CATABOLISM AND ANABOLISM OF SOME AMINO ACIDS

1. UMMASALAMA AMINU
BMS/19/BCH/00813
COURSE: Metabolism of Amino Acids
ASSIGNMENT:
Tyrosine-Derived Neurotransmitters / Hormones
Biologically Important Compounds Derived from Tyrosine
Tyrosine serves as a precursor for following several
biologically important compounds (Fig. 14.20).
1. Catecholamines
– Dopamine
– Norepinephrine
– Epinephrine
2. Melanin pigmen
3. Thyroxine
Biosynthesis of Catecholamines

2. • Ep i n e p h r i n e ( a d re n a l i n e ) , n o re p i n e p h r i n e
(noradrenaline) and dopamine are collectively called
catecholamines. They are synthesized from tyrosine
• Epinephrine and norepinephrine are produced by adrenal
medulla and serve as hormones, where as dopamine and
norepinephrine produced in the CNS and postganglionic
sympathetic nerves act as neurotransmitter
Metabolism of tyrosine-synthesis of catecholamines (dopamine,
norepinephrine, epinephrine; PLPpyridoxal

3. phosphate).
Metabolism of tyrosine-synthesis of catecholamines (dopamine,
norepinephrine,epinephrine; PLPpyridoxal phosphate).
Catecholamine Catabolism

4. Epinephrine and norepinephrine are catabolized to inactive
compounds through the sequential actions of catecholamine-O-
methyltransferase (COMT) and monoamine oxidase (MAO).
Compounds that inhibit the action of MAO have been shown to
have beneficial effects in the treatment of clinical depression,
even when tricyclic antidepressants are ineffective. The utility
of MAO inhibitors was discovered serendipitously when
patients treated for tuberculosis with isoniazid showed signs of
an improvement in mood; isoniazid was subsequently found to
work by inhibiting MAO.
Biosynthesis of Melanin Pigment

5. Melanin is a pigment. The synthesis of melanin occurs only in
pigment producing cells called melanocytes.
The first step is the conversion of tyrosine to DOPA In
melanocyte, a different enzyme tyrosinase catalyzes this
reaction.
 Tyrosinase also catalyzes the subsequent oxidation of dopa
to dopaquinone.
 It s beieved that the subsequent couple of reactions occur
spontaneously, forming leucodopachrome folowed by
5,6dihydroxyindole. The oxidation of 5,6dihydroxyindole
to indole 5,6quinone is catalysed by tyrosinase,and DOPA
serves as a cofactor. This reaction, inhibited by tyrosine
regulates the synthesis of melanin.
 Melanochromes are formed from indole quinone, which on
polymerization are converted to black melann.
 Another pathway from dopaquinone s aso identified.
 Cystene condenses with dopa quinone and in the next series
of reactions results the synthesis of red melanins. The
structure of melanin pigments is not clearly known.

6. Metabolism of tyrosine—biosynthesis of melanin (Defect
in tyrosinase causes albinism)
Biosynthesis of thyroid hormones
Thyroid hormones—thyroxine (tetraiodothyronine) and
triiodothyronine—are synthesized from the tyrosine
residues of the protein thyroglobulin and activated

7. iodne .Iodination of tyrosine ring occurs to produce mono
and diiodotyrosine from which triiodothyronine (T3) and
thyroxine (T4) are synthesized. The protein thyroglobulin
undergoes proteolytic breakdown to release the free
hormones, T3 and
T4.

8. Metabolism of tyrosine synthesis of thyroid hormones.
Function of tyrosine derived neurotransmitters
1. Dopamine:
- Dopamine is involved in various brain functions, including
reward and motivation, movement control, mood regulation,
and cognitive processes.
- It plays a critical role in the brain's reward system and is
associated with feelings of pleasure and reinforcement.
- Dopamine dysfunction is linked to several neurological and
psychiatric disorders, such as Parkinson's disease, schizophrenia,
and addiction.
2. Norepinephrine (Noradrenaline):
- Norepinephrine functions as both a neurotransmitter and a
stress hormone.
- It is involved in the regulation of arousal, attention, alertness,
and vigilance.
- Norepinephrine is associated with the "fight-or-flight"
response, triggering physiological changes during stressful
situations.

