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Uracil is the precursor of all pyrimidine nucleotides.

Pyrimidine biosynthesis. Uracil is the precursor of all pyrimidine nucleotides. N1 and carbons 4, 5 and 6 are derived from ASP. C2 and N3 are derived from carbamoyl phosphate. The carbamate group of carbamoyl phosphate is activated for group transfer (cf. ARG biosynthesis) . .

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Uracil is the precursor of all pyrimidine nucleotides.

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  1. Pyrimidine biosynthesis Uracil is the precursor of all pyrimidine nucleotides. N1 and carbons 4, 5 and 6 are derived from ASP. C2 and N3 are derived from carbamoyl phosphate.

  2. The carbamate group of carbamoyl phosphate is activated for group transfer (cf. ARG biosynthesis). Aspartate transcarbamoylase transfers it to the amino group of ASP to form N-carbamoyl aspartate.

  3. Dihydro-orotase forms the pyrimidine ring of 5,6-dihydro-orotate. Oxidation then gives orotate. N. B. The pyrimidine ring is assembled and then attached to ribose. The purine ring is constructed on a ribose sugar.

  4. + PRPP - CO2 Orotate condenses with PRPP to form orotidine monophosphate (OMP). Decarboxylation of OMP gives UMP.

  5. UMP is converted to UTP. Subsequent amination generates CTP. Formation of deoxyribonucleotides. The ribonucleotides ADP, GDP, CDP and UDP are converted to deoxyribonucleotides (dNDPs) by ribonucleotide reductase.

  6. Synthesis of dTMP dUDP is hydrolysed to dUMP. dTMP is synthesised by methylation of dUMP. This reaction is catalysed by thymidylate synthase with N5-N10 methylene THF as methyl group donor.

  7. The methylene group is reduced to a methyl group at the expenseof oxidation of the cofactor to dihydrofolate. + dUMP + dTMP DHF is converted back to THF by dihydrofolate reductase (DHFR).

  8. Rapidly proliferating cells like cancer cells require a steady supply of dTMP. Most mammalian cells grow slowly and require less dTMP (exceptions: cells of the bone marrow, intestinal mucosa and hair follicles). Thymidylate synthase is a good target for anti-cancer drugs. 5-Fluorodeoxyuridylate (F-dUMP) is an irreversible inhibitor of thymidylate synthase. It is an important anti-cancer drug.

  9. Higher organisms cannot synthesise THF and must obtain folate in their diet. Folate undergoes 2 reductions to form the active coenzyme THF. Both reductions require NADPH. Both are catalysed by dihydrofolate reductase (DHFR).

  10. DHFR is also a good target for anti-cancer drugs. If DHFR is inhibited, THF runs out and all THF-dependent reactions are blocked. Folate R = H, aminopterin R = CH3, methotrexate Aminopterin and methotrexate inhibit DHFR and are used to treat childhood leukaemias.

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