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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

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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

  1. Step 1 · Cytosolic thiolase (acetyl-CoA acetyltransferase 2) Acetyl-CoA + Acetyl-CoA ⇌ Acetoacetyl-CoA + coenzyme AJoins two acetyl-CoA into four-carbon acetoacetyl-CoA.If it fails: Deficiency of the mitochondrial thiolase (a different isoenzyme) impairs ketolysis and isoleucine breakdown.
  2. Step 2 · Cytosolic HMG-CoA synthase (HMGCS1) irreversible Acetoacetyl-CoA + Acetyl-CoA + H₂O → HMG-CoA + coenzyme AAdds 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.
  3. Step 3 · HMG-CoA reductase irreversible HMG-CoA + NADPH → Mevalonate + nadp + coenzyme AReduces 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 →
  4. Step 4 · Mevalonate kinase (MVK) irreversible Mevalonate + ATP → Mevalonate 5-phosphate + ADPFirst 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.
  5. Step 5 · Phosphomevalonate kinase (PMVK) irreversible Mevalonate 5-phosphate + ATP → Mevalonate 5-pyrophosphate + ADPSecond phosphorylation: forms the pyrophosphate that will activate the isoprene.If it fails: PMVK variants are linked to porokeratosis, a skin disorder.
  6. Step 6 · Diphosphomevalonate decarboxylase (MVD) irreversible Mevalonate 5-pyrophosphate + ATP → Isopentenyl pyrophosphate + ADP + phosphate (Pi) + CO₂Spends 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.
  7. Step 7 · IPP isomerase and farnesyl diphosphate synthase (FDPS) irreversible Isopentenyl pyrophosphate + Dimethylallyl pyrophosphate (DMAPP) → Farnesyl pyrophosphate + pyrophosphateThe 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).
  8. Step 8 · Squalene synthase (FDFT1) irreversible Farnesyl pyrophosphate + Farnesyl pyrophosphate + NADPH → Squalene + nadp + pyrophosphateJoins 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.
  9. Step 9 · Squalene epoxidase (SQLE) irreversible Squalene + o2 + NADPH → 2,3-Oxidosqualene + nadp + H₂OAdds 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.
  10. Step 10 · Lanosterol synthase (oxidosqualene cyclase, LSS) irreversible 2,3-Oxidosqualene → LanosterolFolds 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 →
  11. Step 11 · Lanosterol 14α-demethylase (CYP51A1) and the following enzymes irreversible Lanosterol + o2 + NADPH → 7-Dehydrocholesterol + CO₂A 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).
  12. Step 12 · 7-Dehydrocholesterol reductase (DHCR7) irreversible 7-Dehydrocholesterol + NADPH → Cholesterol + nadpReduces 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 →

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.

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.

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

Sources: Cholesterol biosynthesis (R-HSA-191273) (Reactome, 2026); DHCR7 gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Statins: MedlinePlus (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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