[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [Biochemistry](https://durgical.com/en/biochemistry/) › Cholesterol synthesis (mevalonate pathway)

[Biochemistry](https://durgical.com/en/biochemistry/) · Metabolic pathway

# Cholesterol synthesis (mevalonate pathway)

The liver and other cells build cholesterol from acetyl-CoA in the cytosol and ER; HMG-CoA reductase sets the pace of the pathway.

Updated 2026-11-01

## Interactive map

## Key facts

- All 27 carbons of cholesterol come from acetyl-CoA: 18 acetyl-CoA are used per molecule.
- The rate-limiting, regulated step is HMG-CoA reductase (HMG-CoA → mevalonate, using 2 NADPH), the target of statins.
- Each mevalonate costs 3 acetyl-CoA, 3 ATP and 2 NADPH; six isoprene units (C5) make squalene (C30).
- It runs in the cytosol and on the endoplasmic reticulum membrane; the NADPH comes mainly from the pentose phosphate pathway.
- Cytosolic HMG-CoA goes to cholesterol; mitochondrial HMG-CoA (HMG-CoA synthase 2) goes to ketone bodies.

**Also called**
Mevalonate pathway, Cholesterogenesis

## Regulation

- SREBP-2: when ER cholesterol falls, it moves to the Golgi, is cleaved and, in the nucleus, switches on the HMG-CoA reductase and LDL receptor genes.
- Sterols and lanosterol make HMG-CoA reductase bind INSIG, get ubiquitinated and be degraded.
- Insulin favours synthesis; glucagon and AMPK (which phosphorylates and inactivates the reductase) slow it.
- Dietary cholesterol, delivered to the liver in chylomicron remnants, lowers hepatic synthesis.

