Aromatic amino acids and

molecules derived from

amino acids

Ms M. Mombeshora
HBC 202 Lecture 06
 Aromatic Amino Acids

Example of essential amino acid synthesis

Involve Shikimate and Chorismate intermediates

• Phenylalanine
• Tyrosine
• Tryptophan
 Shikimate SHIKIMIC ACID
Pathways
CHORISMIC ACID

PREPHENIC PHENYL-C3 ANTHRANILIC

ACID COMPOUNDS ACID

CINNAMIC
TYROSINE ACIDS

PHENYL-C1
PHENYLALANINE COMPOUNDS TRYPTOPHAN

Tyrosine and phenylalanine synthesis covered in previous lecture

 Synthesis of tryptophan from
chorismate
Step 1

Chorismate

Glutamine
Anthranilate synthase Glutamate
Pyruvate

Anthranilate
 Synthesis of tryptophan from
chorismate
Step 2

Anthranilate
Anthranilate
PRPP
phosphoribosyl
PPi
transferase
N-(5´-phosphoribosyl)-
anthranilate
 Synthesis of tryptophan from
chorismate
Step 3
N-(5´-phosphoribosyl)-
anthranilate

N-(5’-phosphoribosyl)- anthranilate isomerase

Enol-1- -carboxyphenylamino-
1-deoxyribulose phosphate
 Synthesis of tryptophan from
chorismate
Step 4

Enol-1- -carboxyphenylamino-
1-deoxyribulose phosphate

Indole-3-glycerol phosphate synthase

Indole-3-glycerol phosphate
 Synthesis of tryptophan from
chorismate
Step 5

Indole-3-glycerol phosphate

Glyceraldehyde-3-phosphate
Tryptophan synthase Serine

H2O

Tryptophan
Molecules derived from amino
acids
 Physiologically active amines
• There are five established biogenic amine
neurotransmitters: the three catecholamines
– Dopamine
– Norepinephrine (noradrenaline)
– Epinephrine (adrenaline)

– Histamine
– Serotonin
 Physiologically active amines
• All the catecholamines are derived from a common
precursor, the amino acid tyrosine
– so named because they share the catechol moiety
• The first step in catecholamine synthesis is catalysed by
tyrosine hydroxylase
– The reaction requires oxygen as a co-substrate and
tetrahydrobiopterin as a cofactor to synthesise
dihydroxyphenylalanine (DOPA)
• Tyrosine hydroxylase is rate-limiting for the synthesis of
all three transmitters
– its presence is a valuable criterion for identifying
catecholaminergic neurons
 Physiologically active amines
Additional bioactive

• -Aminobutyric acid (GABA)

• Hormones
• Neurotransmitters
 Physiologically active amines
• Synthesis involve decarboxylation of precursor
amino acid
– PLP (pyridoxal phosphate)-dependent, aa
decarboxylases
• Tyrosine  dopamine, Epinephrine,
norepinephrine
• Glutamate  GABA
• Histidine  histamine
• Tryptophan  serotonin
 Catecholamines
• Epinephrine, norepinephrine, dopamine
• Amine derivatives of catechol
• Reactions:
– Tyr  L- dopa
• Tyr hydroxylase
– L-dopa  dopamine + CO2
• Aromatic acid decarboxylase
– Dopamine  norepinephrine
• Dopamine β-hydroxylase
– Norepinephrine  epinephrine
Physiologically active amines

Parent molecule
 Synthesis of bioactive amines
Biosynthetic pathway for the catecholamine
neurotransmitters
• The amino acid tyrosine is the precursor for all
three catecholamines
• First step the reaction catalysed by tyrosine
hydroxylase
– rate-limiting step
Synthesis of
dopamine from
tyrosine
Synthesis of noepinephrine from
dopamine
Synthesis of epinephrine from
norepinephrine
 Actions of dopamine
• Co-ordination of body movements
• In Parkinson's disease the dopaminergic neurons degenerate,
leading to a characteristic motor dysfunction
• Although dopamine does not readily cross the blood-brain-
barrier
• Its precursor, levodopa, does
• The disease can be treated by administering levodopa
together with carbidopa, a dopamine decarboxylase inhibitor
• Dopamine involved in motivation, reward, and reinforcement
• For example, cocaine and other addictive drugs act by
stimulating the release of dopamine from specific brain areas
 Actions of epinephrine
• As an insulin antagonist
– Activates muscle glycogen phosphorylase
• Glucose-6-P used in glycolysis
– Triggers phosphorylation (activation) of
hormone-sensitive lipase in fat cells
• Mobilizes fat by hydrolyzing triglycerides
– Glycogen breakdown in liver
– Activates gluconeogenesis in liver
– Inhibits fatty acid synthesis
 Actions of norepinephrine
• Not nearly as active as epinephrine
– During extreme stress
• Circulatory system
– Constricts great veins (2 receptor)
– Vasoconstrictive to skin (1 receptor)
– Vasoconstriction (1 receptor) effects on
• GI tract
• Spleen
• Pancreas
• Kidneys
 GABA
• Glutamate  GABA + CO2
– Glu decarboxylase
• GABA Is the major
inhibitory neuro-
transmitter in brain
– Glu is the major
excitatory neuro-
transmitter
• Stimulation of neurons by
GABA
 Histamine
• Histamine is synthesised from
the amino acid histidine
• Histidine  histamine + CO2
– His decarboxylase
• Histamines involved in
– Allergic response
• H1 receptors in gut,
bronchi
• Stimulation 
smooth muscle
contraction
 Histamine
• Histamines involved in
– Control of acid secretion in stomach
• H2 receptors
–stimulation   HCl secretion
–H2 antagonists
»cimetidine
»ranitidine
• H2 receptors in heart
– Stimulation   heart rate
 Serotonin
• Derived from tryptophan
• By a two-step process requires the enzymes
– tryptophan-5-hydroxylase
– decarboxylase
• Trp  5-hydroxytryptophan (Step 1)
– Trp hydroxylase
– Requires 5,6,7,8 tetrahydrobiopterin
 Serotonin
• Derived from tryptophan
• By a two-step process requires the enzymes
– tryptophan-5-hydroxylase
– decarboxylase
• 5-hydroxytryptophanserotonin+ CO2(Step 2)
– Aromatic acid decarboxylase
• Serotonin causes
– Smooth muscle contraction
– Brain neurotransmitter
Synthesis of serotonin from
tryptophan
Melatonin
 Regulation of Catecholamine
Biosynthesis
• The concentration of catecholamines in nerve terminals
remains relatively constant despite frequent fluctuations in
neuronal activity
• This homeostasis is achieved through the regulation of TH
activity
• TH is phosphorylated and activated by both calcium
and cAMP dependent protein kinases A longer-term
regulation of CA synthesis also occurs
• This regulation is mediated through altered transcription of
TH mRNA and altered TH mRNA stability
• Both mechanisms lead to increased levels of TH protein.
 Regulation of Serotonin Biosynthesis

• The level of serotonin is regulated principally by the amount of

tryptophan available to serotonergic neurons
• This has two important implications for the level of serotonin in the
brain
– because tryptophan is not synthesized in mammals, the level of
tryptophan available for serotonin biosynthesis is dependent on
diet. Thus, diets high in tryptophan can markedly elevate
serotonin levels
– because tryptophan is transported across the blood brain
barrier by a transport system which also transports certain
other amino acids, diets high in these amino acids can reduce
the level of serotonin in the brain by competing with tryptophan
for transport into the CNS
• Altered serotonin level in the CNS can have marked consequences
on behaviour -wellbeing and happiness-