9. - Dysregulation of norepinephrine is implicated in conditions
like depression, anxiety disorders, and attention deficit
hyperactivity disorder (ADHD).
3. Epinephrine (Adrenaline):
- Epinephrine is primarily known for its role as a hormone
released during stress and emergencies.
- As a neurotransmitter, it modulates the body's response to
stress, increasing heart rate, blood pressure, and energy
availability.
- Epinephrine is involved in the regulation of attention, memory,
and learning processes.
- It is produced in the adrenal glands and released into the
bloodstream in response to stress or danger.
4. Regulation and Synthesis:
- The synthesis of dopamine, norepinephrine, and epinephrine
involves a series of enzymatic reactions.
- Tyrosine hydroxylase is the rate-limiting enzyme responsible
for converting tyrosine to L-DOPA, the precursor of dopamine.
- Further enzymatic steps are involved in the conversion of L-
DOPA to dopamine and its subsequent conversion to
norepinephrine and epinephrine.

10. Tryptophan-Derived Neurotransmitters
Metabolism of Tryptophan
• Tryptophan is an essential amino acid, containing indol ring.
Tryptophan is oxidized to produce alanine, which is glucogenic
and acetyl-CoA, which is ketogenic. Thus, tryptophan is both
glucogenic and ketogenic.
• Tryptophan is a precursor for the synthesis of:
– Vitamin niacin (vitamin B3)
– Neurotransmitter serotonin
– Hormone melatonin.
• Tryptophan is metabolized by two pathways:
1. Kynurenine pathway
2. Serotonin pathway.
Kynurenine Pathway
In this pathway tryptophan is oxidized to kynurenine and
alanine. Kynurenine is then converted to either vitamin niacin
or acetyl-CoA
• The initial reaction is an oxidation of tryptophan to
formylkynurenine, catalyzed by the enzyme tryptophan
oxygenase also called tryptophan pyrrolase, which is feedback
inhibited by nicotinic acid derivatives, e.g. NADH or NADPH.
• Formylkynurenine is converted to kynurenine by removal of
formyl group with the enzyme kynurenine formylase.

11. • Kynurenine is then metabolized to 3-hydroxy kynurenine by
kynurenine hydroxylase.
• Ne x t 3 - hydroxykynurenine is converted t o 3-
hydroxyanthranilate and alanine by kynureninase, a PLP-
dependent enzyme. A deficiency of vitaminB6 (pyridoxin)
results in failure to catabolize the hydroxykynurenine, forming
xanthurenate and excreted in urine in vitamin B6 deficiency.
• Next 3-hydroxyanthranilate undergoes decarboxylation
forming vitamin niacin which can be converted to NAD+ and
NADP+ or 3-hydroxyanthranilate can also be converted through
a number of steps to acetyl-CoA.
For every 60 mg of tryptophan, 1 mg equivalent of niacin can
be generated.

12. Metabolism of tryptophan-kynurenine pathway
(PLP–Pyridoxal phosphate;
QPRT–Quinolinate phosphoribosyl transferase; PRPP–
Phosphoribosyl pyrophosphate)
Serotonin Pathway
• Tryptophan is first oxidized to 5-hydroxytryptophan by
tryptophan hydroxylase, which requires, tetrahydrobiopterin as
a cofactor.

13. ☆5-hydroxytryptophan undergoes decarboxylation to yield
serotonin (5-hydroxytryptamine)
• Acetylation of serotonin followed by methylation in the pineal
gland forms a hormone melatonin.
Serotonin
• Serotonin is synthesized from tryptophan by neurons, pineal
glands and intestinal argentaffin cells. In normal adult, about
1% of tryptophan is converted to serotonin.
Functions of serotonin
• Serotonin is a neurotransmitter and stimulates cerebral
activity. Therefore, serotonin deficiency causes a decrease in
cerebral (brain) activity, which leads to depression.
• In humans, serotonin is involved in a variety of behavioral
patterns, including sleep, body temperature and blood pressure.
• Serotonin produced in intestinal cells stimulates the release
of gastrointestinal peptide hormones.
• Serotonin serves as precursor of melatonin in the pineal gland.
Melatonin
• Melatonin is a hormone produced from serotonin by the
pineal gland