## The steps, one by one

- **Step 1 · Cytosolic thiolase (acetyl-CoA acetyltransferase 2)** [Acetyl-CoA](https://durgical.com/en/biochemistry/molecules/acetyl-coa/) + [Acetyl-CoA](https://durgical.com/en/biochemistry/molecules/acetyl-coa/) ⇌ Acetoacetyl-CoA + coenzyme A Joins two acetyl-CoA into four-carbon acetoacetyl-CoA. **If it fails:** Deficiency of the mitochondrial thiolase (a different isoenzyme) impairs ketolysis and isoleucine breakdown.
- **Step 2 · Cytosolic HMG-CoA synthase (HMGCS1)** irreversible Acetoacetyl-CoA + [Acetyl-CoA](https://durgical.com/en/biochemistry/molecules/acetyl-coa/) + H₂O → HMG-CoA + coenzyme A Adds a third acetyl-CoA to make six-carbon HMG-CoA. **If it fails:** The mitochondrial isoenzyme (HMGCS2) makes ketone bodies; its deficiency causes hypoketotic hypoglycaemia during fasting.
- **Step 3 · [HMG-CoA reductase](https://durgical.com/en/biochemistry/enzymes/hmg-coa-reductase/)** irreversible HMG-CoA + [NADPH](https://durgical.com/en/biochemistry/molecules/nadph/) → [Mevalonate](https://durgical.com/en/biochemistry/molecules/mevalonate/) + nadp + coenzyme A Reduces HMG-CoA to mevalonate with two NADPH: the rate-limiting step that sets how much cholesterol is made. **If it fails:** Statins can cause myopathy and, rarely, an immune-mediated necrotising myopathy with antibodies against HMG-CoA reductase. [Atherosclerosis and dyslipidaemia →](https://durgical.com/en/conditions/atherosclerosis-and-dyslipidaemia/)
- **Step 4 · Mevalonate kinase (MVK)** irreversible [Mevalonate](https://durgical.com/en/biochemistry/molecules/mevalonate/) + [ATP](https://durgical.com/en/biochemistry/molecules/atp/) → Mevalonate 5-phosphate + ADP First of three ATP-driven phosphorylations: adds a phosphate to carbon 5. **If it fails:** Its deficiency causes hyper-IgD syndrome with periodic fevers and, when activity is almost absent, mevalonic aciduria.
- **Step 5 · Phosphomevalonate kinase (PMVK)** irreversible Mevalonate 5-phosphate + [ATP](https://durgical.com/en/biochemistry/molecules/atp/) → Mevalonate 5-pyrophosphate + ADP Second phosphorylation: forms the pyrophosphate that will activate the isoprene. **If it fails:** PMVK variants are linked to porokeratosis, a skin disorder.
- **Step 6 · Diphosphomevalonate decarboxylase (MVD)** irreversible Mevalonate 5-pyrophosphate + [ATP](https://durgical.com/en/biochemistry/molecules/atp/) → [Isopentenyl pyrophosphate](https://durgical.com/en/biochemistry/molecules/isopentenyl-pyrophosphate/) + ADP + phosphate (Pi) + CO₂ Spends one ATP to remove the carboxyl: out comes the active five-carbon isoprene, isopentenyl pyrophosphate. **If it fails:** MVD variants have also been described in porokeratosis.
- **Step 7 · IPP isomerase and farnesyl diphosphate synthase (FDPS)** irreversible [Isopentenyl pyrophosphate](https://durgical.com/en/biochemistry/molecules/isopentenyl-pyrophosphate/) + Dimethylallyl pyrophosphate (DMAPP) → Farnesyl pyrophosphate + pyrophosphate The isomerase turns one IPP into DMAPP; the synthase joins DMAPP head-to-tail with two IPP: geranyl-PP (C10), then farnesyl-PP (C15). **If it fails:** Farnesyl-PP is also used to prenylate proteins such as Ras; without it the osteoclast stops working (the bisphosphonate effect).
- **Step 8 · Squalene synthase (FDFT1)** irreversible Farnesyl pyrophosphate + Farnesyl pyrophosphate + [NADPH](https://durgical.com/en/biochemistry/molecules/nadph/) → [Squalene](https://durgical.com/en/biochemistry/molecules/squalene/) + nadp + pyrophosphate Joins two farnesyl-PP tail-to-tail into squalene (C30), the first compound used only for sterols. **If it fails:** Its very rare deficiency causes a syndrome of malformations and seizures resembling Smith–Lemli–Opitz.
- **Step 9 · [Squalene epoxidase (SQLE)](https://durgical.com/en/biochemistry/enzymes/squalene-epoxidase/)** irreversible [Squalene](https://durgical.com/en/biochemistry/molecules/squalene/) + o2 + [NADPH](https://durgical.com/en/biochemistry/molecules/nadph/) → 2,3-Oxidosqualene + nadp + H₂O Adds an epoxide to one end of squalene; it is the pathway's second control point. **If it fails:** It is increased in some tumours and is being studied as a cancer target.
- **Step 10 · Lanosterol synthase (oxidosqualene cyclase, LSS)** irreversible 2,3-Oxidosqualene → [Lanosterol](https://durgical.com/en/biochemistry/molecules/lanosterol/) Folds the chain and closes all four rings in a single reaction: the first sterol, lanosterol, is born. **If it fails:** LSS variants are linked to congenital cataracts. [Cataract →](https://durgical.com/en/conditions/cataract/)
- **Step 11 · Lanosterol 14α-demethylase (CYP51A1) and the following enzymes** irreversible [Lanosterol](https://durgical.com/en/biochemistry/molecules/lanosterol/) + o2 + [NADPH](https://durgical.com/en/biochemistry/molecules/nadph/) → 7-Dehydrocholesterol + CO₂ A series of ER reactions removes three methyl groups (C30 → C27) and shifts double bonds; the Kandutsch–Russell route reaches 7-dehydrocholesterol. **If it fails:** Defects of enzymes in this stretch cause rare malformation syndromes, such as lathosterolosis or desmosterolosis (Bloch route).
- **Step 12 · 7-Dehydrocholesterol reductase (DHCR7)** irreversible 7-Dehydrocholesterol + [NADPH](https://durgical.com/en/biochemistry/molecules/nadph/) → [Cholesterol](https://durgical.com/en/biochemistry/molecules/cholesterol/) + nadp Reduces the C7–C8 double bond and leaves cholesterol. In the skin, UVB light turns the same 7-dehydrocholesterol into vitamin D3. **If it fails:** Its deficiency is Smith–Lemli–Opitz syndrome: cholesterol is short and 7-dehydrocholesterol builds up. [Smith–Lemli–Opitz syndrome →](https://durgical.com/en/conditions/smith-lemli-opitz-syndrome/)

