Ketogenesis

1. 1

   2 acetyl-CoA → acetoacetyl-CoA + CoA-SH

   Mitochondrial thiolase (acetyl-CoA acetyltransferase, T2/ACAT1) 2.3.1.9 ST-0082 Reversible CoA-SH
   In Acetyl-CoA

   Out Acetoacetyl-CoA CoA-SH
   › Notes

   Mitochondrial thiolase (acetyl-CoA acetyltransferase) condenses two acetyl-CoA molecules. This reaction is reversible and is shared conceptually with the terminal thiolysis step of β-oxidation.

2. 2

   Acetoacetyl-CoA + acetyl-CoA + H2O → 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) + CoA-SH

   Mitochondrial HMG-CoA synthase (HMGCS2) 2.3.3.10 ST-0083 Irreversible/directional rate-limiting CoA-SH H2O
   In Acetoacetyl-CoA Acetyl-CoA H2O

   Out 3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) CoA-SH
   › Notes

   Mitochondrial HMG-CoA synthase (HMGCS2) catalyzes this condensation. It is the rate-limiting and committed step of ketogenesis; it is distinct from cytosolic HMG-CoA synthase used in cholesterol synthesis.

3. 3

   HMG-CoA → acetoacetate + acetyl-CoA

   HMG-CoA lyase (HMGCL) 4.1.3.4 ST-0084 Irreversible/directional
   In HMG-CoA

   Out Acetoacetate Acetyl-CoA
   › Notes

   HMG-CoA lyase cleaves HMG-CoA to the first ketone body, acetoacetate, and acetyl-CoA. No nucleotide cofactor is required.

4. 4

   Acetoacetate + NADH + H+ ⇌ D-β-hydroxybutyrate + NAD+

   D-beta-hydroxybutyrate dehydrogenase (BDH1) 1.1.1.30 ST-0085 Reversible NAD+ NADH
   In Acetoacetate NADH H+

   Out D-beta-hydroxybutyrate NAD+
   › Notes

   Mitochondrial D-β-hydroxybutyrate dehydrogenase interconverts the two principal ketone bodies. The mitochondrial NADH/NAD+ ratio determines their ratio: high NADH generated by β-oxidation favors D-β-hydroxybutyrate.

5. 5

   Acetoacetate → acetone + CO2

   Non-enzymatic (spontaneous decarboxylation) ST-0086 Irreversible/directional
   In Acetoacetate

   Out Acetone CO2
   › Notes

   Acetoacetate undergoes slow, largely spontaneous nonenzymatic decarboxylation to acetone in humans; acetone is volatile and exhaled. This is not a productive ATP-generating step and is not a regulated enzymatic reaction.

Showing all 5 steps.

Overview

Ketogenesis converts excess hepatic mitochondrial acetyl-CoA into the water-soluble ketone bodies acetoacetate and D-β-hydroxybutyrate; acetone is a minor spontaneous breakdown product. It is activated in prolonged fasting, starvation, sustained exercise, uncontrolled type 1 diabetes mellitus, and other states with high glucagon-to-insulin signaling. Ketone bodies export energy from liver to extrahepatic tissues while sparing glucose and, during prolonged fasting, reducing the need for proteolysis to supply gluconeogenic amino acids.

Cellular location

Ketogenesis occurs exclusively in the mitochondrial matrix of hepatocytes, chiefly periportal liver cells. The liver synthesizes but cannot consume ketone bodies because it lacks succinyl-CoA:3-ketoacid CoA transferase (SCOT/OXCT1). Ketone bodies cross membranes and circulate freely without lipoprotein carriers or albumin.

Net energetics

Ketogenesis itself does not produce ATP; it repackages acetyl-CoA into exportable fuel. Net formation of acetoacetate uses 2 acetyl-CoA and releases two CoA-SH; formation of D-β-hydroxybutyrate additionally consumes 1 NADH + H+ per acetoacetate reduced. The energy is recovered in extrahepatic tissues during ketolysis and subsequent oxidation of acetyl-CoA.

Clinical significance

Physiological ketosis supports brain, skeletal muscle, and heart during carbohydrate scarcity, while erythrocytes cannot use ketones because they lack mitochondria. In insulin-deficient diabetes, unchecked lipolysis and ketogenesis can produce high-anion-gap metabolic acidosis—diabetic ketoacidosis (DKA)—with dehydration, Kussmaul respirations, and fruity acetone breath. HMG-CoA lyase deficiency impairs ketone production and may cause hypoketotic hypoglycemia during fasting or illness. Nutritional ketosis is regulated and generally much less acidemic than DKA because insulin is present.