14. • Synthesis of melatonin is regulated by light dark cycle. It is
synthesized mostly at night.
• It is an inhibitor of melanocyte stimulating hormone (MSH)
and adrenocorticotropic hormone (ACTH).
• Melatonin is a sleep inducing substance and is involved in
regulation of circadian rhythm of body. It may also be involved
in regulating reproductive functions.
Metabolism of tryptophan-serotonin and melatonin
synthesis(PLP Pyridoxal phosphate; MAO Monoamine oxidase)
(Gamma) γ-Aminobutyric Acid (GABA) from Glutamate

15. The amino acid derivative, γ-aminobutyrate (GABA; also called
4-aminobutyrate) is a major inhibitory neurotransmitter
responsible for the regulation of presynaptic transmission in
the CNS, and also in the retina. Neurons that secrete GABA are
termed GABAergic.
GABA cannot cross the blood-brain-barrier and as such must be
synthesized within neurons in the CNS. The synthesis of GABA
in the brain occurs via a metabolic pathway referred to as the
GABA shunt. Glucose is the principal precursor for GABA
production via its conversion to α-ketoglutarate in the TCA
cycle.
Within the context of the GABA shunt 2-oxoglutarate (α-
ketoglutarate) is transaminated to the amino acid glutamate by
GABA α-oxoglutarate transaminase (GABA-T). Glutamic acid
decarboxylase (GAD) catalyzes the decarboxylation of glutamic
acid to form GABA. There are two GAD genes in humans
identified as GAD1 and GAD2.
The GAD1 gene is located on chromosome 2q31.1 and is
composed of 21 exons that generate two alternatively spliced
mRNAs. One of these mRNAs encodes a 594 amino acid protein
(GAD67). The other mRNA encodes a 224 amino acid protein
(GAD25).

16. The GAD2 gene is located on chromosome 10p12.1 and is
composed of 16 exons that generate two alternatively spliced
mRNAs, both of which encode the same 585 amino acid protein
(GAD65).
The GAD designations for the major proteins produced by these
two genes are reflective of their molecular weights. Both the
GAD1 and GAD2 genes are expressed in the brain and GAD2
expression also occurs in the pancreas. The activity of GAD
requires pyridoxal phosphate (PLP) as a cofactor. PLP is
generated from the B6 vitamins (pyridoxine, pyridoxal, and
pyridoxamine) through the action of pyridoxal kinase. Pyridoxal
kinase itself requires zinc for activation.
A deficiency in zinc or defects in pyridoxal kinase can lead to
seizure disorders, particularly in seizure-prone pre-eclamptic
patients (hypertensive condition in late pregnancy). The
presence of anti-GAD antibodies (both anti-GAD65 and anti-
GAD67) is a strong predictor of the future development of type
1 diabetes in high-risk populations.
Synthesis of gamma-aminobutyric acid (GABA)
Synthesis of gamma-aminobutyric acid (GABA)

17. GABA exerts its effects by binding to two distinct receptors,
GABA-A (GABAA) and GABA-B (GABAB) that ion channel
(ionotropic) receptors. GABA-A receptors are chloride channels
that in response to GABA binding increases chloride influx into
the neuron. The GABA-B receptors are potassium channels that
when activated by GABA leads to potassium efflux from the
cell.Metabolism of γ-aminobutyrate. (α-KA, α-keto acids; α-AA,
α-amino acids; PLP, pyridoxal phosphate.)
Metabolism of γ-aminobutyrate. (α-KA, α-keto acids; α-AA, α-
amino acids; PLP, pyridoxal phosphate.)
Functions of GABA:
1. Inhibitory Neurotransmission: GABA acts as the primary
inhibitory neurotransmitter in the brain. It binds to GABA
receptors located on postsynaptic neurons, leading to the
opening of chloride channels. This influx of chloride ions
hyperpolarizes the postsynaptic neuron, making it less likely to

