyl phosphate (by CPS-2; activated by ATP&PRPP).
2) CP+aspartate–> carbamoyl aspartate (by aspartate transcarbamylase).
3) Carbamoyl aspartate –> dihydroorate (by dihydrooratase).
* **1-3 done by multifunctional enzyme CAD.
4) Dihydroorate–>orotate (by dihydroorotate DH)
5) Orate + PRPP –> OMP (by orotate phosphoribosyl transferase)
6) OMP –> UMP (by OMP decarboxylase; inhibited by UMP).
* **5-6 done by UMP synthetase
7) (UMP–>)UTP + ATP + gln–> CTP + ADP + glu (by CTP synthetase)

Question 3

Synthesis of dNT

Answer 3

NDP + reduced thioredoxin –> dNDP + oxidized thioredoxin (by nucleotide reductase; inhibited by dATP, activated by ATP).
Oxidized thioredoxin is reduced by NADPH.

Question 4

Synthesis of TMP

Answer 4

dUMP + 5,10-methylene-THF –> TMP+odixized dihydrofolate (by thymidylate synthase).

Oxidized dihydrofolate becomes THF (dihydrofolate reductase + NADPH).

Question 5

Salvage pathway for pyrimidine

Answer 5

uridine-cystidine kinase: nucleoside–>nucleotide.

Question 6

Degradation pathway for pyrimidine

Answer 6

Pyrimidine rings cleaved and degraded into soluble structures.

Question 7

Drug targets for pyrimidines

Answer 7

1. 5-FU. competitively inhibits thymidylate synthase (dUMP–>TMP). Inhibits DNA synthesis (chemotherapy for tumors).
2. Methotrexate and aminopterin. Folate analogs that competitively inhibit dihydrofolate reductase. can’t form THF.
3. Nucleoside analogs: AZT inhibits HIV reverse transcriptase (thymine analog)
4. Sulfoamides: bacterial folate synthesis inhibitor.