Purine De Novo Synthesis (IMP synthesis through to AMP/GMP)
- Compartment
- Cytosol
- Main tissue
- Liver (mainly)
- Rate-limiting
- Glutamine-PRPP amidotransferase
- Steps
- 15
Reaction steps
In source order, 15 total
-
1
Ribose 5-phosphate → 5-phosphoribosyl-1-pyrophosphate (PRPP)
Out PRPP› Notes
Ribose-phosphate pyrophosphokinase (PRPP synthetase) transfers pyrophosphate from ATP to ribose 5-phosphate: ribose 5-phosphate + ATP → PRPP + AMP. Mg2+ and inorganic phosphate are required/activating; this reaction consumes two high-energy phosphate equivalents because ATP is converted to AMP. It is irreversible in vivo and is a major control point that supplies PRPP to both de novo and salvage pathways, but it is not the committed step of purine synthesis.
-
2
PRPP → 5-phosphoribosylamine (5-PRA)
In PRPP› Notes
Glutamine-PRPP amidotransferase catalyzes PRPP + glutamine + H2O → 5-PRA + glutamate + PPi. The enzyme uses an internal glutaminase domain to generate ammonia, which is channeled to the phosphoribosyl-transferase domain; PPi hydrolysis drives the reaction forward. This is the committed, rate-limiting, and effectively irreversible step of de novo purine synthesis.
-
3
5-PRA → glycinamide ribonucleotide (GAR)
› Notes
Phosphoribosylamine--glycine ligase (GAR synthetase) catalyzes 5-PRA + glycine + ATP → GAR + ADP + Pi. Mg2+ is required; glycine contributes C4, C5, and N7 of the future purine ring.
-
4
GAR → formylglycinamide ribonucleotide (FGAR)
› Notes
GAR transformylase transfers a formyl group: GAR + 10-formyl-THF → FGAR + THF. This is the first of two folate-dependent one-carbon transfer steps and introduces C8 of the purine ring.
-
5
FGAR → formylglycinamidine ribonucleotide (FGAM)
› Notes
FGAM synthetase catalyzes FGAR + glutamine + ATP + H2O → FGAM + glutamate + ADP + Pi. The glutamine-derived nitrogen becomes N3 of the purine ring; ATP activates the formyl group before amidination.
-
6
FGAM → 5-aminoimidazole ribonucleotide (AIR)
› Notes
AIR synthetase catalyzes ATP-dependent ring closure: FGAM + ATP → AIR + ADP + Pi. This irreversible cyclization forms the imidazole portion of the purine nucleus.
-
7
AIR → carboxyaminoimidazole ribonucleotide (CAIR)
› Notes
AIR carboxylase catalyzes AIR + CO2 (derived from bicarbonate) → CAIR. In mammalian cells, the class II AIR carboxylase activity of PAICS performs direct carboxylation and does not require ATP; this differs from the two-enzyme, ATP-dependent bacterial route. The carboxyl carbon becomes C6 of the purine ring.
-
8
CAIR → succinylaminoimidazolecarboxamide ribonucleotide (SAICAR)
› Notes
SAICAR synthetase catalyzes CAIR + aspartate + ATP → SAICAR + ADP + Pi. Aspartate donates N1 of the purine ring, while its carbon skeleton is later released as fumarate.
-
9
SAICAR → 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)
› Notes
Adenylosuccinate lyase catalyzes SAICAR → AICAR + fumarate. This nonhydrolytic elimination releases the aspartate carbon skeleton as fumarate, linking purine synthesis to the tricarboxylic acid cycle.
-
10
AICAR → 5-formamidoimidazole-4-carboxamide ribonucleotide (FAICAR)
› Notes
AICAR transformylase catalyzes AICAR + 10-formyl-THF → FAICAR + THF. The donated formyl carbon becomes C2 of the purine ring.
-
11
FAICAR → IMP
› Notes
IMP cyclohydrolase catalyzes FAICAR → IMP + H2O (net ring closure with dehydration/rearrangement as represented by the enzyme mechanism). This completes the six-membered ring and is effectively irreversible under cellular conditions. IMP contains hypoxanthine and is the branch point for AMP and GMP.
-
12
IMP → adenylosuccinate
In IMPOut Adenylosuccinate› Notes
Adenylosuccinate synthetase catalyzes IMP + aspartate + GTP → adenylosuccinate + GDP + Pi. GTP, rather than ATP, drives addition of the amino group donor aspartate; this reciprocal use of GTP favors balanced AMP/GMP production. This is the committed step of the AMP branch.
