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Pathway

Urea cycle

Homo sapiens · Mitochondrial matrix & cytosol (liver) · 5 reactions

The liver urea cycle packages two nitrogen atoms into urea for excretion. One nitrogen enters as mitochondrial ammonia and the other as cytosolic aspartate; ornithine is regenerated after each turn.

REACTOME IDENTIFIERR-HSA-70635View source record ↗

Pathway scope

NETWORK MAP

Transport and ammonia/aspartate inputs are only partly represented, so this map does not report a full net equation.

Overview

EXPLORE BY LEVEL

Urea cycle is a set of connected chemical steps in human cells. The liver urea cycle packages two nitrogen atoms into urea for excretion. One nitrogen enters as mitochondrial ammonia and the other as cytosolic aspartate; ornithine is regenerated after each turn.

WHY THE FLOW CHANGES

Regulation

Compare fed and fasting

The liver increases nitrogen disposal when amino-acid breakdown rises.

Can speed upN-acetylglutamate

N-acetylglutamate activates carbamoyl-phosphate synthetase I, the first committed mitochondrial step.

Context mattersArginine availability

Arginine supports N-acetylglutamate synthesis and helps signal amino-acid supply.

Context mattersProtein intake and catabolism

Longer-term enzyme expression adjusts to nitrogen load; the response is not a single on/off switch.

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. Mitochondrial entry

    CPS1 uses ATP to make carbamoyl phosphate, which transfers its carbamoyl group to ornithine.

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

  2. Cytosolic cycle

    Citrulline receives nitrogen from aspartate, then releases fumarate and forms arginine.

    1. Step 3Irreversible · ATP → AMP + PPi
    2. Step 4Irreversible

  3. Urea release and regeneration

    Arginase releases urea and regenerates ornithine for transport back into mitochondria.

    1. Step 5Irreversible · H2O → —

Reaction steps

1Carbamoyl phosphate synthesisAmmonium + Bicarbonate → Carbamoyl phosphateIrreversible

CPS1 uses two ATP to combine ammonia and bicarbonate into carbamoyl phosphate.

REACTION · PER TURN + + yields + +
Enzyme
EC 6.3.4.16 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per ammonium
Once
Stage
Mitochondrial entry
MECHANISM & CONTEXT

CPS1 is in the mitochondrial matrix and requires N-acetylglutamate as an allosteric activator. The activator is not consumed in the reaction.

Evidence for this step: Urea cycle (R-HSA-70635)

2Citrulline formationCarbamoyl phosphate + Ornithine → CitrullineIrreversible

Ornithine transcarbamylase transfers the carbamoyl group to ornithine.

REACTION · PER TURN + yields +
Enzyme
EC 2.1.3.3 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per ammonium
Once
Stage
Mitochondrial entry
MECHANISM & CONTEXT

Citrulline is transported to the cytosol while ornithine is returned to the mitochondrial matrix.

Evidence for this step: Urea cycle (R-HSA-70635)

3Argininosuccinate formationCitrulline + Aspartate → ArgininosuccinateIrreversible

Argininosuccinate synthase joins citrulline to aspartate, using ATP to AMP.

REACTION · PER TURN + + yields + +
Enzyme
EC 6.3.4.5 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per ammonium
Once
Stage
Cytosolic cycle
MECHANISM & CONTEXT

Aspartate donates the second nitrogen that will appear in urea. Cleavage of pyrophosphate makes this ligation strongly favorable.

Evidence for this step: Urea cycle (R-HSA-70635)

4Fumarate and arginine formationArgininosuccinate → Arginine + FumarateIrreversible

Argininosuccinate lyase produces arginine and fumarate.

REACTION · PER TURNyields +
Enzyme
EC 4.3.2.1 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per ammonium
Once
Stage
Cytosolic cycle
MECHANISM & CONTEXT

Fumarate can enter the TCA-linked aspartate-argininosuccinate shunt, connecting nitrogen disposal to central carbon metabolism.

Evidence for this step: Urea cycle (R-HSA-70635)

5Urea releaseArginine → Ornithine + UreaIrreversible

Arginase hydrolyzes arginine, releasing urea and regenerating ornithine.

REACTION · PER TURN + yields +
Enzyme
EC 3.5.3.1 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per ammonium
Once
Stage
Urea release and regeneration
MECHANISM & CONTEXT

Urea enters the blood and is excreted by the kidneys. Ornithine returns to mitochondria for another turn.

Evidence for this step: Urea cycle (R-HSA-70635)

Research sources, claims, and curation

Urea cycle (R-HSA-70635)

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

Claims

The liver urea cycle packages two nitrogen atoms into urea for excretion. One nitrogen enters as mitochondrial ammonia and the other as cytosolic aspartate; ornithine is regenerated after each turn.

Curation notes

  • Transport of ornithine and citrulline between mitochondria and cytosol is required but summarized rather than assigned a stoichiometric reaction.
  • The displayed ATP uses are two ATP to ADP and one ATP to AMP, equivalent to four high-energy phosphate bonds.
  • The pathway is primarily hepatic; related enzymes can have other tissue roles.