Learning Objectives

• Trace the de novo pathways for purine and pyrimidine synthesis.
• Differentiate between CPS1 (Urea Cycle) and CPS2 (Pyrimidine Synthesis).
• Master the pharmacological targets of key immunosuppressive and antineoplastic drugs.
• Understand the folate cycle and its role in dTMP production.

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1. De Novo Synthesis Overview

Nucleotide synthesis begins with Ribose 5-Phosphate, which is converted to PRPP. From here, the pathways diverge into purine and pyrimidine production.

Key Enzyme Distinction (High-Yield)

• CPS1: Located in the mitochondria; involved in the Urea Cycle (Liver).
• CPS2: Located in the cytosol; involved in Pyrimidine Synthesis (Most cells).

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2. Pharmacology: Pyrimidine Pathway Inhibitors

Drugs in this category primarily target the production of UMP and dTMP (DNA synthesis).

• Leflunomide: Inhibits dihydroorotate dehydrogenase (prevents orotic acid formation).
• 5-Fluorouracil (5-FU): Its metabolite (5-F-dUMP) inhibits Thymidylate Synthase, decreasing dTMP.
• Hydroxyurea: Inhibits Ribonucleotide Reductase (blocks conversion of UDP to dUDP). Also affects purine synthesis.

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3. Pharmacology: Purine Pathway Inhibitors

These drugs interfere with the formation of IMP, AMP, and GMP.

• 6-Mercaptopurine (6-MP) & Azathioprine: Inhibit de novo purine synthesis.Note: Azathioprine is a prodrug of 6-MP. Be careful with Allopurinol (XO inhibitor) as it increases 6-MP toxicity!
• Mycophenolate & Ribavirin: Inhibit Inosine Monophosphate (IMP) Dehydrogenase, blocking GMP production.

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4. The Folate Cycle & DHF Reductase

Folate is essential for providing methyl groups to transform dUMP into dTMP. This is a common target for antibiotics and chemotherapy.

Drug	Target Organism	Mechanism
Methotrexate (MTX)	Humans	Inhibits Dihydrofolate (DHF) Reductase.
Trimethoprim (TMP)	Bacteria	Inhibits Bacterial DHF Reductase.
Pyrimethamine	Protozoa	Inhibits Protozoal DHF Reductase.

 

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