Ketone body formation template

2 acetyl-CoA → acetoacetyl-CoA (thiolase) → (S)-HMG-CoA (mitochondrial HMG-CoA synthase) → acetoacetate + acetyl-CoA (HMG-CoA lyase) → D-β-hydroxybutyrate (NADH) or acetone (spontaneous decarboxylation).

What the template shows

• In fasting or diabetes, liver mitochondria turn excess acetyl-CoA into acetoacetate, D-β-hydroxybutyrate and acetone
• Ketogenesis (liver mitochondrial matrix)
• acetyl-CoA (×2)
• acetoacetyl-CoA
• (S)-HMG-CoA
• Acetone: spontaneous decarboxylation of acetoacetate
• Volatile and not used for fuel: breathed out (fruity breath in ketoacidosis)
• Trigger: in fasting, low insulin and high glucagon send oxaloacetate into gluconeogenesis, so acetyl-CoA from β-oxidation cannot enter the citric acid cycle and builds up.
• Mitochondrial HMG-CoA synthase is the control point; the same reaction in the cytosol (cytosolic isozyme) starts cholesterol synthesis.
• Heart, muscle and (after days of fasting) brain burn acetoacetate: succinyl-CoA:3-ketoacid CoA transferase makes acetoacetyl-CoA. The liver lacks this enzyme, so it exports ketone bodies.
• In type 1 diabetes, ketone bodies can exceed buffering: ketoacidosis. D-β-hydroxybutyrate is (R)-3-hydroxybutanoate; acids are drawn neutral.

Drawn with 50 atoms, 5 arrows, 2 shapes – every one editable in MolDraw.

Sources

• Nelson & Cox, Lehninger Principles of Biochemistry, 8th ed., 2021, ch. 17 Textbook
• Berg, Tymoczko, Gatto & Stryer, Biochemistry, 9th ed., 2019 Textbook
• Voet & Voet, Biochemistry, 4th ed., Wiley 2011 Textbook