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[Biochemistry](https://durgical.com/en/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.

**Also called**
3-hydroxy-3-methylglutaryl-CoA reductase

**EC number**
[1.1.1.34](https://www.enzyme-database.org/query.php?ec=1.1.1.34)

**Genes**
HMGCR

**Structure (PDB)**
[1HWK](https://www.rcsb.org/structure/1HWK)

## 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

- [Atorvastatin](https://durgical.com/en/pharmacology/atorvastatin/)
- [Simvastatin](https://durgical.com/en/pharmacology/simvastatin/)
- [Rosuvastatin](https://durgical.com/en/pharmacology/rosuvastatin/)
- [Pravastatin](https://durgical.com/en/pharmacology/pravastatin/)
- [Fluvastatin](https://durgical.com/en/pharmacology/fluvastatin/)
- [Lovastatin](https://durgical.com/en/pharmacology/lovastatin/)

## Pathways

- [Cholesterol synthesis (mevalonate pathway)](https://durgical.com/en/biochemistry/pathways/cholesterol-synthesis/)

## Related conditions

- [Atherosclerosis and dyslipidaemia](https://durgical.com/en/conditions/atherosclerosis-and-dyslipidaemia/)
- [Myocardial Infarction (Heart Attack)](https://durgical.com/en/conditions/myocardial-infarction/)
- [Ischaemic stroke](https://durgical.com/en/conditions/ischaemic-stroke/)

## 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.

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

Sources: [HMGCR: 3-hydroxy-3-methylglutaryl-coenzyme A reductase (human)](https://rest.uniprot.org/uniprotkb/P04035.txt) (UniProt, 2026); [1HWK: COMPLEX OF THE CATALYTIC PORTION OF HUMAN HMG-COA REDUCTASE WITH ATORVASTATIN](https://www.rcsb.org/structure/1HWK) (RCSB Protein Data Bank, 2026); [Cholesterol biosynthesis (R-HSA-191273)](https://reactome.org/PathwayBrowser/#/R-HSA-191273) (Reactome, 2026); [ATORVASTATIN CALCIUM tablet](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=604a011e-6c64-4895-8f6e-d28f119c4c22) (DailyMed, US National Library of Medicine, 2026); [Atorvastatin: MedlinePlus Drug Information](https://medlineplus.gov/druginfo/meds/a600045.html) (MedlinePlus, US National Library of Medicine, 2026).

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License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/biochemistry/enzymes/hmg-coa-reductase/