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Pathway

Cholesterol biosynthesis

Homo sapiens · Cytosol & endoplasmic reticulum · 11 reactions

Cells build cholesterol from acetyl-CoA through the mevalonate pathway. Acetyl units form HMG-CoA, HMG-CoA reductase makes mevalonate, and activated isoprenes assemble into squalene, lanosterol, and finally cholesterol.

REACTOME IDENTIFIERR-HSA-191273View source record ↗

Pathway scope

NETWORK MAP

Several repeated condensations and the multi-step sterol tail are grouped; a balanced overall equation is not calculated.

Overview

EXPLORE BY LEVEL

Cholesterol biosynthesis is a set of connected chemical steps in human cells. Cells build cholesterol from acetyl-CoA through the mevalonate . Acetyl units form HMG-CoA, HMG-CoA reductase makes mevalonate, and activated isoprenes assemble into squalene, lanosterol, and finally cholesterol.

WHY THE FLOW CHANGES

Regulation

Compare fed and fasting

HMG-CoA reductase is controlled by sterol supply and energy state.

Can slow downCellular sterols

Sterol feedback decreases the production and stability of HMG-CoA reductase.

Can slow downAMPK phosphorylation

Energy-stress signaling phosphorylates and inhibits HMG-CoA reductase.

Context mattersInsulin and sterol demand

Hormones and cellular sterol demand regulate synthesis at multiple levels.

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. Mevalonate formation

    Three acetyl-CoA units are assembled and reduced to mevalonate.

    1. Step 1Irreversible · — → CoA
    2. Step 2Irreversible · H2O → CoA
    3. Step 3Irreversible · NADPH → CoA + NADP+

  2. Activated isoprene units

    Mevalonate is phosphorylated and decarboxylated to isopentenyl diphosphate.

    1. Step 4Irreversible · ATP → ADP
    2. Step 5Irreversible · ATP → ADP
    3. Step 6Irreversible · ATP → ADP + CO2 + Pi
    4. Step 7Reversible
    5. Step 8Irreversible
    6. Step 9Irreversible

  3. Squalene assembly

    Isoprenoid units are joined into the 30-carbon precursor squalene.

    1. Step 10Irreversible · NADPH → NADP+

  4. Cyclization and sterol remodeling

    Squalene is epoxidized and cyclized to lanosterol, then remodeled to cholesterol.

    1. Step 11Irreversible

Reaction steps

1Acetoacetyl-CoA formationAcetyl-CoA → Acetoacetyl-CoAIrreversible

Thiolase condenses two acetyl-CoA molecules to form acetoacetyl-CoA.

REACTION · PER TURNyields +
Enzyme
EC 2.3.1.16 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per acetyl-coa
Once
Stage
Mevalonate formation
MECHANISM & CONTEXT

This first condensation produces the four-carbon intermediate used by HMG-CoA synthase.

Evidence for this step: Cholesterol biosynthesis (R-HSA-191273)

2HMG-CoA formationAcetoacetyl-CoA + Acetyl-CoA → 3-Hydroxy-3-methylglutaryl-CoAIrreversible

Cytosolic HMG-CoA synthase adds a third acetyl unit to acetoacetyl-CoA.

REACTION · PER TURN + + yields +
Enzyme
EC 2.3.3.10 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per acetyl-coa
Once
Stage
Mevalonate formation
MECHANISM & CONTEXT

The enzyme forms HMG-CoA, which is reduced by HMG-CoA reductase in the next step.

Evidence for this step: Cholesterol biosynthesis (R-HSA-191273)

3Mevalonate formation3-Hydroxy-3-methylglutaryl-CoA → MevalonateIrreversible

HMG-CoA reductase uses NADPH to produce mevalonate.

REACTION · PER TURN + yields + +
Enzyme
EC 1.1.1.34 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per acetyl-coa
Once
Stage
Mevalonate formation
MECHANISM & CONTEXT

HMG-CoA reductase is the major regulated step targeted by statin medicines.

Evidence for this step: Cholesterol biosynthesis (R-HSA-191273)

4Mevalonate phosphorylationMevalonate → Mevalonate 5-phosphateIrreversible

Mevalonate kinase phosphorylates mevalonate.

REACTION · PER TURN + yields +
Enzyme
EC 2.7.1.36 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per acetyl-coa
Once
Stage
Activated isoprene units
MECHANISM & CONTEXT

This ATP-dependent step begins activation of mevalonate for decarboxylation.

Evidence for this step: Cholesterol biosynthesis (R-HSA-191273)

5Second phosphorylationMevalonate 5-phosphate → Mevalonate 5-diphosphateIrreversible

Phosphomevalonate kinase makes mevalonate 5-diphosphate.

