glutamic acid

**Biochemistry** - Acidic amino acid (with aspartate). Side chain carboxyl group (pKa ~4.1) is negatively charged at physiologic pH. Mnemonic: "Asp and Glu are acidic (negatively charged)." - Non-essential: synthesized from alpha-ketoglutarate (TCA intermediate) via transamination (ALT/AST) or by glutamate dehydrogenase (reductive amination, requires NADPH/NADH). - Glutamate dehydrogenase: reversible; oxidative deamination releases NH4+ in liver (feeds urea cycle). - Transamination reactions use pyridoxal phosphate (vitamin B6). Glutamate is the major amino group acceptor/donor: ALT (alanine + alpha-KG <-> pyruvate + glutamate); AST (aspartate + alpha-KG <-> oxaloacetate + glutamate). - Ammonia transport/detox: glutamine synthetase (glutamate + NH3 + ATP -> glutamine) in brain (astrocytes), muscle, and other tissues; glutaminase in kidney (generates NH4+ for urinary acid excretion) and intestine; liver periportal/perivenous handling via urea cycle and glutamine synthesis. - Glutamate is a component of N-acetylglutamate (NAG), the essential allosteric activator of carbamoyl phosphate synthetase I (urea cycle). NAG synthase is activated by arginine. - Precursor of GABA via glutamate decarboxylase (GAD), which requires vitamin B6. It is also a precursor for glutathione (Glu-Cys-Gly), proline, ornithine, and arginine. Gamma-carboxyglutamate (vitamin K-dependent gamma-carboxylation of glutamate residues) is needed for clotting factors II, VII, IX, X and proteins C and S, which bind Ca2+. - Glutamate residues in hemoglobin: HbS arises from a point mutation, **glutamic acid -> valine at position 6 of the beta chain** (hydrophilic -> hydrophobic), causing polymerization when deoxygenated. HbC has glutamic acid -> lysine at the same position (loss of negative charge; milder hemolytic disease).

**Neuroscience/Pharmacology** - Principal excitatory neurotransmitter in the CNS. Receptors: ionotropic (NMDA, AMPA, kainate) and metabotropic (mGluR). - NMDA receptor: ligand- and voltage-gated; requires glycine (or D-serine) co-agonist; Mg2+ block removed by depolarization; permeable to Ca2+ and Na+. Involved in long-term potentiation (learning/memory). - Excitotoxicity: excess glutamate/Ca2+ influx contributes to neuronal death in stroke/ischemia, epilepsy, and neurodegenerative disease (e.g., ALS, Huntington, Alzheimer). - Drugs: memantine (NMDA antagonist, Alzheimer disease); ketamine and PCP (NMDA antagonists, dissociative anesthesia/psychosis; esketamine for treatment-resistant depression); riluzole (decreases glutamate release, prolongs survival in ALS); felbamate, perampanel (AMPA antagonist), topiramate (AMPA/kainate blockade, among other mechanisms) are antiepileptics. Dextromethorphan is a weak NMDA antagonist. - Schizophrenia: NMDA hypofunction hypothesis (PCP/ketamine can mimic positive and negative symptoms). - Anti-NMDA receptor encephalitis: autoantibodies against the NR1 subunit, often in young women with ovarian teratoma; presents with psychiatric symptoms, seizures, dyskinesias, autonomic instability, and catatonia/hypoventilation. - Glutamate transport: reuptake mainly by astrocytic EAAT transporters, then converted to glutamine (glutamate-glutamine cycle) and returned to neurons.

**Other high-yield points** - Monosodium glutamate (MSG) is a flavor enhancer (umami taste via T1R1/T1R3 receptors). - Hyperammonemia: depletion of alpha-KG and glutamate in brain as ammonia is detoxified to glutamine; glutamine accumulation in astrocytes causes cerebral edema. Treat with lactulose and rifaximin (hepatic encephalopathy). - Glutamate is charged at physiologic pH, so it is found on protein surfaces, interacts with positively charged residues (Lys, Arg), and shifts toward the anode in electrophoresis. - Don't confuse glutamic acid (Glu, E) with glutamine (Gln, Q, a polar uncharged amide) — often tested in the context of ammonia metabolism and in point mutations (e.g., Glu->Val in HbS).