Purine Metabolism
Purines (Adenine and Guanine) are double-ring nitrogenous bases essential for DNA, RNA, ATP, NAD+, FAD, and cAMP. The body synthesizes them de novo and can salvage preformed bases.
De Novo Purine Synthesis
Occurs in the cytosol, primarily in the liver. The purine ring is assembled on Ribose-5-phosphate (from HMP shunt) through 11 steps. The first committed step: PRPP + Glutamine → 5-phosphoribosylamine [GPAT/PRPP Amidotransferase — inhibited by AMP, GMP (end-product feedback)].
The process requires: Glycine, Glutamine, THFA (one-carbon units), CO₂, Aspartate (N source), ATP (energy). Products: IMP (Inosine monophosphate) → AMP or GMP.
Energy expensive: Uses 5 PRPP + multiple ATP. The Purine Ring Atoms: N1 from Aspartate; C2, C8 from Formyl-THF; N3, N9 from Glutamine; C4, C5, N7 from Glycine; C6 from CO₂.
Salvage Pathway
Preformed purines from diet or nucleic acid turnover are recycled — saves energy:
- HGPRT (Hypoxanthine-Guanine Phosphoribosyltransferase): Hypoxanthine + PRPP → IMP; Guanine + PRPP → GMP
- APRT (Adenine Phosphoribosyltransferase): Adenine + PRPP → AMP
- Deficiency of HGPRT → Lesch-Nyhan syndrome (X-linked; ↑uric acid, gout, neurological symptoms, self-mutilation, choreoathetosis)
Purine Catabolism
AMP → IMP → Hypoxanthine → Xanthine [Xanthine Oxidase] → Uric Acid (poorly soluble, excreted in urine)
GMP → Guanosine → Guanine → Xanthine → Uric Acid
Uric acid is the final product of purine catabolism in humans (unlike most mammals which produce allantoin). At physiologic pH, exists as urate monosodium salt.
Gout
Caused by hyperuricemia (↑serum urate >6.8 mg/dL) → precipitation of monosodium urate crystals in joints (negatively birefringent, needle-shaped under polarized microscopy). Acute gout: Excruciating pain, redness, swelling in first MTP joint (podagra, big toe typical). Chronic tophaceous gout: Urate deposits in soft tissues.
- Causes: Decreased excretion (most common — 90%; Aspirin at low dose also reduces excretion), Increased production (10%; HGPRT def., PRPP synthetase overactivity, myeloproliferative disorders, tumor lysis)
- Acute treatment: NSAIDs (Indomethacin), Colchicine (inhibits microtubule polymerization → stops neutrophil migration), Steroids
- Chronic prevention: Allopurinol (XO inhibitor → ↑hypoxanthine, ↓uric acid); Febuxostat (non-purine XO inhibitor); Probenecid (uricosuric — ↑renal excretion)
Drugs Affecting Purine Synthesis
- 6-Mercaptopurine (6-MP): Incorporated as false substrate → feedback inhibitor of PRPP amidotransferase; used in leukemia. Activated by HGPRT; Azathioprine is prodrug.
- Methotrexate: DHFR inhibitor → depletes THF → blocks de novo purine and pyrimidine synthesis
- Hydroxyurea: Inhibits Ribonucleotide Reductase (dNTP synthesis)