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Pathway

Gluconeogenesis

Homo sapiens · Mitochondria, cytosol & endoplasmic reticulum · 5 reactions

Gluconeogenesis makes glucose from lactate, glycerol, and glucogenic amino acids, mainly in liver and kidney. It bypasses the three irreversible glycolysis reactions and shares the other reversible steps in the opposite direction.

REACTOME IDENTIFIERR-HSA-70263View source record ↗

Pathway scope

NETWORK MAP

The route uses different energy and reducing-equivalent inputs depending on the precursor and shuttle used; no single net yield is shown for this grouped map.

Overview

EXPLORE BY LEVEL

Gluconeogenesis is a set of connected chemical steps in human cells. Gluconeogenesis makes from lactate, glycerol, and glucogenic amino acids, mainly in liver and kidney. It bypasses the three irreversible glycolysis reactions and shares the other reversible steps in the opposite direction.

WHY THE FLOW CHANGES

Regulation

Compare fed and fasting

The liver adjusts glucose production during fasting; opposing pathways are coordinated.

Can slow downAMP and fructose 2,6-bisphosphate

Both inhibit fructose-1,6-bisphosphatase, a key gluconeogenic control point.

Can speed upAcetyl-CoA

Acetyl-CoA activates pyruvate carboxylase and signals fatty-acid oxidation.

Context mattersGlucagon in liver

Fasting signaling lowers fructose 2,6-bisphosphate and favors glucose output; this is not a universal direct switch in every tissue.

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. Pyruvate bypass

    Mitochondrial carboxylation and decarboxylation route pyruvate to phosphoenolpyruvate; transport variants depend on the precursor and tissue.

    1. Step 1Irreversible · HCO3− + ATP → ADP + Pi
    2. Step 2Irreversible · GTP → CO2 + GDP

  2. Shared reversible reactions

    The near-equilibrium reactions of glycolysis run in reverse toward fructose 1,6-bisphosphate.

    1. Step 3Reversible · H2O → —
    2. Step 4Irreversible · H2O → Pi

  3. Glucose formation

    A second phosphatase bypass produces glucose 6-phosphate, and the endoplasmic reticulum releases free glucose in liver and kidney.

    1. Step 5Irreversible

Reaction steps

1Carboxylation of pyruvatePyruvate → OxaloacetateIrreversible

Pyruvate gains a carbon dioxide equivalent to form oxaloacetate, using ATP and biotin.

REACTION · PER TURN + + yields + +
Enzyme
EC 6.4.1.1 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per pyruvate
Once
Stage
Pyruvate bypass
MECHANISM & CONTEXT

Pyruvate carboxylase acts in the mitochondrial matrix and is activated by acetyl-CoA. Oxaloacetate does not cross the inner mitochondrial membrane directly; cells use malate/aspartate or phosphoenolpyruvate transport routes.

Evidence for this step: Gluconeogenesis (R-HSA-70263)

2Conversion of oxaloacetate to phosphoenolpyruvateOxaloacetate → PhosphoenolpyruvateIrreversible

PEP carboxykinase uses GTP to decarboxylate and phosphorylate oxaloacetate.

REACTION · PER TURN + yields + +
Enzyme
EC 4.1.1.32 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per pyruvate
Once
Stage
Pyruvate bypass
MECHANISM & CONTEXT

Cytosolic PCK1 supports glucose production from lactate-derived carbon. A mitochondrial PCK2 route can also form PEP in selected contexts; this page emphasizes the classic cytosolic teaching route.

Evidence for this step: Gluconeogenesis (R-HSA-70263)

3Reverse the glycolytic payoff sequencePhosphoenolpyruvate ⇌ 2-PhosphoglycerateReversible

The reversible lower-glycolysis reactions proceed from PEP toward glyceraldehyde 3-phosphate.

REACTION · PER TURN + reversibly yields
Enzyme
EC 4.2.1.11 ↗
Cofactors
No metal cofactor listed.
Reversibility
Reversible, operating near equilibrium in cells.
Runs per pyruvate
Once
Stage
Shared reversible reactions
MECHANISM & CONTEXT

This grouped step stands for enolase, phosphoglycerate mutase, phosphoglycerate kinase, glyceraldehyde-3-phosphate dehydrogenase, and triose-phosphate isomerase. It uses ATP and NADH overall; the individual shared reactions remain listed in glycolysis.

Evidence for this step: Gluconeogenesis (R-HSA-70263)

4Fructose 1,6-bisphosphate dephosphorylationFructose 1,6-bisphosphate → Fructose 6-phosphateIrreversible

Fructose-1,6-bisphosphatase bypasses the irreversible PFK-1 step by hydrolysis.

REACTION · PER TURN + yields +
Enzyme
EC 3.1.3.11 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per pyruvate
Once
Stage
Shared reversible reactions
MECHANISM & CONTEXT

This is a key regulated bypass. It is reciprocally controlled with phosphofructokinase-1 so opposing pathways do not run at high rates simultaneously.

Evidence for this step: Gluconeogenesis (R-HSA-70263)

5Isomerization and glucose 6-phosphate formationFructose 6-phosphate → Glucose 6-phosphateIrreversible

The remaining shared upper-glycolysis reactions form glucose 6-phosphate.

REACTION · PER TURNyields
Enzyme
EC 5.3.1.9 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per pyruvate
Once
Stage
Glucose formation
MECHANISM & CONTEXT

Aldolase, triose-phosphate isomerase, and phosphoglucose isomerase connect fructose 6-phosphate back to glucose 6-phosphate. Glucose 6-phosphatase, found in the endoplasmic reticulum of glucose-exporting tissues, then releases glucose.

Evidence for this step: Gluconeogenesis (R-HSA-70263)

Research sources, claims, and curation

Gluconeogenesis (R-HSA-70263)

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

Claims

Gluconeogenesis makes glucose from lactate, glycerol, and glucogenic amino acids, mainly in liver and kidney. It bypasses the three irreversible glycolysis reactions and shares the other reversible steps in the opposite direction.

Curation notes

  • This is a teaching map, not a complete flux-balanced net equation: the reverse glycolytic segment is grouped and precursor shuttles vary by tissue.
  • Reactome places gluconeogenesis mainly in liver and kidney and documents mitochondrial, cytosolic, and ER steps.
  • The map emphasizes lactate/pyruvate entry; glycerol and amino-acid entry routes are summarized in the explanation rather than enumerated as separate reactions.