## Clinical notes

- Statins inhibit HMG-CoA reductase; the liver responds with more LDL receptors and blood LDL falls.
- Nitrogen-containing bisphosphonates (such as zoledronic acid) inhibit osteoclast farnesyl diphosphate synthase and slow bone resorption.
- Smith–Lemli–Opitz syndrome (loss of the last step, DHCR7) shows that the embryo must make its own cholesterol.
- Terbinafine inhibits the fungal squalene epoxidase and azoles its CYP51: steps that also exist in the human pathway.

## Related conditions

- [Smith–Lemli–Opitz syndrome](https://durgical.com/en/conditions/smith-lemli-opitz-syndrome/)
- [Familial hypercholesterolemia](https://durgical.com/en/conditions/familial-hypercholesterolemia/)
- [Atherosclerosis and dyslipidaemia](https://durgical.com/en/conditions/atherosclerosis-and-dyslipidaemia/)

## Related

- [Acetyl-CoA](https://durgical.com/en/biochemistry/molecules/acetyl-coa/)
- [HMG-CoA reductase](https://durgical.com/en/biochemistry/enzymes/hmg-coa-reductase/)
- [Mevalonate](https://durgical.com/en/biochemistry/molecules/mevalonate/)
- [Isopentenyl pyrophosphate (IPP)](https://durgical.com/en/biochemistry/molecules/isopentenyl-pyrophosphate/)
- [Squalene](https://durgical.com/en/biochemistry/molecules/squalene/)
- [Squalene epoxidase](https://durgical.com/en/biochemistry/enzymes/squalene-epoxidase/)
- [Lanosterol](https://durgical.com/en/biochemistry/molecules/lanosterol/)
- [Cholesterol](https://durgical.com/en/biochemistry/molecules/cholesterol/)
- [LDL receptor](https://durgical.com/en/biochemistry/enzymes/ldl-receptor/)
- [Lipoprotein metabolism](https://durgical.com/en/biochemistry/topics/lipoprotein-metabolism/)
- [Bile acid synthesis](https://durgical.com/en/biochemistry/topics/bile-acid-synthesis/)
- [Steroid hormone synthesis (overview)](https://durgical.com/en/biochemistry/topics/steroid-hormone-synthesis/)

## Test yourself

Think of the answer, then tap the question to see it.

## What is the rate-limiting step of cholesterol synthesis and which drugs block it?

HMG-CoA reductase (HMG-CoA → mevalonate); statins inhibit it.

## Why does cytosolic HMG-CoA not become ketone bodies?

HMG-CoA lyase, which makes acetoacetate, is mitochondrial; cytosolic HMG-CoA goes on to mevalonate.

## Which enzyme of this pathway do nitrogen-containing bisphosphonates inhibit?

Osteoclast farnesyl diphosphate synthase: protein prenylation fails and the cell stops resorbing bone.

## Which precursor do cholesterol and vitamin D3 share?

7-Dehydrocholesterol: DHCR7 reduces it to cholesterol and UVB light in the skin turns it into vitamin D3.

[Add to my cards (4)](https://durgical.app/estudiar/?add=/en/biochemistry/pathways/cholesterol-synthesis/)

Educational information, not medical advice. For any symptom, see a health professional.

Sources: [Cholesterol biosynthesis (R-HSA-191273)](https://reactome.org/PathwayBrowser/#/R-HSA-191273) (Reactome, 2026); [DHCR7 gene: MedlinePlus Genetics](https://medlineplus.gov/genetics/gene/dhcr7/) (MedlinePlus, US National Library of Medicine, 2026); [Statins: MedlinePlus](https://medlineplus.gov/statins.html) (MedlinePlus, US National Library of Medicine, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).

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Source: https://durgical.com/en/biochemistry/pathways/cholesterol-synthesis/
License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/biochemistry/pathways/cholesterol-synthesis/