U01.01.003 De novo pyrimidine and purine synthesis

Various immunosuppressive, antineoplastic, and antibiotic drugs interfere with nucleotide synthesis. Here is a breakdown of the pathways and key drugs involved:

Pathways and Key Enzymes

Pyrimidine Synthesis:

Carbamoyl Phosphate: Formed from glutamine and CO₂.
CPS2 (Carbamoyl Phosphate Synthetase II): Catalyzes the formation of carbamoyl phosphate in the cytosol.
UMP Synthase: Converts orotic acid to UMP. Impaired in orotic aciduria.
UMP: Converted to UDP, dUDP, and then to dUMP.
dUMP: Converted to dTMP by thymidylate synthase.
DHF (Dihydrofolate) and THF (Tetrahydrofolate): Involved in the conversion processes.

Purine Synthesis:

PRPP (Phosphoribosyl Pyrophosphate) Synthetase: Catalyzes the formation of PRPP from ribose 5-phosphate.
IMP (Inosine Monophosphate): Precursor for AMP and GMP.
De Novo Pathway: Requires aspartate, glycine, glutamine, and THF.
Salvage Pathway: Purine bases can be reused.

Key Drugs and Their Effects

Drug	Target	Effect on Synthesis
Leflunomide	Dihydroorotate dehydrogenase	Inhibits pyrimidine synthesis
5-Fluorouracil (5-FU)	Thymidylate synthase	Inhibits dTMP formation
Capecitabine	Thymidylate synthase	Prodrug for 5-FU
6-Mercaptopurine (6-MP)	De novo purine synthesis	Inhibits purine synthesis
Azathioprine	De novo purine synthesis	Prodrug for 6-MP
Mycophenolate	Inosine monophosphate dehydrogenase	Inhibits purine synthesis
Ribavirin	Inosine monophosphate dehydrogenase	Inhibits purine synthesis
Hydroxyurea	Ribonucleotide reductase	Inhibits both purine and pyrimidine synthesis
Methotrexate (MTX)	Dihydrofolate reductase	Inhibits dTMP formation
Trimethoprim (TMP)	Dihydrofolate reductase	Inhibits bacterial dTMP formation
Pyrimethamine	Dihydrofolate reductase	Inhibits protozoal dTMP formation

Key Drugs and Their Effects

Points to Remember

Pyrimidine Synthesis:
- Leflunomide inhibits dihydroorotate dehydrogenase.
- 5-Fluorouracil (5-FU) and capecitabine inhibit thymidylate synthase, affecting dTMP production.
Purine Synthesis:
- 6-Mercaptopurine (6-MP) and azathioprine inhibit de novo purine synthesis.
- Mycophenolate and ribavirin inhibit inosine monophosphate dehydrogenase.
Purine and Pyrimidine Synthesis:
- Hydroxyurea inhibits ribonucleotide reductase, impacting both pathways.
- Methotrexate (MTX), trimethoprim (TMP), and pyrimethamine inhibit dihydrofolate reductase, affecting dTMP production across different organisms.

This breakdown provides a comprehensive overview of nucleotide synthesis pathways and the drugs that target them, crucial for understanding their roles in medical treatments.

USMLE Step 1 Review Series

Curriculum

U01.01.003 De novo pyrimidine and purine synthesis

Pathways and Key Enzymes

Key Drugs and Their Effects

Points to Remember

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