De novo pyrimidine and purine synthesis

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Purine synthesis

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Pyrimidine synthesis

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Folate acid pathway

Folate Pathway: The Basics

Folate (Vitamin B9) is converted to Tetrahydrofolate (THF), an essential coenzyme for:

  1. Purine synthesis (Adenine, Guanine)
  2. Thymidine synthesis (via N5,N10-methylene THF and thymidylate synthase)
  3. Amino acid metabolism

Key Enzymes & Inhibitors:

  1. Dihydropteroate Synthase (Bacteria only)
    • Drug: Sulfonamides (e.g., Sulfamethoxazole - SMX)
      • MoA: PABA analogs; block bacterial folic acid synthesis.
      • Use: UTIs, PJP (often with Trimethoprim).
      • AEs: Hypersensitivity (SJS), photosensitivity, crystalluria, G6PD hemolysis, kernicterus.
  2. Dihydrofolate Reductase (DHFR)
    • Drug: Trimethoprim (TMP) (Primarily bacterial DHFR)
      • MoA: Inhibits bacterial DHFR ⟹ ↓THF.
      • Use: UTIs, PJP (synergistic with SMX = TMP-SMX/Co-trimoxazole).
      • AEs: Megaloblastic anemia, leukopenia, hyperkalemia. (Leucovorin can reduce bone marrow effects).
    • Drug: Methotrexate (MTX) (Human DHFR)
      • MoA: Inhibits human DHFR ⟹ ↓THF ⟹ ↓DNA/RNA synthesis.
      • Use: Cancer, rheumatoid arthritis, psoriasis, ectopic pregnancy, immunosuppression.
      • AEs: Myelosuppression (dose-limiting), mucositis, hepatotoxicity, pulmonary fibrosis, nephrotoxicity, teratogenic.
      • Leucovorin (Folinic Acid) Rescue: Bypasses DHFR block in normal cells to reduce MTX toxicity.
        • Leucovorin is 5-formyl-tetrahydrofolate. This means its core pteridine ring structure is already in the fully reduced (tetrahydro) state, the same state that DHFR aims to achieve.
    • Drug: Pyrimethamine (Protozoal DHFR)
      • MoA: Inhibits protozoal DHFR.
      • Use: Toxoplasmosis (with sulfadiazine), malaria.
      • AEs: Megaloblastic anemia. (Leucovorin can reduce bone marrow effects).
  3. Thymidylate Synthase (Requires N5,N10-methylene THF from folate pathway)
    • Drug: 5-Fluorouracil (5-FU)
      • MoA: Pyrimidine analog; active metabolite FdUMP forms a complex with thymidylate synthase and N5,N10-methylene THF, inhibiting dTMP ("thymineless death").
      • Use: Solid tumors (e.g., colorectal, breast, pancreatic).
      • AEs: Myelosuppression, mucositis/diarrhea, hand-foot syndrome, photosensitivity.
      • Leucovorin (Folinic Acid) Potentiation: Enhances 5-FU efficacy by stabilizing the inhibitory complex (different role than with MTX).
      • Note: DPD deficiency increases 5-FU toxicity.
Drug Target Enzyme/Process Primary Use(s) Key Adverse Effects Leucovorin Interaction
Sulfonamides Bacterial Dihydropteroate Synthase UTIs, PJP (bacterial infections) Hypersensitivity, photosensitivity, crystalluria, G6PD hemolysis N/A
Trimethoprim Bacterial Dihydrofolate Reductase (DHFR) UTIs, PJP (bacterial infections, with SMX) Megaloblastic anemia, leukopenia, hyperkalemia Rescue (bone marrow)
Methotrexate Human Dihydrofolate Reductase (DHFR) Cancer, autoimmune disease, ectopic pregnancy Myelosuppression, mucositis, hepatotoxicity, teratogenic Rescue (reduces toxicity)
Pyrimethamine Protozoal Dihydrofolate Reductase (DHFR) Toxoplasmosis, malaria Megaloblastic anemia Rescue (bone marrow)
5-Fluorouracil Thymidylate Synthase (via FdUMP & N5,N10-methylene THF complex) Solid tumors (e.g., colorectal cancer) Myelosuppression, mucositis, diarrhea, hand-foot syndrome Potentiation (increases efficacy)

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Para-aminobenzoic acid (PABA) is a folic acid precursor in prokaryotes. Sulfonamide antibiotics are chemical analogues of PABA that inhibit the enzyme dihydropteroate synthetase, preventing bacterial conversion of PABA to folic acid. Humans lack the ability to convert PABA to folic acid and require dietary folate.
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The enzyme thymidylate synthase is responsible for converting deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Although most enzymes involved in one-carbon metabolism maintain folate in its active tetrahydrofolate form, thymidylate synthase is unique in that it oxidizes 5,10-methylenetetrahydrofolate to dihydrofolate. This makes de novo thymidine synthesis particularly susceptible to folate-deficient conditions because tetrahydrofolate must be continuously regenerated by dihydrofolate reductase.