branched-chain amino acids

**Members and properties** - Leucine, isoleucine, valine: all essential (must come from diet). Aliphatic, nonpolar, hydrophobic side chains. - Leucine: exclusively ketogenic (with lysine). Isoleucine: both ketogenic and glucogenic (also phenylalanine, tyrosine, tryptophan). Valine: glucogenic (via succinyl-CoA). - Mnemonic for essential AAs: "PVT TIM HALL" (Phe, Val, Thr, Trp, Ile, Met, His, Arg, Leu, Lys).

**Metabolism** 1. Reversible transamination by branched-chain aminotransferase (BCAT) (requires vitamin B6/PLP), mostly in skeletal muscle (the liver has low BCAT activity). This produces branched-chain α-keto acids and transfers the amino group to α-ketoglutarate to form glutamate. 2. Irreversible oxidative decarboxylation by branched-chain α-ketoacid dehydrogenase (BCKDH) complex, mostly in the liver. Its cofactors are the same as for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase: thiamine pyrophosphate (B1), lipoate, CoA (B5), FAD (B2), and NAD+ (B3). Mnemonic: "Tender Loving Care For Nancy." 3. Products: leucine → acetyl-CoA + acetoacetate; isoleucine → acetyl-CoA + succinyl-CoA; valine → succinyl-CoA.

**Maple syrup urine disease (MSUD)** - Autosomal recessive deficiency of BCKDH (impaired decarboxylation of α-ketoacids of leucine, isoleucine, valine). - Presentation: in the first days of life after protein feeding. Poor feeding, vomiting, lethargy, irritability, cerebral edema, seizures, and coma. Urine and cerumen smell of maple syrup or burnt sugar. Ketoacidosis may also be present. Leucine and its α-ketoacid are the main neurotoxins. - Diagnosis: elevated plasma leucine, isoleucine, valine, and alloisoleucine (pathognomonic). Newborn screening by tandem mass spectrometry. - Treatment: lifelong dietary restriction of BCAAs, with thiamine supplementation in thiamine-responsive variants. Acute crises need aggressive caloric support and sometimes dialysis. Liver transplantation can be curative.

**Other clinical correlates** - Muscle and exercise: BCAAs are oxidized in muscle for energy. During fasting and exercise, muscle releases alanine and glutamine (nitrogen carriers) to the liver and gut (glucose-alanine cycle). - Insulin resistance and type 2 diabetes: elevated circulating BCAAs are associated with obesity and insulin resistance, and they are a biomarker for later T2DM. - Liver cirrhosis and hepatic encephalopathy: low BCAA-to-aromatic AA ratio (Fischer ratio). BCAA supplementation is sometimes used, with limited evidence, for hepatic encephalopathy. Aromatic AAs cross the BBB via the same LAT1 transporter, so the imbalance favors false neurotransmitters. - Leucine activates mTORC1, which stimulates muscle protein synthesis. This is the basis of the popularity of BCAA supplements. - Other transport-related disorders: Hartnup disease (neutral AA transporter defect, causing pellagra-like symptoms) also affects neutral AA absorption, including BCAAs. - Intermittent MSUD: a milder variant with symptoms only during catabolic stress (infection, fasting).

**High-yield pearls** - MSUD is a "decarboxylase" problem, not a transaminase defect. - Cofactor overlap: BCKDH, PDH, and α-KGDH all use the same five cofactors. - Leucine and lysine are the only purely ketogenic amino acids.