Conversion of Amino Acids to Specialized Products

1. Conversion of Amino Acids to Specialized Products

2. 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)

3. 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

4. Ephedrine and Pseudoephedrine Resemble Catecholamines Pseudoephedrine

5. 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.

6. 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)

7. 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

8. Ephedrine and Pseudoephedrine Resemble Catecholamines Pseudoephedrine

9. 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.

11. 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

12. Pharmacology of Selective Reuptake

13. 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

14. 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

15. Glutathione Synthesis