nonessential amino acids

**Definition:** Amino acids that humans can synthesize endogenously in sufficient quantity. Strictly nonessential: alanine, aspartate, asparagine, glutamate, serine. Conditionally essential (synthesis may be inadequate in growth, illness, or enzyme deficiency): arginine, cysteine, glycine, glutamine, proline, tyrosine.

**Essential amino acids (mnemonic PVT TIM HALL):** Phenylalanine, Valine, Threonine, Tryptophan, Isoleucine, Methionine, Histidine, Arginine (partially), Leucine, Lysine. Arginine and histidine are especially required during growth (children, pregnancy). Purely ketogenic: leucine and lysine.

**Biosynthetic origins (high-yield):** - Alanine: transamination of pyruvate (ALT); carries nitrogen from muscle to liver (glucose-alanine cycle). - Aspartate: transamination of oxaloacetate (AST). - Glutamate: transamination of alpha-ketoglutarate, or via glutamate dehydrogenase (reductive amination of alpha-ketoglutarate). Central nitrogen-handling amino acid. - Asparagine: from aspartate + glutamine via asparagine synthetase (ATP-dependent). Asparaginase is used in ALL because leukemic cells lack asparagine synthetase. - Glutamine: from glutamate via glutamine synthetase (ammonia detoxification, especially in brain and muscle). - Serine: from 3-phosphoglycerate (glycolytic intermediate). Precursor of glycine, cysteine, and phospholipids. - Glycine: from serine via serine hydroxymethyltransferase (requires B6 and tetrahydrofolate). - Proline: from glutamate. - Arginine: from the urea cycle (argininosuccinate lyase); this is why it's conditionally essential, since the cycle in the kidney and liver does not yield enough in growth. - Cysteine: from methionine (essential) + serine via homocysteine and cystathionine (cystathionine synthase, B6). Becomes essential in homocystinuria (cystathionine synthase deficiency). - Tyrosine: from phenylalanine via phenylalanine hydroxylase (requires tetrahydrobiopterin, BH4). Becomes essential in phenylketonuria (PKU).

**Clinical correlations:** - PKU: phenylalanine hydroxylase or BH4 deficiency causes phenylalanine accumulation and tyrosine deficiency. Presents with intellectual disability, musty odor, fair skin, and eczema. Treatment: low-phenylalanine diet and supplemented tyrosine. Avoid aspartame (contains phenylalanine). Maternal PKU causes microcephaly, congenital heart defects, and growth retardation in the fetus. - Homocystinuria: cystathionine synthase deficiency leads to cysteine becoming essential. Presents with Marfan-like habitus, downwards lens dislocation, thrombosis, and intellectual disability. Treatment: B6, low methionine, and cysteine supplementation, with betaine. - Urea cycle disorders: arginine becomes essential and is supplemented in some disorders (e.g., citrullinemia, argininosuccinic aciduria). - Kwashiorkor/malnutrition: protein deficiency leads to edema, fatty liver, and a "flaky paint" dermatosis. - Asparaginase therapy for ALL depletes circulating asparagine. Toxicities include pancreatitis, thrombosis, and hypersensitivity. - Transaminases AST/ALT: use alpha-ketoglutarate/glutamate and require pyridoxal phosphate (B6). Elevated levels indicate hepatocellular injury.

**Pearl:** "Nonessential" doesn't mean "unimportant." Many are precursors of neurotransmitters (glutamate, glycine, aspartate, GABA from glutamate), heme (glycine), purines (glycine, aspartate, glutamine), pyrimidines (aspartate, glutamine), creatine (glycine, arginine), nitric oxide (arginine), and glutathione (glutamate, cysteine, glycine).