Biochemistry · Metabolic pathway

De novo purine synthesis !

Cells build the purine ring piece by piece on a phosphorylated ribose until they reach IMP, which then becomes AMP and GMP.

Updated 2026-11-01

Interactive map

Balance: ATP -6CO₂ -1NADH +1

Key facts

The ring is assembled on ribose-5-phosphate (as PRPP): sugar first, base second. Common product: IMP.
PRPP amidotransferase is the committed, rate-limiting step; AMP, GMP and IMP inhibit it and PRPP activates it.
Ring atom sources: glycine (C4, C5, N7), glutamine (N3, N9), aspartate (N1), CO₂ (C6) and two formyl groups from N¹⁰-formyl-THF (C2, C8).
It costs about 6 high-energy bonds per IMP from ribose-5-phosphate (2 to make PRPP and 4 along the way).
From IMP: AMP is made with GTP and aspartate; GMP with ATP and glutamine. Each branch spends the other's energy currency, which keeps them balanced.

In detail

Step 3 onwards: GART is a trifunctional protein (GAR synthetase, GAR transformylase, AIR synthetase).
PAICS joins two activities: AIR carboxylase (adds CO₂, forming CAIR) and SAICAR synthetase (adds aspartate).
ATIC is also bifunctional: AICAR transformylase adds the second formyl (FAICAR) and IMP cyclohydrolase closes the ring.
GMP branch: IMPDH (IMP → XMP, with NAD⁺) then GMP synthetase (XMP → GMP, with glutamine and ATP).
AMP branch: adenylosuccinate synthetase (IMP + aspartate + GTP → adenylosuccinate) and adenylosuccinate lyase (releases fumarate, leaving AMP).
The enzymes cluster into a transient complex called the purinosome when the cell needs many purines.

Also called: IMP biosynthesis

Regulation

PRPP synthetase: ADP and GDP inhibit it; inorganic phosphate activates it.
PRPP amidotransferase: feedback inhibition by AMP, GMP and IMP (synergistic when both kinds are present); PRPP activates it.
At the branches, AMP inhibits adenylosuccinate synthetase and GMP inhibits IMPDH.

The steps, one by one

Step 1 · PRPP synthetase irreversible Ribose 5-phosphate + ATP → PRPP + ampMoves a pyrophosphate from ATP onto C1 of ribose-5-phosphate, making PRPP, the activated ribose.If it fails: Superactivity (X-linked) causes gout and uric acid stones at a young age. Gout →
Step 2 · Glutamine-PRPP amidotransferase irreversible PRPP + Glutamine + H₂O → 5-Phosphoribosylamine (PRA) + Glutamate + pyrophosphateCommitted step: the amide nitrogen of glutamine replaces the pyrophosphate at C1, giving the future N9.If it fails: Excess activity driven by extra PRPP raises uric acid production.
Step 3 · GAR synthetase (GART domain) irreversible 5-Phosphoribosylamine (PRA) + Glycine + ATP → Glycinamide ribonucleotide (GAR) + ADP + phosphate (Pi)Attaches a whole glycine (C4, C5, N7) to phosphoribosylamine, spending one ATP.If it fails: No common human defects of this step are known.
Step 4 · GAR transformylase (GART domain) irreversible Glycinamide ribonucleotide (GAR) + N¹⁰-Formyl-tetrahydrofolate → Formylglycinamide ribonucleotide (FGAR) + Tetrahydrofolate (THF)First formyl group from folate: it supplies ring carbon C8.If it fails: Folate deficiency slows this step and step 9: fewer purines for DNA, with megaloblastic anaemia.
Step 5 · FGAM synthetase (PFAS) irreversible Formylglycinamide ribonucleotide (FGAR) + Glutamine + ATP + H₂O → Formylglycinamidine ribonucleotide (FGAM) + Glutamate + ADP + phosphate (Pi)A second glutamine supplies N3.If it fails: No clinically important human defects are known.
Step 6 · AIR synthetase (GART domain) irreversible Formylglycinamidine ribonucleotide (FGAM) + ATP → 5-Aminoimidazole ribonucleotide (AIR) + ADP + phosphate (Pi) + H₂OCloses the first ring, the five-membered imidazole.If it fails: No clinically important human defects are known.
Step 7 · PAICS (AIR carboxylase + SAICAR synthetase) irreversible 5-Aminoimidazole ribonucleotide (AIR) + CO₂ + Aspartate + ATP → SAICAR (succinylaminoimidazole carboxamide ribonucleotide) + ADP + phosphate (Pi)Adds CO₂ (C6) without biotin, then an aspartate whose nitrogen will become N1.If it fails: PAICS deficiency is very rare and severe in newborns.
Step 8 · Adenylosuccinate lyase (ADSL) SAICAR (succinylaminoimidazole carboxamide ribonucleotide) ⇌ AICAR (aminoimidazole carboxamide ribonucleotide) + fumarateCuts away the aspartate skeleton: fumarate leaves and only its nitrogen stays.If it fails: ADSL deficiency causes epilepsy, autism and developmental delay; succinylpurines appear in urine.
Step 9 · ATIC (AICAR transformylase + IMP cyclohydrolase) irreversible AICAR (aminoimidazole carboxamide ribonucleotide) + N¹⁰-Formyl-tetrahydrofolate → IMP + Tetrahydrofolate (THF) + H₂OSecond formyl group from folate (C2) and closure of the six-membered ring: IMP appears.If it fails: Methotrexate inhibits it and AICAR builds up, releasing adenosine: part of its anti-inflammatory effect.
Step 10 · IMP dehydrogenase (IMPDH) irreversible IMP + NAD⁺ + H₂O → Xanthosine monophosphate (XMP) + NADHOpens the GMP branch: oxidises IMP to XMP; GMP synthetase then makes GMP.If it fails: IMPDH1 variants cause retinitis pigmentosa; blocking it with mycophenolate prevents transplant rejection.

Clinical notes

More PRPP (PRPP synthetase superactivity) or less recycling (HGPRT deficiency) speeds the pathway up and raises uric acid.
Antifolates (methotrexate) remove the formyl-THF needed in steps 4 and 9 and slow cell division.
Mycophenolate blocks IMPDH: lymphocytes, which rely on this pathway, stop proliferating.
6-Mercaptopurine, activated by HGPRT, mimics IMP and inhibits the amidotransferase.

Test yourself

Think of the answer, then tap the question to see it.

What is the rate-limiting step of de novo purine synthesis, and what inhibits it?

Glutamine-PRPP amidotransferase; AMP, GMP and IMP inhibit it by feedback.

Which amino acids donate atoms to the purine ring?

Glycine (C4, C5, N7), glutamine (N3, N9) and aspartate (N1); the rest comes from CO₂ and folate.

Why do antifolates slow purine synthesis?

Steps 4 and 9 need N¹⁰-formyl-THF; without regenerated THF there are no formyl groups for C8 and C2.

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Educational information, not medical advice. For any symptom, see a health professional.

Sources: Purine ribonucleoside monophosphate biosynthesis (Reactome, 2026); Metabolism of nucleotides (Reactome, 2026); PPAT: Amidophosphoribosyltransferase (human) (UniProt, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).

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