Amino Acid Derivatives: Catecholamines, Serotonin & Nitric Oxide

Amino acid essentials

Essential amino acids. Nine amino acids must come from the diet: phenylalanine, valine, threonine, tryptophan, isoleucine, methionine, histidine, leucine and lysine (mnemonic: PVT TIM HaLL). Arginine becomes conditionally essential during growth or severe stress, tyrosine becomes essential when phenylalanine hydroxylase fails (PKU), and cysteine is built from methionine's sulfur.

Glucogenic vs ketogenic. Leucine and lysine are the only purely ketogenic amino acids: they end as acetyl-CoA or acetoacetate and can never feed gluconeogenesis. Isoleucine, phenylalanine, threonine, tryptophan and tyrosine are both ketogenic and glucogenic; the rest, including methionine, valine and histidine, are purely glucogenic.

Side-chain charge. At physiologic pH, aspartate and glutamate carry negative side chains (acidic). Arginine (the most basic) and lysine carry positive charges, while histidine (side-chain pKa near 6) is basic but mostly uncharged at pH 7.4. Arginine and lysine are abundant in histones, whose positive charge binds the negatively charged phosphate backbone of DNA.

Catecholamine synthesis

Tyrosine hydroxylase. This BH4-dependent step sets the overall rate. Metyrosine inhibits it and can reduce catecholamine output before pheochromocytoma surgery.

DOPA decarboxylase. The same pyridoxal phosphate enzyme also turns 5-hydroxytryptophan into serotonin. In Parkinson disease L-DOPA is given because it crosses the blood-brain barrier and dopamine does not; carbidopa blocks peripheral DOPA decarboxylase so more L-DOPA reaches the brain.

Dopamine β-hydroxylase. Located within synaptic and chromaffin vesicles, it converts dopamine to norepinephrine using ascorbate as the electron donor and copper as its metal cofactor.

PNMT and the adrenal portal system. Phenylethanolamine N-methyltransferase transfers a methyl group from S-adenosylmethionine (SAM) to norepinephrine, forming epinephrine. Cortisol-rich blood from the cortex drains through the medulla via the intra-adrenal portal circulation and induces PNMT, so the adrenal medulla is the main source of epinephrine.

Extra-adrenal paragangliomas (for example at the organ of Zuckerkandl) miss this cortisol bath, so they secrete mainly norepinephrine and raise normetanephrine rather than metanephrine.

Tetrahydrobiopterin (BH4). BH4 is the shared cofactor of phenylalanine, tyrosine and tryptophan hydroxylases and nitric oxide synthase, and dihydropteridine reductase (DHPR) regenerates it. BH4 synthesis or recycling defects raise phenylalanine and also cut dopamine and serotonin production, so infants deteriorate despite phenylalanine restriction (low CSF homovanillic acid and 5-HIAA). They also need neurotransmitter precursors (L-DOPA, 5-hydroxytryptophan).

Other fates of tyrosine and tryptophan

Thyroid hormone. Tyrosyl residues within thyroglobulin are iodinated by thyroid peroxidase to monoiodotyrosine and diiodotyrosine, which couple into T3 and T4.

Melanin and albinism. In melanocytes, copper-dependent tyrosinase oxidizes tyrosine to DOPA and then dopaquinone, the precursor of melanin. Oculocutaneous albinism type 1 is autosomal recessive tyrosinase deficiency: melanocytes are present in normal numbers but make no pigment. Patients have white hair, pale skin, nystagmus, photophobia and reduced visual acuity, with a high risk of sun-induced skin cancer. Vitiligo, by contrast, destroys melanocytes.

Serotonin. Tryptophan hydroxylase (BH4) forms 5-hydroxytryptophan, and the B6-dependent decarboxylase converts it to serotonin (5-HT). About 90% of body serotonin is made by gut enterochromaffin cells; in the brain, serotonergic neurons sit in the raphe nuclei. Platelets store serotonin but do not synthesize it.

Melatonin. In the pineal gland, serotonin is N-acetylated and then methylated (SAM) to melatonin, released at night. Light reaching the retina signals through the suprachiasmatic nucleus to suppress it.

Niacin. Through the kynurenine pathway tryptophan can be converted to niacin, the precursor of NAD+ and NADP+, a route that requires riboflavin (B2) and pyridoxine (B6).

When tryptophan runs short. Pellagra (diarrhea, photosensitive dermatitis, dementia) can follow when a carcinoid tumor diverts tryptophan into serotonin, when Hartnup disease wastes it, or when B6 deficiency (isoniazid) blocks its conversion. A maize-based diet is the classic dietary cause.

Histidine, glutamate, glycine and arginine

Histamine. Histidine decarboxylase (pyridoxal phosphate) forms histamine in mast cells, basophils and gastric enterochromaffin-like cells.

GABA. Glutamate decarboxylase (pyridoxal phosphate) turns glutamate into GABA, the main inhibitory CNS transmitter. Isoniazid depletes B6 and lowers GABA; overdose seizures are treated with IV pyridoxine. Anti-GAD65 antibodies mark type 1 diabetes and stiff-person syndrome.

Glutathione. This tripeptide (γ-glutamyl-cysteinyl-glycine) is the main intracellular antioxidant. Reduced glutathione neutralizes hydrogen peroxide via selenium-dependent glutathione peroxidase and is regenerated by NADPH-dependent glutathione reductase. Acetaminophen's toxic metabolite NAPQI consumes it; N-acetylcysteine replenishes it.

Nitric oxide. Nitric oxide synthase (endothelial, neuronal and inducible macrophage forms) oxidizes arginine to NO and citrulline, using BH4, NADPH and O2. NO diffuses into smooth muscle and activates soluble guanylyl cyclase; cGMP activates protein kinase G, lowering intracellular Ca2+ and causing relaxation. Nitrates donate NO, and PDE-5 inhibitors such as sildenafil slow cGMP breakdown.

Creatine and urea. Arginine donates its guanidino group to glycine, and a SAM methyl group completes creatine. Muscle creatine phosphate breaks down to creatinine at a steady rate proportional to muscle mass. Arginase splits arginine into urea and ornithine, the last step of the urea cycle.

Breakdown products and tumor markers

MAO and COMT. Monoamine oxidase and catechol-O-methyltransferase degrade catecholamines; MAO also inactivates serotonin. Dietary tyramine (aged cheese, cured meats) is normally cleared by gut and liver MAO-A, so MAO inhibitors can let it trigger a hypertensive crisis.

Hartnup disease

Defect. Hartnup disease is autosomal recessive loss of SLC6A19 (B0AT1), the neutral amino acid transporter of the renal proximal tubule and small intestine. Neutral amino acids, including tryptophan, spill into the urine and are poorly absorbed.

Presentation. Tryptophan shortage limits niacin synthesis, producing a photosensitive pellagra-like rash, intermittent cerebellar ataxia and psychiatric change; many affected people stay asymptomatic until poor diet, sun or illness intervenes. Urine shows neutral aminoaciduria with normal cystine and dibasic amino acids, unlike cystinuria.

Treatment. A high-protein diet works because dipeptides are absorbed intact through a different carrier, the peptide transporter PEPT1; nicotinic acid replaces the missing niacin, and sun protection limits the rash.