Valine to succinyl-CoA, through propionyl-CoA and methylmalonyl-CoA
Route: Valine → α-Ketoisovalerate → Isobutyryl-CoA → Methacrylyl-CoA → (S)-3-Hydroxyisobutyryl-CoA → (S)-3-Hydroxyisobutyrate → (S)-Methylmalonate semialdehyde → Propionyl-CoA → (S)-Methylmalonyl-CoA → (R)-Methylmalonyl-CoA → Suc-CoA
A branched-chain aminotransferase moves the amino group of valine to α-ketoglutarate and leaves α-ketoisovalerate. The branched-chain α-ketoacid dehydrogenase complex then removes CO₂ and attaches CoA, which gives isobutyryl-CoA. This complex also handles the α-ketoacids of leucine and isoleucine. It is a homolog of pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, and all three share the same E3 component. The structure and EC number are those of its E1 component; the chips show the reaction of the whole complex. Isobutyryl-CoA dehydrogenase then puts a double bond into the chain, which gives methacrylyl-CoA, and enoyl-CoA hydratase adds water to make (S)-3-hydroxyisobutyryl-CoA. A hydrolase removes the CoA, and a dehydrogenase uses NAD⁺ to turn the alcohol of (S)-3-hydroxyisobutyrate into an aldehyde, methylmalonate semialdehyde. Methylmalonate semialdehyde dehydrogenase takes CoA, NAD⁺ and water, releases bicarbonate and gives propionyl-CoA. Propionyl-CoA carboxylase, a biotin enzyme, adds a carboxyl group at the cost of ATP and makes (S)-methylmalonyl-CoA. An epimerase converts it to the (R) form, and methylmalonyl-CoA mutase, which needs vitamin B₁₂, moves the carbonyl-CoA group from carbon 2 to the methyl carbon in exchange for a hydrogen atom, which gives succinyl-CoA, an intermediate of the Krebs cycle. The three steps from propionyl-CoA also serve the breakdown of odd-chain fatty acids, isoleucine, methionine and threonine. In maple syrup urine disease the branched-chain α-ketoacid dehydrogenase is missing or defective, so the α-ketoacids of valine, isoleucine 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 | Isobutyryl-CoA dehydrogenase | 1.3.8.5 | FAD | FADH₂ |
| 4 | Enoyl-CoA hydratase | 4.2.1.17 | H₂O | |
| 5 | 3-Hydroxyisobutyryl-CoA hydrolase | 3.1.2.4 | H₂O | CoA-SH |
| 6 | 3-Hydroxyisobutyrate dehydrogenase | 1.1.1.31 | NAD⁺ | NADH |
| 7 | Methylmalonate-semialdehyde dehydrogenase (acylating) | 1.2.1.27 | NAD⁺, CoA-SH, H₂O | NADH, HCO₃⁻ |
| 8 | Propionyl-CoA carboxylase | 6.4.1.3 | ATP, HCO₃⁻ | ADP, Pᵢ |
| 9 | Methylmalonyl-CoA epimerase | 5.1.99.1 | ||
| 10 | 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).