Biochemistry · Enzyme
HMG-CoA reductase !
HMG-CoA reductase makes mevalonate, the slow step that sets how much cholesterol the cell builds. Statins block it.
Updated 2026-11-01
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Key facts
- HMG-CoA + 2 NADPH → mevalonate + CoA + 2 NADP⁺: the rate-limiting step of the mevalonate pathway.
- Mevalonate feeds cholesterol and other isoprenoids; Reactome counts 15 reactions from acetyl-CoA to lanosterol.
- It sits in the membranes of the endoplasmic reticulum and the peroxisome.
- Affinity for its substrate is high: UniProt lists a Km of about 14 µM for HMG-CoA.
Structure
- The human chain has 888 amino acids and crosses the membrane several times; the catalytic portion was crystallised on its own.
- Structure 1HWK shows the human catalytic portion with atorvastatin bound.
Regulation
- Sterols and other mevalonate products switch it down (feedback).
- When sterols rise, the enzyme binds INSIG proteins and is tagged with ubiquitin and destroyed in the ER.
- Phosphorylation lowers its activity (described in rodent enzyme and inferred for human).
Inhibitors and toxins
- Statins (atorvastatin, simvastatin): selective, competitive inhibitors.
Clinical notes
- Less cholesterol made in the liver means more LDL receptors on liver cells, which pull LDL out of the blood.
- That is why statins lower LDL cholesterol and the risk of heart attack and stroke.
- Their best-known serious adverse effect is muscle damage (myopathy, rarely rhabdomyolysis).
- Statins are stopped when pregnancy is recognised because they may harm the fetus.
Drugs that act here
Pathways
Related conditions
Test yourself
Think of the answer, then tap the question to see it.
Which reaction does HMG-CoA reductase catalyse?
HMG-CoA to mevalonate, using two NADPH: the rate-limiting step of cholesterol synthesis.
How does blocking this enzyme lower LDL in the blood?
The liver makes less cholesterol, puts more LDL receptors on its cells and takes up more LDL from plasma.
What happens to HMG-CoA reductase when sterols build up in the cell?
It binds INSIG proteins in the ER, gets tagged with ubiquitin and is broken down.
Which muscle problem should a person on a statin report?
Unexplained muscle pain, tenderness or weakness, a sign of myopathy.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: HMGCR: 3-hydroxy-3-methylglutaryl-coenzyme A reductase (human) (UniProt, 2026); 1HWK: COMPLEX OF THE CATALYTIC PORTION OF HUMAN HMG-COA REDUCTASE WITH ATORVASTATIN (RCSB Protein Data Bank, 2026); Cholesterol biosynthesis (R-HSA-191273) (Reactome, 2026); ATORVASTATIN CALCIUM tablet (DailyMed, US National Library of Medicine, 2026); Atorvastatin: MedlinePlus Drug Information (MedlinePlus, US National Library of Medicine, 2026).
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Representative model, for educational purposes only.