Leucine breakdown

Route: Leucine → α-Ketoisocaproate → Isovaleryl-CoA → 3-Methylcrotonyl-CoA → 3-Methylglutaconyl-CoA → 3-Hydroxy-3-methylglutaryl-CoA → Acetoacetate + Acetyl-CoA

Leucine is transaminated to α-ketoisocaproate, which the branched-chain α-ketoacid dehydrogenase complex turns into isovaleryl-CoA with loss of CO₂. The structure and EC number are those of the E1 component of that complex; the chips show the reaction of the whole complex. Isovaleryl-CoA dehydrogenase uses FAD to make a double bond, which gives 3-methylcrotonyl-CoA, in the same way as the first step of fatty acid oxidation. 3-Methylcrotonyl-CoA carboxylase, a biotin enzyme, then adds a carboxyl group to a methyl group at the cost of ATP, which gives 3-methylglutaconyl-CoA. A hydratase adds water and makes HMG-CoA. HMG-CoA lyase cuts it into acetyl-CoA and acetoacetate. This is the same lyase that closes the ketone body route in the liver. In maple syrup urine disease the branched-chain α-ketoacid dehydrogenase is missing or defective, so the α-ketoacids of leucine, valine and isoleucine and the amino acids themselves rise in blood and urine, and the urine smells of maple syrup. The enzymes after the first step work in mitochondria. The aminotransferase has a mitochondrial form (the one shown) and a cytosolic form. The FAD shown is bound to the dehydrogenase. It passes its electrons to electron-transferring flavoprotein, and from there they reach ubiquinone in the respiratory chain.

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Steps

Molecules

Build any of these from its atoms.

• Leucine Build it
• α-Ketoisocaproate Build it
• Isovaleryl-CoA
• 3-Methylcrotonyl-CoA
• 3-Methylglutaconyl-CoA
• 3-Hydroxy-3-methylglutaryl-CoA
• Acetoacetate Build it
• Acetyl-CoA

Enzyme names and EC numbers are those used on the interactive board. Checked against sources: see the claim table in the repository (tools/pathway_data/checks).