18. generate an action potential. As a result, GABA dampens or
inhibits the activity of neighboring neurons, effectively reducing
their excitability.
2. Regulation of Neural Excitability: GABAergic neurons and
GABA receptors are widely distributed throughout the brain,
allowing GABA to modulate neural excitability in various
regions. By inhibiting excessive neuronal firing, GABA helps to
maintain the balance between excitation and inhibition in
neural circuits. This balance is crucial for normal brain function,
preventing overexcitation and maintaining stability.
Histamine from Histidine
Histamine is a potent neurotransmitter that binds to specific
histamine receptors. Histamine is synthesized by the enzymatic
decarboxylation of the amino acid histidine by the enzyme L-
histidine decarboxylase (HDC). Within the gastrointestinal tract
bacteria also produce histamine via a similar decarboxylation
reaction. The principal cells that synthesize and release
histamine are mast cells and basophils of the immune system,
enterochromaffin-like cells of the gastrointestinal system, and
neurons. The synthesis and storage of histamine by mast cells
and basophils represents the greatest store (>90%) of the
neurotransmitter. Within the brain the neurons that synthesize

19. histamine are within the tuberomammillary nucleus of the
hypothalamus.
Synthesis of histamine
Synthesis of histamine from histidine.
Histidine decarboxylase is encoded by the HDC gene. The HDC
gene is located on chromosome 15q21.2 and is composed of 14
exons that generate two alternatively spliced mRNAs encoding
two distinct isoforms of the enzyme. The isoform 1 protein is
composed of 662 amino acids and the isoform 2 protein is
composed of 629 amino acids.

20. Histamine metabolic pathway.
Abbreviations : HDC: histidine decarboxylase; DAO: diamine
oxidase; HNMT: histamine-N-methyl transferase; ALDH:
aldehyde dehydrogenase; MAO: monoamine oxidase; IAPT:
imidazole acetic acid phosphoribosyltransferase. Green is the
factors to enhance the endogenous ability of enzyme reaction.
Red is the factors that directly/indirectly inhibits the enzyme
reaction
Histamine Receptors

21. Humans express four distinct histamine receptors identified as
H1R, H2R, H3R, and H4R. All four histamine receptors are
members of the G-protein coupled receptor superfamily. The
H1R protein is encoded by the HRH1 gene, the H2R protein is
encoded by the HRH2 gene, the H3R protein is encoded by the
HRH3 gene, and the H4R protein is encoded by the HRH4.
Functions of Histamine
1. Inflammation and Immune Response: Histamine plays a
crucial role in the immune response and inflammatory
processes. It is released by immune cells, such as mast cells and
basophils, in response to allergens, pathogens, or tissue injury.
Histamine promotes vasodilation, increases blood vessel
permeability, and recruits immune cells to the site of
inflammation, facilitating an immune response.
2. Allergic Reactions: Histamine is well-known for its
involvement in allergic reactions. In individuals with allergies,
exposure to allergens triggers the release of histamine, leading
to symptoms such as itching, sneezing, runny nose, watery eyes,
and skin rashes. Histamine binds to specific receptors on target
cells, such as H1 receptors in smooth muscle cells and H2
receptors in gastric cells, contributing to the allergic response.
3. Neurotransmission: Histamine acts as a neurotransmitter in
the central nervous system, where it functions in various brain
processes. It is involved in the regulation of wakefulness,

22. arousal, and attention. Histaminergic neurons in the brainstem
project to different regions of the brain and release histamine
to modulate neuronal activity. Drugs that block H1 receptors,
such as antihistamines, can cause sedation due to their effects
on the histaminergic system.
Nitric Oxide Synthesis and Function
Vasodilators, such bradykinin, do not exert their effects upon
the vascular smooth muscle cell in the absence of the overlying
endothelium. For example, when bradykinin binds to
bradykinin B2 receptors on the surface of endothelial cells, a
signal cascade, coupled to the activation phospholipase Cβ
(PLCβ), is initiated. The PLCβ-mediated release of inositol
trisphosphate, IP3 (from membrane-associated
phosphatidylinositol-4,5-bisphosphate, PIP2), leads to the
release of intracellular stores of Ca2+. In turn, the elevation in
Ca2+ leads to the liberation of endothelium-derived relaxing
factor (EDRF) which then diffuses into the adjacent smooth
muscle. EDRF was found to be the free radical diatomic gas, NO.
NO is formed by the action of NO synthase (NOS) on the amino
acid arginine .