REACTION · PER TURN + yields +
Enzyme
EC 2.7.4.2 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per acetyl-coa
Once
Stage
Activated isoprene units
MECHANISM & CONTEXT

The added phosphate prepares the intermediate for ATP-dependent decarboxylation.

Evidence for this step: Cholesterol biosynthesis (R-HSA-191273)

6Isopentenyl diphosphate formationMevalonate 5-diphosphate → Isopentenyl diphosphateIrreversible

Mevalonate diphosphate decarboxylase produces the five-carbon isoprene unit IPP.

REACTION · PER TURN + yields + + +
Enzyme
EC 4.1.1.33 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per acetyl-coa
Once
Stage
Activated isoprene units
MECHANISM & CONTEXT

IPP is then reversibly isomerized to dimethylallyl diphosphate, the primer for prenyl-chain synthesis.

Evidence for this step: Cholesterol biosynthesis (R-HSA-191273)

7IPP isomerizationIsopentenyl diphosphate ⇌ Dimethylallyl diphosphateReversible

IPP isomerase supplies dimethylallyl diphosphate for chain initiation.

REACTION · PER TURNreversibly yields
Enzyme
EC 5.3.3.2 ↗
Cofactors
No metal cofactor listed.
Reversibility
Reversible, operating near equilibrium in cells.
Runs per acetyl-coa
Once
Stage
Activated isoprene units
MECHANISM & CONTEXT

Cells maintain an interconvertible pool of IPP and DMAPP; the map shows one route that supplies the required starter unit.

Evidence for this step: Cholesterol biosynthesis (R-HSA-191273)

8Geranyl diphosphate formationDimethylallyl diphosphate + Isopentenyl diphosphate → Geranyl diphosphateIrreversible

Farnesyl diphosphate synthase adds IPP to DMAPP to form a ten-carbon intermediate.

REACTION · PER TURN + yields
Enzyme
EC 2.5.1.10 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per acetyl-coa
Once
Stage
Activated isoprene units
MECHANISM & CONTEXT

This condensation releases diphosphate, omitted from this high-level map.

Evidence for this step: Cholesterol biosynthesis (R-HSA-191273)

9Farnesyl diphosphate formationGeranyl diphosphate + Isopentenyl diphosphate → Farnesyl diphosphateIrreversible

A second IPP addition forms the 15-carbon farnesyl diphosphate.

REACTION · PER TURN + yields
Enzyme
EC 2.5.1.10 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per acetyl-coa
Once
Stage
Activated isoprene units
MECHANISM & CONTEXT

Farnesyl diphosphate is a branch point for cholesterol and other isoprenoids.

Evidence for this step: Cholesterol biosynthesis (R-HSA-191273)

10Squalene formationFarnesyl diphosphate → SqualeneIrreversible

Squalene synthase reductively joins two farnesyl diphosphate molecules.

REACTION · PER TURN + yields +
Enzyme
EC 2.5.1.21 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per acetyl-coa
Once
Stage
Squalene assembly
MECHANISM & CONTEXT

This is the first committed reaction toward sterols rather than other farnesyl-derived products.

Evidence for this step: Cholesterol biosynthesis (R-HSA-191273)

11Lanosterol and cholesterol formationSqualene → LanosterolIrreversible

Squalene is epoxidized and cyclized to lanosterol; multiple ER reactions then produce cholesterol.

REACTION · PER TURNyields
Enzyme
EC 5.4.99.7 ↗
Cofactors
No metal cofactor listed.
Reversibility
Irreversible under cellular conditions. This is a control point.
Runs per acetyl-coa
Once
Stage
Cyclization and sterol remodeling
MECHANISM & CONTEXT

The epoxidation and cyclization plus later demethylation, reduction, and double-bond rearrangements are grouped. Human cells use Bloch and modified Kandutsch-Russell routes from lanosterol-derived intermediates.

Evidence for this step: Cholesterol biosynthesis (R-HSA-191273)

Research sources, claims, and curation

Cholesterol biosynthesis (R-HSA-191273)

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

Claims

Cells build cholesterol from acetyl-CoA through the mevalonate pathway. Acetyl units form HMG-CoA, HMG-CoA reductase makes mevalonate, and activated isoprenes assemble into squalene, lanosterol, and finally cholesterol.

Curation notes

  • The pathway spans roughly 30 biochemical reactions; the page groups repeated and multi-enzyme segments for an introductory map.
  • Cholesterol formation from lanosterol can follow more than one sterol route. The map does not imply a single exclusive sequence for every tissue.
  • HMG-CoA reductase is a regulated control point, but regulation is described rather than modeled as a reaction.