Purine metabolism involves two main pathways:
- De novo synthesis – builds purines from scratch using ribose-5-phosphate.
- Salvage pathway – recycles free purine bases (guanine, hypoxanthine, adenine) to form nucleotides.
Defects in salvage enzymes cause significant clinical diseases, notably Adenosine Deaminase (ADA) deficiency and Lesch-Nyhan Syndrome (HGPRT deficiency).
Pathway Summary
| Process | Enzyme | Product / Function | Clinical Correlation |
|---|---|---|---|
| Adenine salvage | APRT (Adenine phosphoribosyltransferase) | Adenine → AMP | Rare deficiency |
| Hypoxanthine & Guanine salvage | HGPRT (Hypoxanthine-guanine phosphoribosyltransferase) | Hypoxanthine → IMP, Guanine → GMP | Defective in Lesch-Nyhan syndrome |
| Adenosine degradation | ADA (Adenosine deaminase) | Adenosine → Inosine | Defective in SCID |
| Purine catabolism | XO (Xanthine oxidase) | Hypoxanthine → Xanthine → Uric acid | Target of Allopurinol, Febuxostat |
Key Enzymes and Disorders
- Adenosine Deaminase (ADA) Deficiency
- Role: Converts adenosine → inosine (involved in purine degradation).
- Defect: Leads to accumulation of deoxyadenosine → dATP, which inhibits ribonucleotide reductase, blocking DNA synthesis.
- Effect: Toxic to lymphocytes → Severe Combined Immunodeficiency (SCID) (autosomal recessive).
- Clinical features:
- Recurrent infections,
- Failure to thrive,
- Absence of thymic shadow.
- Treatment Options Include Bone marrow transplant or gene therapy.
- Lesch–Nyhan Syndrome (HGPRT Deficiency)
- Role: HGPRT salvages hypoxanthine → IMP and guanine → GMP.
- Defect: HGPRT deficiency results in an excess of PRPP and de novo purine synthesis, leading to increased uric acid levels.
- Inheritance: X-linked recessive.
- Findings:
- Intellectual disability
- Self-mutilation, aggression
- Gout, hyperuricemia (orange “sand” = sodium urate crystals)
- Dystonia, macrocytosis
- Treatment: Allopurinol, Febuxostat.
| Feature | Mechanism |
|---|---|
| ↑ Uric acid | Overproduction from unregulated synthesis |
| Neurologic symptoms | Dopaminergic dysfunction |
| Gout/Crystals | Sodium urate deposition |
Clinical Connections
| Drug | Target | Purpose |
|---|---|---|
| Allopurinol | Xanthine oxidase inhibitor | ↓ Uric acid in gout/Lesch–Nyhan |
| Febuxostat | Non-purine XO inhibitor | Alternative to allopurinol |
| Cladribine, Pentostatin | ADA inhibitors | Used in hairy cell leukemia |
Learning Objective
By the end of this session, the student should be able to:
- Explain the role of purine salvage enzymes and describe the clinical manifestations, biochemical basis, and treatments of ADA deficiency and Lesch–Nyhan syndrome.