23. Generation of nitric oxide (NO) from L-arginine in the presence
of nitric oxide synthase enzyme.
1.Synthesis
a.Liberated in the conversion of L-arginine to citrulline
b.The enzyme nitric oxide synthase (NOS)is a complex enzyme
requiring NADPH, flavin adenine dinucleotide (FAD), flavin
mononucleotide(FMN),and tetra hydrobiopterin(BH4).
c.NOS is found in three major isoforms.
(1)Neuronal NOS (nNOS or NOS-1).
(2)Macrophage or inducible NOS (iNOS or NOS-2).

24. (3)EndothelialNOS(eNOS or NOS-3).
2.Function
a.iNOS is important in macrophages for creating NO for the
generation of free radicals,
which are bactericidal.
b.NO stimulates the influx of Ca2+ in to vascular endothelial
cells, with the activation of
cyclic guanosine monophosphate(cGMP) resulting in relaxation
of vascular smooth
muscle (NO is also known as endothelium-derived relaxation
factor [EDRF]).
Creatine Biosynthesis

25. Path
way of creatine metabolism. Catalyzed by AGAT (1), catalyzed
by GAMT (2), catalyzed by creatine kinase (CK) (3),
spontaneous (4), catalyzed by creatine amidohydrolase (5),
catalyzed by glycine oxidase (6), and catalyzed by
semicarbazide-sensitive amine oxidase (SSAO) (7). Dotted
pathway indicates recently hypothesized toxic formation of
formaldehyde

26. Synthesis of creatine and creatinine
Synthesis of creatine and creatine phosphate: The synthesis of
creatine begins from arginine and glycine via the renal enzyme
glycine amidinotransferase (GATM). The product,
guanidinoacetate, is transported to the liver where it is
methylated via the action of guanidinoacetate N-
methyltransferase (GAMT) forming creatine. The methyl group
is donated from S-adenosylmethionine (SAM). Creatine is
released to the blood and picked up by the brain and skeletal
muscle cells via the action of the SLC6A8 transporter. Creatine
kinase (creatine phosphokinase) transfers a phosphate from
ATP generating the high-energy intermediate, creatine
phosphate.
Creatine synthesis occurs predominantly in the kidneys and the
liver. The synthesis of creatine begins in the kidneys using the
amino acids arginine and glycine. The formation of
guanidinoacetate (GAA) from these two amino acids is

27. catalyzed by the enzyme glycine amidinotransferase, also called
L-arginine:glycine amidinotransferase (AGAT).
Glycine amidinotransferase is encoded by the GATM gene
located on chromosome 15q21.1 and is composed of 13 exons
that generate two alternatively spliced mRNAs that encode
proteins of 423 amino acids (isoform 1) and 294 amino acids
(isoform 2). The GAMT encoded proteins localize to the
mitochondria.
Creatine degradation
• Creatine and creatine phosphate spontaneously form
creatinine as an end product • Creatinine is excreted in the
urine • Serum creatinine is a sensitive indicator of kidney
disease (Kidney function test) i.e. serum creatinine increases
with the impairment of kidney function
Creatine Degradation Creatinine CREATINE DEGRADATION IN
MUSCLES BLOOD Pi Creatine Kidney ATP ATP Urine ADP ADP
Creatine phosphate

28. Functions of creatine biosynthesis:
1. **Energy Storage**: Creatine is converted into
phosphocreatine in muscle cells, where it serves as a rapidly
available source of high-energy phosphate bonds. This allows
for quick energy release during activities like sprinting and
weightlifting.
2. **ATP Regeneration**: Phosphocreatine helps regenerate
adenosine triphosphate (ATP), the primary energy currency of
cells. When muscles contract, ATP is used up, and
phosphocreatine helps replenish it, allowing for sustained
muscle function.
3. **Muscle Performance**: Creatine supplementation is
popular among athletes and bodybuilders because it can
enhance muscle performance and endurance, leading to
improved strength and exercise capacity.

