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[Biochemistry](https://durgical.com/en/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 -6 CO₂ -1 NADH +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](https://durgical.com/en/biochemistry/enzymes/prpp-synthetase/)** irreversible [Ribose 5-phosphate](https://durgical.com/en/biochemistry/molecules/ribose-5-phosphate/) + [ATP](https://durgical.com/en/biochemistry/molecules/atp/) → [PRPP](https://durgical.com/en/biochemistry/molecules/prpp/) + amp Moves 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 →](https://durgical.com/en/conditions/gout/)
- **Step 2 · [Glutamine-PRPP amidotransferase](https://durgical.com/en/biochemistry/enzymes/glutamine-prpp-amidotransferase/)** irreversible [PRPP](https://durgical.com/en/biochemistry/molecules/prpp/) + [Glutamine](https://durgical.com/en/biochemistry/molecules/glutamine/) + H₂O → 5-Phosphoribosylamine (PRA) + [Glutamate](https://durgical.com/en/biochemistry/molecules/glutamate/) + pyrophosphate Committed 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](https://durgical.com/en/biochemistry/molecules/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](https://durgical.com/en/biochemistry/molecules/glutamine/) + [ATP](https://durgical.com/en/biochemistry/molecules/atp/) + H₂O → Formylglycinamidine ribonucleotide (FGAM) + [Glutamate](https://durgical.com/en/biochemistry/molecules/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](https://durgical.com/en/biochemistry/molecules/atp/) → 5-Aminoimidazole ribonucleotide (AIR) + ADP + phosphate (Pi) + H₂O Closes 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](https://durgical.com/en/biochemistry/molecules/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) + fumarate Cuts 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](https://durgical.com/en/biochemistry/molecules/imp/) + Tetrahydrofolate (THF) + H₂O Second 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)](https://durgical.com/en/biochemistry/enzymes/imp-dehydrogenase/)** irreversible [IMP](https://durgical.com/en/biochemistry/molecules/imp/) + [NAD⁺](https://durgical.com/en/biochemistry/molecules/nad/) + H₂O → Xanthosine monophosphate (XMP) + NADH Opens 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.

## Related conditions

- [Gout](https://durgical.com/en/conditions/gout/)
- [Lesch-Nyhan syndrome](https://durgical.com/en/conditions/lesch-nyhan-syndrome/)

## Related

- [PRPP (phosphoribosyl pyrophosphate)](https://durgical.com/en/biochemistry/molecules/prpp/)
- [PRPP synthetase](https://durgical.com/en/biochemistry/enzymes/prpp-synthetase/)
- [Glutamine-PRPP amidotransferase](https://durgical.com/en/biochemistry/enzymes/glutamine-prpp-amidotransferase/)
- [IMP (inosine monophosphate)](https://durgical.com/en/biochemistry/molecules/imp/)
- [IMP dehydrogenase (IMPDH)](https://durgical.com/en/biochemistry/enzymes/imp-dehydrogenase/)
- [Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)](https://durgical.com/en/biochemistry/enzymes/hypoxanthine-guanine-phosphoribosyltransferase/)
- [Purine degradation and salvage](https://durgical.com/en/biochemistry/pathways/purine-degradation-and-salvage/)
- [Drugs acting on nucleotide metabolism](https://durgical.com/en/biochemistry/topics/drugs-acting-on-nucleotide-metabolism/)
- [Nucleotide structure](https://durgical.com/en/biochemistry/topics/nucleotide-structure/)
- [ATP (adenosine triphosphate)](https://durgical.com/en/biochemistry/molecules/atp/)
- [NAD⁺ (nicotinamide adenine dinucleotide)](https://durgical.com/en/biochemistry/molecules/nad/)
- [Dihydrofolate reductase (DHFR)](https://durgical.com/en/biochemistry/enzymes/dihydrofolate-reductase/)

## 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.

[Add to my cards (3)](https://durgical.app/estudiar/?add=/en/biochemistry/pathways/de-novo-purine-synthesis/)

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

Sources: [Purine ribonucleoside monophosphate biosynthesis](https://reactome.org/PathwayBrowser/#/R-HSA-73817) (Reactome, 2026); [Metabolism of nucleotides](https://reactome.org/PathwayBrowser/#/R-HSA-15869) (Reactome, 2026); [PPAT: Amidophosphoribosyltransferase (human)](https://www.uniprot.org/uniprotkb/Q06203/entry) (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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Representative model, for educational purposes only.

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