Purine & Pyrimidine Metabolism
A board-focused walkthrough of purine and pyrimidine metabolism — de novo synthesis, salvage, and catabolism — tied to the two ways STEP 1 tests it: chemotherapy/immunosuppressant drug targets and inherited enzyme deficiencies (Lesch-Nyhan, ADA-SCID, hereditary orotic aciduria). Emphasizes next-best-step discriminators such as orotic aciduria vs. OTC deficiency.
Why this is high-yield
Nucleotides are made two ways: de novo synthesis (from scratch, energy-expensive) and the salvage pathway (recycling free bases). The USMLE tests this topic through two lenses — drug targets (chemo/immunosuppressants) and inherited enzyme deficiencies.
Remember the key asymmetry in catabolism: purines (A, G) are degraded to uric acid, which is poorly soluble and precipitates (gout, urate stones), whereas pyrimidines (C, U, T) break down into soluble products (CO₂, NH₃, β-alanine, β-aminoisobutyrate). That single fact explains why purine defects cause hyperuricemia and pyrimidine defects do not.
- De novo purine synthesis: ribose-5-P → PRPP → committed/rate-limiting step by glutamine–PRPP amidotransferase; the ring is built onto ribose, first product is IMP → AMP/GMP. Requires glycine, aspartate, glutamine, N10-formyl-THF (folate).
- De novo pyrimidine synthesis: carbamoyl phosphate (CPS II, cytosol) + aspartate → orotic acid, then PRPP is added (UMP synthase) → UMP → UDP/UTP/CTP; the ring is built first, then attached to ribose.
- Ribonucleotide reductase converts ribonucleotides → deoxyribonucleotides (target of hydroxyurea).
- Salvage enzymes: HGPRT (hypoxanthine/guanine → IMP/GMP) and APRT (adenine → AMP).
- Purine catabolism: adenosine → inosine (ADA) → hypoxanthine → xanthine → uric acid via xanthine oxidase (blocked by allopurinol/febuxostat; rasburicase/uricase further degrades urate to soluble allantoin).
Drugs that target nucleotide synthesis
| Drug | Enzyme inhibited | Result / association |
|---|---|---|
| Hydroxyurea | Ribonucleotide reductase | ↓ dNTPs (sickle cell, CML) |
| 6-mercaptopurine / azathioprine / 6-thioguanine | De novo purine synth (PRPP amidotransferase) | ↓ purines; 6-MP/azathioprine toxicity ↑ by allopurinol (XO metabolizes 6-MP) |
| Mycophenolate / ribavirin | IMP dehydrogenase | ↓ GMP |
| Leflunomide | Dihydroorotate dehydrogenase | ↓ pyrimidines |
| 5-fluorouracil (5-FU) | Thymidylate synthase | ↓ dTMP; biochemical rescue with thymidine |
| Methotrexate / trimethoprim / pyrimethamine | Dihydrofolate reductase | ↓ THF → ↓ dTMP (rescue MTX with leucovorin) |
Stem: A 2-year-old boy has delayed development, involuntary writhing movements, and has bitten his own lips and fingertips. Parents report orange 'sand' (crystals) in his diaper. Serum uric acid is markedly elevated.
Diagnosis: Lesch-Nyhan syndrome — HGPRT deficiency, X-linked recessive. Loss of purine salvage → accumulated PRPP drives ↑ de novo synthesis, and unsalvaged bases are degraded → hyperuricemia.
Classic features (HGPRT mnemonic): Hyperuricemia, Gout, Pissed-off (aggression / self-mutilation), int. disability (Retardation), dysTonia / choreoathetosis.
Next best step / management: allopurinol (or febuxostat) to lower uric acid — it prevents gout/stones but does NOT reverse the neurologic disease.
Stem: A 6-month-old has failure to thrive and megaloblastic anemia that does NOT improve with vitamin B12 or folate. Serum ammonia is normal; urine orotic acid is elevated.
Diagnosis: Hereditary orotic aciduria — deficiency of UMP synthase (autosomal recessive); orotic acid cannot be converted to UMP, so pyrimidine (and thus DNA) synthesis stalls.
Key discriminator: normal ammonia excludes OTC deficiency (a urea-cycle disorder that also raises orotic acid but causes hyperammonemia).
Next best step / treatment: oral uridine (uridine triacetate) — bypasses the block, restores pyrimidines, and corrects the anemia.
Orotic aciduria vs. OTC deficiency (both raise orotic acid)
| Feature | Orotic aciduria (UMP synthase) | OTC deficiency |
|---|---|---|
| Pathway | Pyrimidine synthesis | Urea cycle |
| Inheritance | Autosomal recessive | X-linked recessive |
| Urine orotic acid | ↑ | ↑ |
| Ammonia | Normal | ↑ (hyperammonemia) |
| Megaloblastic anemia | Yes | No |
| BUN | Normal | ↓ |
| Treatment | Uridine | Low-protein diet, benzoate/phenylbutyrate |
- ADA (adenosine deaminase) deficiency: most common cause of autosomal recessive SCID. Loss of ADA → ↑ dATP → inhibits ribonucleotide reductase → no dNTPs → lymphocytes can't proliferate (↓ B and T cells). Historic early success with gene therapy.
- Ribonucleotide reductase is the shared choke point (also hydroxyurea's target).
- Hyperuricemia / gout causes: von Gierke disease (G6Pase deficiency), Lesch-Nyhan, PRPP synthetase overactivity, ↓ renal excretion (thiazides, alcohol, lactic/keto acids), and ↑ turnover (tumor lysis syndrome; prevent with hydration + rasburicase).
- Tumor lysis syndrome labs: ↑ uric acid, ↑ K⁺, ↑ phosphate, ↓ Ca²⁺.
- PURines = Adenine + Guanine → *'purines are PURe As Gold'*; 2 fused rings.
- Pyrimidines = Cytosine, Uracil, Thymine → *'CUT the Py (pie)'*; 1 ring.
- Thymine has a meThyl group and is DNA-only; uracil replaces it in RNA.
- DHFR inhibitors by target species: Methotrexate = humans (Man), Trimethoprim = bacteria, Pyrimethamine = protozoa (malaria/toxo).
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