Disorders of Purine and Pyrimidine Metabolism

Purine Power-Up - De Novo & Salvage

Purines (Adenine, Guanine) are made via De Novo or Salvage pathways. 📌 Purines PURE As Gold (2 rings).

• De Novo Synthesis: (Builds from scratch)

  • $Ribose-5-P + ATP \xrightarrow{PRPP \text{ Synthetase}} PRPP$
  • $PRPP + Gln \xrightarrow{GPAT (\text{Rate-limiting})} 5-Phosphoribosylamine \rightarrow \dots \rightarrow IMP$
  • IMP Dehydrogenase: crucial for GMP synthesis from IMP.

  ⭐ IMP is the parent purine nucleotide; AMP & GMP derive from it.

• Salvage Pathway: (Recycles bases with PRPP)

  • Hypoxanthine/Guanine $+ PRPP \xrightarrow{HGPRT} IMP/GMP$.
  • Adenine $+ PRPP \xrightarrow{APRT} AMP$.

Purine Disorders - Gouty Gremlins & More

• Gout: Hyperuricemia (serum uric acid > 6.8 mg/dL) → monosodium urate (MSU) crystal deposition.

  • Causes: Overproduction or underexcretion of uric acid.
  • Acute: Inflammatory arthritis (podagra - 1st MTP joint).
  • Chronic: Tophaceous gout, nephropathy.
  • Diagnosis: Synovial fluid: needle-shaped, negatively birefringent MSU crystals.
  • Treatment:
    • Acute: NSAIDs, colchicine, steroids.
    • Chronic: Allopurinol, febuxostat (xanthine oxidase inhibitors); probenecid (uricosuric).
  • 📌 Gout: Painful Tophi & Podagra.

• Lesch-Nyhan Syndrome (LNS):

  • Defect: HGPRT (Hypoxanthine-Guanine Phosphoribosyltransferase) deficiency; X-linked recessive.
  • Features: Hyperuricemia, self-mutilation, choreoathetosis, intellectual disability, dystonia, gout.
  • 📌 HGPRT - He's Got Purine Recovery Trouble.

• Adenosine Deaminase (ADA) Deficiency:

  • Defect: ADA deficiency → ↑dATP accumulation.
  • Result: Lymphotoxicity (T, B, and NK cells) → Severe Combined Immunodeficiency (SCID). Autosomal recessive.

⭐ Allopurinol and febuxostat are xanthine oxidase inhibitors used in chronic gout management.

Pyrimidine Production - Base Building Blocks

• De Novo Synthesis (Cytosol):
  • Reactants: Glutamine, $CO_2$, Aspartate.
  • Product: Uridine Monophosphate (UMP).
  • Key Enzymes:
    • Carbamoyl Phosphate Synthetase II (CPS-II): Rate-limiting step.
    • Aspartate Transcarbamoylase (ATCase).
    • Dihydroorotate Dehydrogenase (Mitochondrial inner membrane).
    • UMP Synthase (bifunctional: orotate phosphoribosyltransferase & OMP decarboxylase).
• Regulation:
  • CPS-II: Activated by ATP, PRPP; Inhibited by UTP, CTP.
• 📌 Mnemonics:
  • CPS I: mItochondria (Urea cycle). CPS II: cYtosol (pYrimidine synthesis).
  • Pyrimidines CUT Pye: Cytosine, Uracil, Thymine (1 ring).

⭐ UMP synthase is a bifunctional enzyme with orotate phosphoribosyltransferase & OMP decarboxylase activities. This is a common site for genetic defects leading to orotic aciduria type I (megaloblastic anemia unresponsive to B12/folate, growth retardation, orotic acid crystals in urine).

Pyrimidine Problems & Pharma - Orotic Oddities & Options

• Orotic Aciduria: Autosomal recessive.
  • Deficiency: UMP synthase (orotate phosphoribosyltransferase & OMP decarboxylase activity).
  • Symptoms: ↑ Orotic acid in urine (crystals), megaloblastic anemia (B12/folate resistant), failure to thrive.
  • Treatment: Uridine supplementation (bypasses block).
  • 📌 Mnemonic: "Orotic acid in urine, give Uridine to bypass block, improve symptoms."
• Drug Targets in Pyrimidine Pathway:
  • 5-Fluorouracil (5-FU): Inhibits thymidylate synthase (↓dTMP).
  • Methotrexate: Inhibits dihydrofolate reductase (↓THF for pyrimidine/purine synthesis).
  • Hydroxyurea: Inhibits ribonucleotide reductase.
  • Leflunomide: Inhibits dihydroorotate dehydrogenase.

  ⭐ Leflunomide inhibits dihydroorotate dehydrogenase, a key mitochondrial enzyme in de novo pyrimidine synthesis.

High‑Yield Points - ⚡ Biggest Takeaways

• Lesch-Nyhan syndrome: HGPRT deficiency (X-linked), self-mutilation, hyperuricemia, choreoathetosis.
• Adenosine Deaminase (ADA) deficiency: Leads to SCID via ↑dATP, inhibiting ribonucleotide reductase.
• Gout: Characterized by hyperuricemia and needle-shaped monosodium urate crystals (negatively birefringent).
• Allopurinol and febuxostat inhibit xanthine oxidase, reducing uric acid production.
• Orotic Aciduria: UMP synthase deficiency causes megaloblastic anemia (B12/folate resistant) and ↑orotic acid; treat with uridine.
• Carbamoyl Phosphate Synthetase II (CPS II): Rate-limiting enzyme of de novo pyrimidine synthesis in the cytoplasm.