Amino acids serve as precursors for a diverse range of biologically active molecules beyond their role as protein building blocks. These derivatives include neurotransmitters, hormones, porphyrins, melanin, and signaling molecules that regulate physiology and behavior.
Catecholamines
Catecholamines are synthesized from tyrosine. Tyrosine hydroxylase catalyzes the rate-limiting step, converting tyrosine to L-DOPA. This enzyme is inhibited by catecholamines through feedback regulation and is the target of drugs used in Parkinson disease. DOPA decarboxylase then converts L-DOPA to dopamine. In noradrenergic neurons, dopamine beta-hydroxylase converts dopamine to norepinephrine. In the adrenal medulla, phenylethanolamine N-methyltransferase converts norepinephrine to epinephrine.
Dopamine functions in the brain as a regulator of movement, motivation, and reward. Parkinson disease results from dopamine neuron degeneration in the substantia nigra. Norepinephrine and epinephrine mediate the fight-or-flight response, increasing heart rate, blood pressure, and blood glucose. Catecholamines are inactivated by monoamine oxidase and catechol-O-methyltransferase, which are targets for therapeutic drugs.
Serotonin and Melatonin
Serotonin is synthesized from tryptophan in two steps. Tryptophan hydroxylase adds a hydroxyl group to form 5-hydroxytryptophan, and aromatic amino acid decarboxylase converts it to serotonin. Serotonin regulates mood, appetite, sleep, and pain perception. Selective serotonin reuptake inhibitors are widely used antidepressants that prolong serotonin signaling.
In the pineal gland, serotonin is acetylated by serotonin N-acetyltransferase to form N-acetylserotonin, then methylated by hydroxyindole-O-methyltransferase to produce melatonin, a process analogous to post-translational modifications of proteins. Melatonin regulates circadian rhythms and sleep-wake cycles. Its production is suppressed by light and increases in darkness, signaling the body to prepare for sleep.
Histamine
Histamine is synthesized from histidine by histidine decarboxylase. It is stored in mast cells, basophils, and neurons. Histamine mediates allergic and inflammatory responses, stimulates gastric acid secretion, and acts as a neurotransmitter regulating wakefulness and appetite. Antihistamines targeting the H1 receptor treat allergies, while H2 receptor antagonists reduce gastric acid secretion in peptic ulcer disease. H3 receptors regulate histamine release in the brain.
GABA
Gamma-aminobutyric acid is the major inhibitory neurotransmitter in the brain, synthesized from glutamate by glutamate decarboxylase. GAD requires pyridoxal phosphate as a cofactor. GABA binds to GABAA receptors, which are chloride ion channels, and GABAB receptors, which are G protein-coupled receptors. Benzodiazepines and barbiturates enhance GABAA receptor activity, producing sedation and anxiolytic effects. GABA is metabolized by GABA transaminase to succinic semialdehyde, which enters the citric acid cycle.
Nitric Oxide
Nitric oxide is a gaseous signaling molecule synthesized from arginine by nitric oxide synthase. Three NOS isoforms exist. Neuronal NOS produces NO for neurotransmission. Inducible NOS is expressed in immune cells and produces large amounts of NO for pathogen defense. Endothelial NOS produces NO that diffuses to adjacent smooth muscle cells, activating guanylyl cyclase and causing vasodilation. NO is a paracrine signal with a half-life of seconds, and its downstream effector is cGMP. Nitroglycerin used for angina acts by releasing NO.
Glutathione
Glutathione is a tripeptide composed of glutamate, cysteine, and glycine, with the unusual gamma-glutamyl linkage protecting it from peptidase cleavage. It is the most abundant intracellular thiol, reaching millimolar concentrations. Glutathione serves as the primary cellular antioxidant, reacting directly with reactive oxygen species and serving as a cofactor for glutathione peroxidase and glutathione S-transferase. Reduced glutathione is maintained by glutathione reductase using NADPH. Glutathione depletion contributes to oxidative stress in aging, neurodegeneration, and liver disease.
Porphyrins and Heme
Heme is synthesized from glycine and succinyl-CoA in eight enzymatic steps. The first and rate-limiting reaction condenses glycine with succinyl-CoA to form aminolevulinic acid, catalyzed by ALA synthase. Four ALA molecules are assembled into porphobilinogen, and four porphobilinogens are joined to form hydroxymethylbilane, which cyclizes to uroporphyrinogen III. Decarboxylation and oxidation produce protoporphyrin IX, and ferrochelatase inserts ferrous iron to form heme.
Heme is the prosthetic group of hemoglobin, myoglobin, cytochromes, catalase, and nitric oxide synthase. Disorders of heme synthesis cause porphyrias, characterized by accumulation of pathway intermediates that cause neurological symptoms and photosensitivity.
Polyamines
Polyamines including putrescine, spermidine, and spermine are synthesized from ornithine and methionine. Ornithine decarboxylase catalyzes the committed step. Polyamines are essential for cell proliferation, regulating gene expression, ion channel function, and DNA stability. ODC is a target for anticancer drug development because of its role in cell growth.
Melanin
Melanin is synthesized from tyrosine by tyrosinase, which oxidizes tyrosine to DOPAquinone. The subsequent reactions differ for eumelanin and pheomelanin production. Melanin provides photoprotection in the skin and is critical for vision in the eye. Tyrosinase deficiency causes albinism, characterized by lack of pigment and increased skin cancer risk.
