Biosynthesis and Degradation of Purines
Purines include adenine and guanine, found in DNA, RNA, ATP, GTP, NAD⁺, FAD, CoA and many signaling molecules. Their metabolism is carefully regulated because their breakdown products (uric acid) can accumulate.
De Novo Synthesis of Purine Nucleotides
- The purine ring is synthesized directly on a ribose-5-phosphate backbone.
- The starting molecule is ribose-5-phosphate, formed in the Pentose Phosphate Pathway.
- PRPP (phosphoribosyl pyrophosphate) is formed from ribose-5-phosphate by PRPP synthetase (requires ATP).
- The first committed step is conversion of PRPP → 5-Phosphoribosylamine, catalyzed by glutamine-PRPP amidotransferase.
- The ring atoms come from:
- Glutamine (N)
- Glycine (C + N)
- Aspartate (N)
- CO₂ (C)
- Tetrahydrofolate (formyl groups, C)
- The initial product of the pathway is IMP (inosine monophosphate).
- From IMP, two branches form:
- GMP pathway (requires ATP)
- AMP pathway (requires GTP)
- This cross-dependence helps balance adenine and guanine pools.
Regulation
- Feedback inhibition:
- AMP and GMP inhibit their own synthesis from IMP.
- PRPP amidotransferase is inhibited when purine levels are high.
- PRPP levels rise in purine deficiency, accelerating purine production.
Purine Salvage Pathway
- Salvage recycles free bases (adenine, hypoxanthine, guanine) back into nucleotides.
- Catalyzed mainly by:
- HGPRT (Hypoxanthine-Guanine Phosphoribosyltransferase)
- APRT (Adenine Phosphoribosyltransferase)
- Salvage conserves energy because de novo synthesis is costly.
Degradation of Purines
- AMP and GMP are degraded into xanthine.
- Xanthine oxidase converts xanthine → uric acid.
- Humans excrete uric acid (poorly soluble).
- Excess uric acid leads to gout, where urate crystals accumulate in joints.