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HomeMetabolismNucleotide MetabolismPyrimidine nucleotide synthesis
Pathway

Pyrimidine nucleotide synthesis

Homo sapiens · Cytosol & mitochondrial inner membrane · 6 reactions

De novo pyrimidine synthesis builds the ring first, then attaches it to activated ribose. CAD performs the first three reactions, dihydroorotate dehydrogenase forms orotate at the inner mitochondrial membrane, and UMPS produces UMP.

REACTOME IDENTIFIERR-HSA-500753View source record ↗

Pathway scope

NETWORK MAP

The final phosphorylation and CTP branch are grouped; the map does not present a single balanced net equation.

Overview

EXPLORE BY LEVEL

Pyrimidine nucleotide synthesis is a set of connected chemical steps in human cells. De novo pyrimidine synthesis builds the ring first, then attaches it to activated ribose. CAD performs the first three reactions, dihydroorotate dehydrogenase forms orotate at the inner mitochondrial membrane, and UMPS produces UMP.

WHY THE FLOW CHANGES

Regulation

Compare fed and fasting

Pyrimidine synthesis responds to nucleotide-pool balance.

Can slow downUTP

UTP feedback inhibits the multifunctional CAD enzyme in mammalian cells.

Can speed upPRPP and ATP

Substrate and energy availability can favor de novo synthesis.

Can slow downCTP

CTP feedback restrains CTP synthetase at the later branch step.

How to read this map

This is an instructional map of selected reactions, not a complete inventory of every reaction in the body. Some steps are grouped; transport, alternate routes, tissue differences, or full molecule balances may be summarized. The Research notes explain this map’s specific limits.

Explore the reaction map and enzyme steps

Pathway map

GENERATED FROM STRUCTURED REACTIONS

Select a molecule or enzyme to inspect it. Select a step number to open its full reaction detail.

  1. Pyrimidine-ring synthesis

    Glutamine, bicarbonate, and aspartate form carbamoyl aspartate and then dihydroorotate.

    1. Step 1Irreversible · ATP → ADP + Pi
    2. Step 2Irreversible · ATP → Pi

  2. Orotate formation

    Dihydroorotate dehydrogenase oxidizes the ring intermediate to orotate.

    1. Step 3Irreversible

  3. Ribose attachment and UMP

    Orotate receives PRPP, and OMP decarboxylase produces UMP.

    1. Step 4Irreversible
    2. Step 5Irreversible · — → CO2

  4. Nucleotide triphosphates

    UMP is phosphorylated to UTP; CTP synthetase can use UTP to make CTP.

    1. Step 6Irreversible · ATP → —

Reaction steps

1Carbamoyl phosphate formationGlutamine + Bicarbonate → Carbamoyl phosphate + GlutamateIrreversible

The CAD enzyme complex forms cytosolic carbamoyl phosphate from glutamine and bicarbonate.

REACTION · PER TURN + + yields + + +
Enzyme
EC 6.3.5.5 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per aspartate
Once
Stage
Pyrimidine-ring synthesis
MECHANISM & CONTEXT

Unlike mitochondrial CPS1 in the urea cycle, CAD uses glutamine and supplies carbamoyl phosphate for pyrimidine-ring synthesis.

Evidence for this step: Pyrimidine metabolism (R-HSA-500753)

2Aspartate addition and ring closureCarbamoyl phosphate + Aspartate → DihydroorotateIrreversible

CAD adds aspartate and closes the ring to form dihydroorotate.

REACTION · PER TURN + + yields +
Enzyme
EC 6.3.5.5 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per aspartate
Once
Stage
Pyrimidine-ring synthesis
MECHANISM & CONTEXT

Carbamoyl-aspartate formation and dihydroorotase cyclization are combined here; Reactome models them as individual reactions.

Evidence for this step: Pyrimidine metabolism (R-HSA-500753)

3Orotate formationDihydroorotate + Ubiquinone → Orotate + UbiquinolIrreversible

Dihydroorotate dehydrogenase oxidizes dihydroorotate to orotate and reduces ubiquinone.

REACTION · PER TURN + yields +
Enzyme
EC 1.3.5.2 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per aspartate
Once
Stage
Orotate formation
MECHANISM & CONTEXT

Human DHODH is associated with the inner mitochondrial membrane and links pyrimidine synthesis to the respiratory chain.

Evidence for this step: Pyrimidine metabolism (R-HSA-500753)

4OMP formationOrotate + 5-Phosphoribosyl 1-pyrophosphate → Orotidine 5'-monophosphate + PyrophosphateIrreversible

Orotate phosphoribosyltransferase transfers activated ribose phosphate from PRPP to orotate.

REACTION · PER TURN + yields +
Enzyme
EC 2.4.2.10 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per aspartate
Once
Stage
Ribose attachment and UMP
MECHANISM & CONTEXT

This reaction joins the completed pyrimidine ring to ribose phosphate.

Evidence for this step: Pyrimidine metabolism (R-HSA-500753)

5UMP formationOrotidine 5'-monophosphate → Uridine monophosphateIrreversible

OMP decarboxylase produces UMP, the first pyrimidine nucleotide in the pathway.

REACTION · PER TURNyields +
Enzyme
EC 4.1.1.23 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per aspartate
Once
Stage
Ribose attachment and UMP
MECHANISM & CONTEXT

Both orotate phosphoribosyltransferase and OMP decarboxylase activities are domains of the bifunctional UMPS protein.

Evidence for this step: Pyrimidine metabolism (R-HSA-500753)

6UTP and CTP formationUridine monophosphate + Glutamine → Uridine triphosphate + Cytidine triphosphate + GlutamateIrreversible

Downstream phosphorylation and CTP synthetase convert UMP through UDP and UTP, then make CTP.

REACTION · PER TURN + + yields + +
Enzyme
EC 6.3.5.5 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per aspartate
Once
Stage
Nucleotide triphosphates
MECHANISM & CONTEXT

This final map step groups several nucleotide kinase reactions and the glutamine-dependent CTP synthetase reaction; these are shown as products, not a single balanced equation.

Evidence for this step: Pyrimidine metabolism (R-HSA-500753)

Research sources, claims, and curation

Pyrimidine metabolism (R-HSA-500753)

Reactome · Homo sapiens · Reviewed Reactome human pathway used for reaction sequence and context.

Claims

De novo pyrimidine synthesis builds the ring first, then attaches it to activated ribose. CAD performs the first three reactions, dihydroorotate dehydrogenase forms orotate at the inner mitochondrial membrane, and UMPS produces UMP.

Curation notes

  • Reactome describes orotate formation in four core reactions, with the first three catalyzed by the multifunctional CAD protein.
  • The final UTP and CTP production step is grouped for navigation and is not stoichiometrically balanced.
  • Pyrimidine salvage can also supply nucleotides but is outside this de novo pathway map.