De novo synthesis of nucleotides provides purine and pyrimidine bases necessary for DNA and RNA production.
Many anticancer, antibiotic, and immunosuppressive drugs target enzymes in these pathways to limit cell proliferation.
Pyrimidine Synthesis Pathway
| Step | Key Substrate / Enzyme | Clinical Relevance / Drug Target |
|---|---|---|
| Carbamoyl phosphate formation | CPS II (cytosolic enzyme using glutamine + CO₂ + ATP) | Inhibited by leflunomide (blocks dihydroorotate dehydrogenase) |
| Orotic acid → UMP | Requires aspartate | Defective in orotic aciduria (leads to megaloblastic anemia unresponsive to B₁₂/folate) |
| UMP → dTMP | Thymidylate synthase and dihydrofolate reductase (DHFR) | Inhibited by 5-FU, MTX, TMP, and pyrimethamine |
Key Concept:
Pyrimidine synthesis begins with a preformed base (orotate), while purine synthesis builds the base onto the sugar.
Purine Synthesis Pathway
| Step | Key Intermediate / Enzyme | Drug Target / Mechanism |
|---|---|---|
| Ribose-5-P → PRPP | PRPP synthetase | Overactivity causes gout (↑ purine turnover) |
| IMP → AMP / GMP | Requires aspartate, glycine, glutamine, and THF | 6-MP and azathioprine inhibit de novo purine synthesis |
| IMP → XMP → GMP | Inosine monophosphate dehydrogenase | Inhibited by mycophenolate and ribavirin |
Key Concept:
Purine synthesis is energy-intensive and tightly regulated. Salvage pathway defects (e.g., Lesch–Nyhan syndrome) cause severe neurologic and metabolic abnormalities.
Shared Pathway Inhibitors
| Drug | Target Enzyme | Effect |
|---|---|---|
| Hydroxyurea | Ribonucleotide reductase | ↓ DNA synthesis (used in sickle cell disease) |
| MTX, TMP, Pyrimethamine | DHFR | ↓ dTMP production |
| 5-FU | Thymidylate synthase | ↓ dTMP synthesis (thymineless death) |
Compartmental Localization
| Cycle / Enzyme | Cellular Site | Notes |
|---|---|---|
| CPS I | Mitochondria | Urea cycle (liver only) |
| CPS II | Cytosol | Pyrimidine synthesis (most cells) |
Key Points to Remember
- PRPP synthetase initiates both purine and pyrimidine synthesis.
- CPS II (cytosolic) → pyrimidine synthesis; CPS I (mitochondrial) → urea cycle.
- Orotic aciduria = defect in UMP synthesis (not due to urea cycle defect).
- Antimetabolites act by mimicking substrates or inhibiting key enzymes in nucleotide synthesis.
🎯 Learning Objective
By the end of this topic, medical students should be able to:
Explain the steps of de novo purine and pyrimidine synthesis, identify major enzyme targets of key drugs (anticancer, immunosuppressive, and antimicrobial), and recognize clinical disorders caused by enzyme defects or inhibition.
