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

# Mitochondrial HMG-CoA synthase (HMGCS2)

Mitochondrial HMG-CoA synthase is the enzyme that switches on ketone body production in the liver during fasting.

Updated 2026-11-01

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## Key facts

- Rate-limiting step of ketogenesis: acetoacetyl-CoA + acetyl-CoA → HMG-CoA.
- Mitochondrial and almost liver-only; the cytosolic isoform (HMGCS1) feeds cholesterol synthesis.
- Its gene is switched on by fasting, glucagon and PPARα, and off by insulin.

**Also called**
HMG-CoA synthase 2

**EC number**
[2.3.3.10](https://www.enzyme-database.org/query.php?ec=2.3.3.10)

**Genes**
HMGCS2

**Structure (PDB)**
[2WYA](https://www.rcsb.org/structure/2WYA)

## Regulation

- Controlled by enzyme amount: high transcription in fasting (PPARα, FOXA2), low with insulin.
- Succinylation by succinyl-CoA inactivates it; glucagon lowers that succinylation.

## Inhibitors and toxins

- No inhibitors in clinical use

## Clinical notes

- HMGCS2 deficiency causes crises of hypoketotic hypoglycaemia in infants with fasting or infection.
- In diabetic ketoacidosis HMGCS2 runs at full speed because the insulin that restrains it is missing.

## Pathways

- [Ketogenesis (ketone body synthesis)](https://durgical.com/en/biochemistry/pathways/ketogenesis/)

## Related conditions

- [Diabetic ketoacidosis](https://durgical.com/en/conditions/diabetic-ketoacidosis/)
- [Type 1 diabetes mellitus](https://durgical.com/en/conditions/type-1-diabetes-mellitus/)

## Related

- [Acetyl-CoA](https://durgical.com/en/biochemistry/molecules/acetyl-coa/)
- [Acetoacetate (acetoacetic acid)](https://durgical.com/en/biochemistry/molecules/acetoacetate/)
- [β-Hydroxybutyrate](https://durgical.com/en/biochemistry/molecules/hydroxybutyrate/)
- [HMG-CoA reductase](https://durgical.com/en/biochemistry/enzymes/hmg-coa-reductase/)
- [β-Hydroxybutyrate dehydrogenase (BDH1)](https://durgical.com/en/biochemistry/enzymes/hydroxybutyrate-dehydrogenase/)

## Test yourself

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## How do HMGCS1 and HMGCS2 differ?

HMGCS1 is cytosolic and leads to cholesterol; HMGCS2 is mitochondrial and leads to ketone bodies.

## How is mitochondrial HMG-CoA synthase regulated?

Mainly by its amount: fasting and glucagon raise its gene and insulin lowers it.

## What picture does HMGCS2 deficiency produce?

Hypoglycaemia with low ketones on fasting, similar to a β-oxidation defect.

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

Sources: [HMGCS2: Hydroxymethylglutaryl-CoA synthase, mitochondrial (human)](https://www.uniprot.org/uniprotkb/P54868/entry) (UniProt, 2026); [Synthesis of Ketone Bodies](https://reactome.org/PathwayBrowser/#/R-HSA-77111) (Reactome, 2026); [2WYA: Crystal structure of human mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 (HMGCS2)](https://www.rcsb.org/structure/2WYA) (RCSB Protein Data Bank, 2026).

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Representative model, for educational purposes only.

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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/mitochondrial-hmg-coa-synthase/