Transcript Amino acid metabolism 2

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