Purine metabolism and dietary/drug effects on uric acid
Core concept
The catabolic pathway
- Nucleic acid / ATP turnover -> AMP, GMP
- -> inosine -> hypoxanthine
- -> (xanthine oxidase) -> xanthine
- -> (xanthine oxidase) -> uric acid
- Humans lack uricase - urate is the end product, and it is poorly soluble
- Solubility limit ~0.41 mmol/L (6.8 mg/dL) at 37 C; falls further in cool peripheral joints -> first MTP
- Salvage pathway - HGPRT recycles hypoxanthine/guanine back to IMP/GMP
- Complete HGPRT loss = Lesch-Nyhan (X-linked; gross overproduction, self-mutilation, choreoathetosis)
- Partial = Kelley-Seegmiller (gout + urolithiasis, no neurology)
- PRPP synthetase superactivity - inc substrate flux -> overproduction, X-linked
Handling
- ~90% of hyperuricaemia is renal underexcretion, not overproduction
- Filtered freely, then near-completely reabsorbed in PCT
- URAT1 (SLC22A12) and GLUT9 (SLC2A9) reabsorb - the drug targets
- ABCG2 secretes; loss-of-function variants = common gout risk allele
3 more sections, plus exam facts
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