Isoleucine to acetyl-CoA and succinyl-CoA
Route: Isoleucine → (3S)-α-Keto-β-methylvalerate → (S)-2-Methylbutyryl-CoA → Tiglyl-CoA → (2S,3S)-3-Hydroxy-2-methylbutyryl-CoA → 2-Methylacetoacetyl-CoA → Propionyl-CoA + Acetyl-CoA → (S)-Methylmalonyl-CoA → (R)-Methylmalonyl-CoA → Suc-CoA
After the transamination and the oxidative decarboxylation by the branched-chain α-ketoacid dehydrogenase complex, the reactions of isoleucine resemble fatty acid oxidation. The structure and EC number shown for the complex are those of its E1 component; the chips show the reaction of the whole complex. Short/branched-chain acyl-CoA dehydrogenase makes a double bond in (S)-2-methylbutyryl-CoA and gives tiglyl-CoA. Enoyl-CoA hydratase adds water, which gives (2S,3S)-3-hydroxy-2-methylbutyryl-CoA. In vitro this hydratase converts tiglyl-CoA at about one eighth of its rate on crotonyl-CoA, and Reactome assigns the step to it. A dehydrogenase uses NAD⁺ to make the ketone, 2-methylacetoacetyl-CoA, and a thiolase cuts the chain with CoA into acetyl-CoA and propionyl-CoA. Propionyl-CoA follows the same last three steps as in valine breakdown: carboxylation with biotin and ATP, epimerization, and the rearrangement to succinyl-CoA by the vitamin B₁₂ enzyme methylmalonyl-CoA mutase. Isoleucine therefore gives one acetyl-CoA and one succinyl-CoA. In maple syrup urine disease the branched-chain α-ketoacid dehydrogenase is missing or defective, so the α-ketoacids of isoleucine, valine and leucine 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.
Practice this pathway All pathways
| Step | Enzyme | EC | In | Out |
|---|---|---|---|---|
| 1 | Branched-chain aminotransferase | 2.6.1.42 | α-KG | Glutamate |
| 2 | Branched-chain α-ketoacid dehydrogenase complex (E1 component) | 1.2.4.4 | NAD⁺, CoA-SH | NADH, CO₂ |
| 3 | Short/branched-chain acyl-CoA dehydrogenase | 1.3.8.5 | FAD | FADH₂ |
| 4 | Enoyl-CoA hydratase | 4.2.1.17 | H₂O | |
| 5 | 3-Hydroxy-2-methylbutyryl-CoA dehydrogenase | 1.1.1.178 | NAD⁺ | NADH |
| 6 | Acetyl-CoA acetyltransferase (thiolase) | 2.3.1.9 | CoA-SH | |
| 7 | Propionyl-CoA carboxylase | 6.4.1.3 | ATP, HCO₃⁻ | ADP, Pᵢ |
| 8 | Methylmalonyl-CoA epimerase | 5.1.99.1 | ||
| 9 | Methylmalonyl-CoA mutase | 5.4.99.2 |
Build any of these from its atoms.
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).