Biochemical role of tryptophan, synthesis, and synthesis of new products.

1. METABOLISM OF TRYPTOPHAN
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DIPAKKUMAR SINGHA
ASST. PROFESSOR
CALCUTTAINSTITUTEOF PHARMACEUTICAL
TECHNOLOGY & AHS

2. INDRODUCTION
• In 1890, Ernst Stadelmann discovered tryptophan;
• Hopkins determined the structure in 1901,
and established its essentiality for growth in 1906.
• Tryptophan is an aromatic, essential amino acid with
an indole ring.
• Tryptophan is both glucogenic and ketogenic.

3. SUBSTANCES PRODUCED FROM TRYPTOPHAN
• 1. Alanine (glucogenic)
• 2. Acetoacetyl CoA (ketogenic)
• 3. Formyl group (One-carbon unit)
• 4. Niacin and NAD+
• 5. Serotonin
• 6. Melatonin
• 7. Hydroxyindoleacetic acid (excretory product)
• 8. Indican (excretory product).

5. SYNTHESIS OF NIACIN FROM TRYPTOPHAN
PRPP= phosphoribosyl
pyrophosphate. (1) = quinolinate
phosphoribosyl transferase
Nicotinic Acid Pathway of Tryptophan
i. About 97% molecules of tryptophan are
metabolized in the major pathway. About 3%
molecules are diverted at the level of 3-
hydroxyanthranilic acid, to form NAD+ .
ii. The enzyme, QPRT (quinolinate
hosphoribosyl transferase) is the rate-limiting
step.
iii. About 60 mg of tryptophan will be equivalent
to 1 mg of nicotinic acid. The development of
pellagra like symptoms (see Chapter 37) in the
maize eating population is due to tryptophan
deficiency in maize.
iv. Hydroxyanthranilate production is dependent
on pyridoxal phosphate (step 3, Fig. 18.8). Hence
in vitamin B6 deficiency, nicotinamide deficiency
is also manifested.

6. SEROTONIN
i. Serotonin (5-hydroxytryptamine) is produced in the brain, mast
cells, platelets and gastrointestinal tract mucosa.
ii. Tryptophan is first hydroxylated by tryptophan hydroxylase.
This reaction is very much similar to phenylalanine
hydroxylase . The co-enzyme is tetrahydrobiopterine. The
tetrahydrobiopterine is regenerated using NADPH.
iii. In the next step, 5-hydroxytryptophan is decarboxylated to
5-hydroxytryptamine (5HT), (serotonin). The enzyme,
decarboxylase requires pyridoxal phosphate.
iv. The effect of serotonin is dependent on the amount of
serotonin available at the synaptic site. Part of the serotonin
released is again taken up (reuptake). Selective serotonin
reuptake inhibitors (SSRI) are widely used in the
treatment of psychiatric disorders.

7. FUNCTIONS OF SEROTONIN
1. Serotonin is an important neurotransmitter in brain. In brain
cells, serotonin is in bound form. Reserpine causes rapid release;
this leads to calming effect and depression. On the other hand, 5-
HT is an antidepressant.
2. When ordinary proteins are taken, all amino acids are available in
blood. This causes traffic jam in the amino acid transport systems in
brain cells. Tryptophan, the bulkiest amino acid is therefore taken
up very slowly.
3. However, when carbohydrate-rich diet is taken, insulin secretion
is increased, which will lower the amino acid concentration in
blood. So tryptophan easily enters the brain cells. When tryptophan
is available in brain in excess quantity, serotonin may be generated
to induce sleep.
5. Carbohydrates will induce sleep, while protein rich foods will
cause alertness.
6. Serotonin level is found to be low in patients with depressive
psychosis. Serotonin is involved in mood, sleep, appetite and
temperature regulation. It increases gastrointestinal motility.
7. Sensitivity to pain is reduced by serotonin.

8. SYNTHESIS OF
SEROTONIN
&
MELATONIN

9. CATABOLISM OF SEROTONIN
• Monoamine oxidase (MAO) converts
serotonin to 5-hydroxyindoleacetic acid
(HIAA). MAO will oxidatively deaminate
compounds having an amino group attached
to a carbon atom. This is similar to
degradation of epinephrine (step 6). MAO
inhibitors (e.g. iproniazid) will cause mood
elevation. Small portion of serotonin is
conjugated with sulfate or with glucuronic
acid, and excreted through urine.

10. CARCINOID TUMORS
• i. Serotonin is produced by argentaffin cells of the
gastrointestinal tract and is necessary for GIT motility.
These cells may grow into locally malignant argentaffinomas,
otherwise known as carcinoid tumors. These tumors develop
in small intestine or in the appendix. Serum level of serotonin
is increased in carcinoid tumors (>40 mg/dL). (Sometimes, oat
cell carcinoma of lungs may also show increased serotonin
secretion).
• Melanin is the pigment of hair and skin; it is synthesized
from Tyrosine .
• Melatonin is a neurotransmitter synthesized from
tryptophan

11. MELATONIN
i. Serotonin is acetylated step 4.
ii. Further methylated with the help of S-adenosyl
methionine (SAM) (step 5,
iii. Pineal gland produces melatonin. It is intimately
connected with the diurnal variations, sleep wake cycles and
the biological rhythms.
iv. Melatonin blocks MSH and ACTH secretions. The activity of
melatonin as a neurotransmitter was discovered by Julius
Axelrod who was awarded Nobel prize in 1970.

12. MAJOR EXCRETORY PRODUCTS OF TRYPTOPHAN
Intestinal bacterial putrefaction of
tryptophan results in the production
of several indole compounds. These
are mainly excreted in the feces as
skatoxyl.
Some part is absorbed, detoxified
and excreted in urine as indoxyl and
indican.
Indican is the potassium salt of
indoxyl sulfate. The foul smell of feces
and the natural color of urine is due to
these compounds.
Normal excretion of indican in urine is
4–20 mg/day, which is increased in
Hartnup’s disease.
Liver and intestinal bacteria can
convert tryptophan to tryptamine,
and then to indole-acetate. The major
urinary excretory products of
tryptophan are 5-hydroxy indole

13. HARTNUP’S DISEASE
i. The name originates after the first family in whom the disease
was described. It is an inherited autosomal recessive disease.
ii. Absorption of aromatic amino acids from intestine as well as
reabsorption from renal tubules are defective. So amino acids
are excreted in urine.
iii. The pellagra like symptoms are due to the deficiency of niacin
derived from tryptophan. The common manifestations are
dermatitis and ataxia.
iv. A diagnosis is based on aminoaciduria and increased excretion
of indole compounds detected by the Obermeyer test.
v. Patients improve when put on a high protein diet with
supplementation of niacin and minimum exposure to sunlight. l

14. SUMMARY OF TRYPTOPHAN METABOLISM

15. METABOLIC FATES OF AMINO ACIDS

16. Any question?