Branched-chain amino acids (BCAA) leucine (Leu), isoleucine (Ile), and valine (Val) account for approx. 20% of amino acids in proteins and are major sources of cellular energy, including acetyl-CoA and propionyl-CoA for the Krebs cycle and gluconeogenesis.
BCAA breakdown takes place in the mitochondria after import mediated by SLC25A44. Reversible intramitochondrial transamination by branched-chain amino acid transaminase 2 (BCAT2, predominantly in the muscle) is also important for the production of glutamate from 2-oxoglutarate (cytosolic BCAT1 is a neuronal protein). The branched-chain oxoacid dehydrogenase complex (BCKDC) is evolutionarily related to other 2-oxoacid dehydrogenase complexes and uses a common subunit E3 (PDHC, OGDC, OADC [oxoadipate dehydrogenase complex]); see page 148. BCKDC deficiency causes Maple syrup urine disease, characterized by elevations of blood leucine, isoleucine, and valine.
Deficiencies of subsequent enzymatic reactions cause organic acidurias. Most disorders are diagnosed by the elevation of specific metabolites (e.g. methylcitric acid, 3-OH-isovaleric acid, methylmalonic acid) in urinary organic acid analysis. 3-Methylcrotonyl-CoA carboxylase (two genes MCCC1, MCCC2)and propionyl-CoA carboxylase (two genes PCCA, PCCB) each consist of two subunits and require biotin as a cofactor. Methylmalonyl-CoA mutase (MMUT) requires vitamin B12 (cobalamin, cbl).
Other enzymes and abbreviations (genes):
- Isobutyryl-CoA DH, ACAD8),
- Short-chain enoyl-CoA hydratase 1 (ECHS1),
- 3-Hydroxyisobutyryl-CoA hydrolase (HIBCH),
- 3-Hydroxyisobutyrate DH (HIBADH, no disease known),
- Methylmalonate semialdehyde DH (ALDH6A1),
- 2-Methylbutyryl-CoA DH (ACADSB),
- 2-Methyl-3-hydroxybutyryl-CoA DH (HSD17B10),
- Methylacetoacetyl-CoA thiolase (ACAT1),
- Isovaleryl-CoA DH (IVD),
- 3-Methylglutaconyl-CoA hydratase (AUH),
- HMG-CoA lyase (HMGCL),
- Methylmalonyl-CoA epimerase (MCEE),
- Methylmalonyl-CoA mutase (MMUT)