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.
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
Related conditions
Related
- Acetyl-CoA
- Acetoacetate (acetoacetic acid)
- β-Hydroxybutyrate
- HMG-CoA reductase
- β-Hydroxybutyrate dehydrogenase (BDH1)
Test yourself
Think of the answer, then tap the question to see it.
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.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: HMGCS2: Hydroxymethylglutaryl-CoA synthase, mitochondrial (human) (UniProt, 2026); Synthesis of Ketone Bodies (Reactome, 2026); 2WYA: Crystal structure of human mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 (HMGCS2) (RCSB Protein Data Bank, 2026).
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Representative model, for educational purposes only.