Nucleotide Degradation and Salvage Pathways

Purine Degradation - Uric Acid Unravelled

• Purines (AMP, GMP) ultimately degrade to Uric Acid.
• Key Intermediates: Inosine, Guanosine, Hypoxanthine, Xanthine.
• Xanthine Oxidase (XO): Key enzyme. Catalyzes two steps:
  • Hypoxanthine $\rightarrow$ Xanthine
  • Xanthine $\rightarrow$ Uric Acid. Produces $H_2O_2$.
• Clinical Correlation: Gout (Hyperuricemia).
  • $\uparrow$ Uric acid levels $\rightarrow$ monosodium urate crystal deposition in joints & tissues.
• Significant Enzyme Deficiencies:
  • ADA (Adenosine Deaminase) Deficiency: Accumulation of adenosine & deoxyadenosine $\rightarrow$ lymphotoxicity (especially T & B cells) $\rightarrow$ Severe Combined Immunodeficiency (SCID). 📌 ADA causes SCID.
  • PNP (Purine Nucleoside Phosphorylase) Deficiency: Affects T-cells primarily $\rightarrow$ recurrent infections, neurological issues.

⭐ Allopurinol, a suicide inhibitor, and Febuxostat, a non-purine inhibitor, target Xanthine Oxidase in gout treatment.

Purine Salvage - Rescue & Recycle

• Reclaims purine bases (adenine, guanine, hypoxanthine) from degradation, using PRPP.
• Conserves energy vs. de novo synthesis. Vital for tissues with low de novo capacity (e.g., brain).
• Key Enzymes & Reactions:
  • APRT (Adenine Phosphoribosyltransferase):
    • Adenine + PRPP $\rightarrow$ AMP + PPi
    • Deficiency: APRT nephropathy (2,8-dihydroxyadenine stones).
  • HGPRT (Hypoxanthine-Guanine Phosphoribosyltransferase):
    • Hypoxanthine + PRPP $\rightarrow$ IMP + PPi
    • Guanine + PRPP $\rightarrow$ GMP + PPi
    • Partial deficiency: Kelley-Seegmiller syndrome (gout, urolithiasis).

⭐ Lesch-Nyhan syndrome (HGPRT deficiency) presents with hyperuricemia, gout, self-mutilation, and neurological dysfunction (📌 Mnemonic: HGPRT - Hyperuricemia, Gout, Pissed off [aggression, self-mutilation], Retardation, dysTonia).

Pyrimidine Metabolism - Breakdown & Buildup

• Breakdown (Catabolism):
  • C, U, T → β-Alanine, β-Aminoisobutyrate, $NH_3$, $CO_2$ (water-soluble).
  • Key enzyme: Dihydropyrimidine dehydrogenase (DPD). DPD def.: ↑5-FU toxicity.
• Buildup (De Novo Synthesis):
  • Precursors: Glutamine, $CO_2$, Aspartate.
  • Key: Carbamoyl Phosphate Synthetase II (CPS II) (cytosolic, rate-limiting).
  • Orotic acid → UMP (UMP Synthase).
  • Orotic Aciduria: UMP Synthase defect; megaloblastic anemia, orotic aciduria. Rx: Uridine.
• Salvage: Minor pathway.

⭐ Pyrimidine breakdown yields highly water-soluble products (β-alanine, β-aminoisobutyrate, NH3, CO2), unlike purine catabolism, thus no gout-like syndromes.

Clinical Hotspots - Pathway Pathologies

• Gout:
  • Hyperuricemia (↑purine breakdown / ↓excretion). Allopurinol inhibits xanthine oxidase.
  • Acute inflammatory arthritis (urate crystals), tophi.
  • Triggers: alcohol, red meat, fructose.
• Lesch-Nyhan Syndrome:
  • X-linked HGPRT deficiency (purine salvage defect).
  • Hyperuricemia, gout, self-mutilation, choreoathetosis, intellectual disability.
  • 📌 Hyperuricemia, Gout, Pissed off (aggression/self-mutilation), Retardation (intellectual disability), DysTonia.
• Adenosine Deaminase (ADA) Deficiency:

  ⭐ Adenosine Deaminase (ADA) deficiency causes Severe Combined Immunodeficiency (SCID) due to accumulation of dATP, which is toxic to T and B lymphocytes by inhibiting ribonucleotide reductase.

• Purine Nucleoside Phosphorylase (PNP) Deficiency:
  • Autosomal recessive; causes severe T-cell immunodeficiency. Recurrent infections.

High‑Yield Points - ⚡ Biggest Takeaways

• Purine degradation culminates in uric acid; its overproduction or underexcretion causes gout.
• Adenosine Deaminase (ADA) deficiency is a key cause of Severe Combined Immunodeficiency (SCID).
• Lesch-Nyhan syndrome, due to HGPRT deficiency, features hyperuricemia and self-mutilation.
• Pyrimidine degradation yields water-soluble products like β-alanine and β-aminoisobutyrate.
• Salvage pathways are crucial for recycling purine bases, conserving metabolic energy.
• Allopurinol inhibits xanthine oxidase, treating gout by ↓ uric acid production.
• Ribonucleotide reductase is vital for converting ribonucleotides to deoxyribonucleotides for DNA synthesis.