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Conversion of Amino Acids to Specialized Products Catecholamines •Biologically-active water-soluble amines derived from tyrosine that serve as neurotransmitters in the CNS and as hormones in circulation in response to psychological stress (“fight or flight response”) or hypoglycemia: Epinephrine (adrenaline) Norepinephrine (noradrenlaine) Dopamine •All three and are produced in chromaffin cells of the adrenal medula of the sympathetic nervous system and and post-ganglionic fibers of the sympathetic division of the autonomic nervous system. •Dopamine also acts as a neurotransmitter in the CNS and is synthesized by neuronal cell bodies of the substantia nigra and ventral tegmental area in the midbrain (as well as serotonin) Synthesis of Catecholamines •Tyrosine hydroxylase is the rate-limiting step •DOPA decarboxylase is a pyridoxal-5’-phosphate-dependent enzyme •Dopamine -hydroxylase is a Cu2+-containing enzyme •Catecholamines act at - and -adrenergic receptors •Ephedrine and pseudoephedrine are C1-diastereometric sympathomimetic amines of lower efficacy •Vasoconstriction and hypertensive activity of ephedrine and pseudoephedrine are through -adrenergic receptors Ephedrine and Pseudoephedrine Resemble Catecholamines Pseudoephedrine Degradation of Catecholamines •One released, catecholamines have a half-life of ca. 1 min due to subsequent inactivation •Monoamine oxidase (MAO) inactivates catecholamines by oxidative deamination to yield the corresponding aldehyde •Catechol-O-methyltransferase (COMT) also inactivates catecholamines by methylation using S-adenosylmethionine (SAM) as the one-carbon donor •MAO inhibitors and methamphetamine block catecholamine degradation, allowing their accumulation in the presynaptic neuron and subsequent leakage into circulation, providing an antidepressant action. Catecholamines •Biologically-active water-soluble amines derived from tyrosine that serve as neurotransmitters in the CNS and as hormones in circulation in response to psychological stress (“fight or flight response”) or hypoglycemia: Epinephrine (adrenaline) Norepinephrine (noradrenlaine) Dopamine •All three and are produced in chromaffin cells of the adrenal medula of the sympathetic nervous system and and post-ganglionic fibers of the sympathetic division of the autonomic nervous system. •Dopamine also acts as a neurotransmitter in the CNS and is synthesized by neuronal cell bodies of the substantia nigra and ventral tegmental area in the midbrain (as well as serotonin) Synthesis of Catecholamines •Tyrosine hydroxylase is the rate-limiting step •DOPA decarboxylase is a pyridoxal-5’-phosphate-dependent enzyme •Dopamine -hydroxylase is a Cu2+-containing enzyme •Catecholamines act at - and -adrenergic receptors •Ephedrine and pseudoephedrine are C1-diastereometric sympathomimetic amines of lower efficacy •Vasoconstriction and hypertensive activity of ephedrine and pseudoephedrine are through -adrenergic receptors Ephedrine and Pseudoephedrine Resemble Catecholamines Pseudoephedrine Degradation of Catecholamines •One released, catecholamines have a half-life of ca. 1 min due to subsequent inactivation •Monoamine oxidase (MAO) inactivates catecholamines by oxidative deamination to yield the corresponding aldehyde •Catechol-O-methyltransferase (COMT) also inactivates catecholamines by methylation using S-adenosylmethionine (SAM) as the one-carbon donor •MAO inhibitors and methamphetamine block catecholamine degradation, allowing their accumulation in the presynaptic neuron and subsequent leakage into circulation, providing an antidepressant action. Serotonin Synthesis •Pleiotropic neurotransmitter of serotonergic neurons of the CNS and enterochromaffin cells of the GI •Synthesized predominately in the GI tract •Tryptophan hydroxylase (TPH) is rate-limiting step •TPH exists in two tissue specific isozymes •Genetic polymorphism in TPH2 isozyme predisposes to anxiety and depression •A number of psychoactive drugs (psilocybin, mescaline, amphetamine, cocaine, LSD, and Ecstacy) modulate serotonin levels •Inactivated by MAO Pharmacology of Selective Reuptake Creatine Synthesis •Amidinotransferase is a mitochondrial enzyme catalyzing the rate-limiting step of the pathway •Methyltransferase uses S-Adenosylmethionine as a one-carbon donor to yield creatine •Nearly half of muscle creatine results from dietary intake •Creatine spontaneous cyclizes to creatinine, which is secreted in the urine •Serum creatinine is routinely measured on admission as a test of kidney function. Kidney impairment results in elevated serum creatinine Histamine Synthesis •Histamine is an extracellular chemical messenger mediating a range of cellular responses including allergic and inflammatory reactions •Synthesized by histidine decarboxylase, a pyridoxal-5’-phosphate-dependent enzyme •At least two classes of histamine receptors: H1 and H2 •H1 blockers (Benedryl™) blocks allergic reactions, hives and itching, and causes drowsiness •H2 blockers (Tagamet™) blocks acid secretion from parietal cells of stomach Glutathione Synthesis