-
13
Adenylosuccinate → AMP
Out AMP› Notes
Adenylosuccinate lyase catalyzes adenylosuccinate → AMP + fumarate. The reaction completes AMP synthesis and again releases the aspartate carbon skeleton as fumarate.
-
14
IMP → xanthosine monophosphate (XMP)
› Notes
IMP dehydrogenase (IMPDH) catalyzes IMP + NAD+ + H2O → XMP + NADH + H+. This oxidation establishes the 2-keto group needed for subsequent amination and is the committed, regulatory step of the GMP branch.
-
15
XMP → GMP
› Notes
GMP synthetase catalyzes XMP + glutamine + ATP + H2O → GMP + glutamate + AMP + PPi. ATP is cleaved to AMP and PPi, and the enzyme channels glutamine-derived ammonia to an adenylated XMP intermediate; thus this step consumes two high-energy phosphate equivalents and is effectively irreversible.
Showing all 15 steps.
Regulation
What speeds each enzyme up and what slows it down
PRPP synthetase
Inorganic phosphate; increased ribose 5-phosphate availability
ADP, GDP, and other purine ribonucleotides
No dominant acute hormonal switch; insulin and carbohydrate availability can increase pentose phosphate pathway flux and PRPP supply indirectly.
Glutamine-PRPP amidotransferase
PRPP
IMP, AMP, and GMP (feedback inhibition; combined nucleotide pools are most effective)
No established direct endocrine regulation; expression/flux increase with growth signals and proliferation.
Adenylosuccinate synthetase
Increased IMP and GTP availability
AMP (feedback inhibition)
Predominantly governed by energy status and substrate balance rather than acute hormonal regulation.
IMP dehydrogenase
IMP; increased AMP demand can favor GMP synthesis through reciprocal branch control
GMP and GDP
Increased expression accompanies lymphocyte activation and cell proliferation; no major direct endocrine allosteric control.
Overview
Purine de novo synthesis constructs the purine ring atom-by-atom on ribose 5-phosphate, generating inosine monophosphate (IMP), the common precursor of AMP and GMP. The pathway supplies nucleotides for RNA, DNA (after reduction), energy transfer, second messengers, and activated intermediates, and is especially important in proliferating cells and in tissues with limited salvage capacity. In humans, most early reactions are carried out by multifunctional cytosolic enzymes that can assemble into purinosomes under high purine demand.
Cellular location
The pathway is cytosolic; enzymes are widely expressed, with high flux in liver, intestinal mucosa, bone marrow, developing brain, activated lymphocytes, and rapidly dividing tumor cells. The one-carbon units used in the pathway are supplied as 10-formyltetrahydrofolate (10-formyl-THF), principally from the cytosolic folate-mediated one-carbon network. Ribose 5-phosphate is generated mainly by the oxidative and nonoxidative pentose phosphate pathways.
Net energetics
From ribose 5-phosphate to IMP, human de novo synthesis consumes one ATP → AMP in PRPP formation and four ATP → ADP reactions (GAR synthetase, FGAM synthetase, AIR synthetase, and SAICAR synthetase): six high-energy phosphate equivalents total. It also consumes two glutamine amide nitrogens, one glycine, one aspartate, two 10-formyl-THF one-carbon units, and CO2. Conversion of IMP to AMP consumes one GTP → GDP, making AMP cost six ATP-equivalent bonds plus one GTP-equivalent bond from ribose 5-phosphate; conversion of IMP to GMP consumes one additional ATP → AMP (two high-energy equivalents) and produces one NADH, making GMP cost eight ATP-equivalent bonds; the IMPDH reaction also produces one NADH.
Clinical significance
De novo synthesis is necessary when dietary or intracellular base salvage is insufficient and is a major biosynthetic burden in proliferating tissues. Excess PRPP synthetase activity or diminished feedback inhibition increases purine production and degradation, causing hyperuricemia and gout. Antifolates such as methotrexate and pemetrexed impair the 10-formyl-THF-dependent transformylase reactions, whereas IMPDH inhibitors such as mycophenolate mofetil preferentially suppress guanine nucleotide synthesis in activated lymphocytes. Adenylosuccinate lyase deficiency causes a neurodevelopmental disorder with accumulation of succinylpurines.
Recent literature
Live Europe PMC search
Nothing is fetched until you ask, so the page stays fast and the request is yours rather than automatic.
Europe PMC · ten most recent, newest first