Chapter 32 - Nucletide Metabolism

What is the nomenclature of nucleotides?

Nucleosides and nucleotides

• Nucleoside includes: a base and a sugar

• Nucleotide includes: A base, a sugar, and at least one phosphate

  • can be mono-, di-, or triphosphate

  • can be cyclic

• APT is a nucleotide

Overview of nucleotide biosynthesis

Can be divided into two groups:

• De novo pathways

  • bases assembled from simpler compounds

  • Energetically expensive

  • Timing of attachment to sugar differs for purines and pyrimidines

• Salvage pathways

  • uses already complete bases

  • reconnects bases to ribose

  • energetically cheapers, preferred

both lead to ribonucleotides

What is a pyrimidine ring synthesized from?

• Bicarbonate

• Aspartate

• Ammonia

  • rings is attached to activated ribose PRPP

  • after attachment ring is decarboxylated to form UMP

  • CTP can be formed by amination of UTP from UMP

  • built before linkage to ribose

What is the first step of synthesis of pyrimidines de novo?

Formation of arbamoly phosphate

• catalyzed by carbamoyl phosphate synthetase II, CPS II

  • requires two ATP

  • nitrogen donated from glutamine

What happens after the carbamoyl phosphate is formed?

• Carbamoyl phosphate and aspartate combine to create aspartate transcarbamoylase

  • then is cyclized by dihydroorotase and then oxidized to orotate

How is the pyrimidine attached to ribose?

Attachment depends on activated ribose from PRPP

• linkage to PRPP forms nucleotide orotidylate

• orotidylate is then decarboxylated to form uridylate

How does the pyrimidine salvage pathway work?

Pyrimidine bases from the breakdown of DNA/RNA can be reused

• example: Formation of thymidylate from thymine

  • catalyzed by thymidine kinase

Overview of purines de novo

Purine rings are assembled on ribose phosphate

• pyrophosphate on PRPP replaced by amine

  • required precursors:

    • Glycine

    • Glutamine

    • Aspartate

    • also depends on tetrahydrofolate

How is adenylate and guanylate created?

Inosine monophosphate is used to make standard purine nucleotides

How are deoxyribonucleotides formed?

Formed by the reduction of ribonucleotides

• carried out by ribonucleotide reductase

• rxn requires NADPH

What regulates pyrimidine biosynthesis

Aspartate transcarbamoylase

• activated by ATP

• inhibited by CTP

net effect balance purine and pyrimidine levels

CPS II also feedback inhibited

• bacteria and eukaryotes