29. 4. **Brain Function**: Although most creatine is found in
muscle tissue, it is also present in the brain. Creatine may play a
role in cognitive function and neuroprotection, although more
research is needed in this area.
5. **Overall Cellular Health**: Creatine's role in maintaining
cellular energy balance contributes to the overall health of cells,
especially those with high energy demands.
Polyamines
The polyamines are highly cationic molecules that tend to bind nucleic
acids with high affinity. Because of this interaction activity, it is believed
that the polyamines are important participants in DNA synthesis, or in
the regulation of that process. In addition to their function in DNA
replication, polyamines and polyamine derivatives are involved in the
processes of protein synthesis, ion channel function (particularly the
inwardly rectifying potassium channels), regulation of gene expression,
cell proliferation, and apoptosis (programmed cell death).
•Biological amines made up of multiple amino acids
called polyamines, e.g.
- Putrescine
–Spermidine

30. -Spermine.
•Polyamines are positively charged at physiological pH and
associate with negatively charged nuclear DNA.
These are present in high concentration in semen. The
concentration of polyamines in brain is about 2 mm.
Functions of polyamines
•Polyamines are involved in regulation of transcription and
translation.
•They act as a growth factor and function in cell proliferation
and growth.
•Polyamines are involved in stabilization of intact cells,
subcellular organelles and membranes.
Biosynthesis of polyamines
•Putrescine, spermidine and spermine are derived from
ornithine and methionine.
•Ornithine is derived from arginine. Arginine undergoes a
decarboxylation to form putrescine and carbon dioxide by an
enzyme ornithine decarboxylase.
•S-Adenosylmethionine undergoes a decarboxylation to form
5-adenosylmethiopropylamine, by an enzyme
Sadenosylmethionine decarboxylase.

31. •S-Adenosylmethiopropylamine donates aminopropyl group to
putrescine and then to spermidine to form spermine.
•It is presumed that the 15% of methionine which cannot be
used for cysteine synthesis in minimal diets is used for
polyamine synthesis.
Biosynthesis of polyamines.(SAM: S-Adenosylmethionine
Polyamine Catabolism
Synthesis of the polyamines is regulated by several
independent mechanisms. In addition to these mechanism of
control, intracellular polyamine levels are also regulated via
their catabolism. Putrescine is catabolized by amine oxidase,
copper containing 1 encoded by the AOC1 gene, while
spermidine and spermine are catabolized by
spermidine/spermine N1-acetyltransferase 1 (also known as

32. diamine acetyltransferase 1) encoded by the SAT1 gene (also
identified as SSAT).
The AOC1 gene is located on chromosome 7q36.1 and is
composed of 7 exons that generate two alternatively spliced
mRNAs. The AOC1 isoform 1 encoding mRNA encodes a
precursor protein of 770 amino acids. The AOC1 isoform 2
encoding mRNA encodes a precursor protein of 751 amino
acids. In addition to putrescine, the AOC1 encoded enzyme is
responsible for the catabolism of histamine and other related
biogenic amines. Because the AOC1 enzymes are inhibited by
amiloride (a potassium-sparing diuretic), they are also
identified as amiloride-sensitive amine oxidase.
The SAT1 gene is located on the X chromosome (Xp22.11) and
is composed of 7 exons that generate two alternatively spliced
mRNAs. Only one of the mRNAs encodes a functional SAT1
enzyme as the other mRNA is subjected to nonsense-mediated
mRNA decay. The functional SAT1 enzyme is a 171 amino acid
protein.

33. Catabolism and excretion of polyamines
•The enzyme polyamine oxidase present in liver peroxisomes
oxidizes spermine to spremidine and spermidine to putrescine.
• Putrescine is then oxidized by a copper containing diamine
oxidase to CO2 and NH3.
• Major portions of putrescine and spermidine are excreted in
urine after conjugation with acetyl-CoA as acetylated
derivatives.