Ketogenesis

Step 1

Thiolase condenses two acetyl-CoA molecules → acetoacetyl-CoA (4C). One CoA is released.

Step 2

HMG-CoA synthase adds a third acetyl-CoA to acetoacetyl-CoA → HMG-CoA (6C). This is the committed step. HMG-CoA is a branch point: in the mitochondria it goes to ketogenesis; in the cytoplasm it goes to cholesterol synthesis.

Step 3

HMG-CoA lyase cleaves HMG-CoA → acetoacetate + acetyl-CoA.

Step 4

Acetoacetate has two fates: (a) 3-hydroxybutyrate dehydrogenase reduces it using NADH → 3-hydroxybutyrate (βOHB), or (b) spontaneous nonenzymatic decarboxylation → acetone + CO₂. Acetoacetate and 3-hydroxybutyrate are the main circulating ketone bodies exported to peripheral tissues and the brain.