Tryptophan is an essential amino acid that is metabolized through two main pathways - the kynurenine pathway and serotonin pathway. The kynurenine pathway leads to the production of NAD+ and takes place mainly in the liver. This pathway involves the enzymes tryptophan pyrrolase and kynureninase. Deficiencies in these enzymes or vitamin B6 can cause reduced NAD+ synthesis and manifestations of pellagra. The serotonin pathway produces the neurotransmitter serotonin from tryptophan in various tissues like the brain, gut and blood platelets. Serotonin is involved in behaviors, sleep, and gastrointestinal function. Melatonin is also derived from serotonin metabolism and regulates circadian rhyth

2.  Tryptophan is aromatic & essential amino acid.
 It contains an indole ring & chemically it is α-
amino β-indole propionic acid.
 Tryptopan is both glucogenic & ketogenic.

3.  Alanine (glucogenic)
 Acetoacetyl CoA (ketogenic)
 Formyl group (One-carbon unit)
 Niacin & NAD+
 Serotonin
 Melatonin
 Hydroxy indole acetic acid (excretory
product)

4.  Kynurenine (kynurenine-anthraniIate)
pathway.
 Serotonin pathway.
 Kynurenine (kynurenine-anthraniIate)
pathway:
 Mostly occurs in liver leading to oxidation of
tryptophan & the synthesis of NAD+ & NADP+

5.  Tryptophan pyrrolase or oxygenase cleaves
the five-membered ring of the indole nucleus
to produce formylkynurenine.
 Tryptophan pyrrolase is a metalloprotein
containing an iron porphyrin ring.
 The enzyme is inducible by corticosteroids.

6.  Total 11 carbon atoms of tryptophan are
catabolized as formyl group (1C which enters
the one carbon pool),
 Alanine (3C, entering the glucose pathway)
 Acetoacetate (4C, going to ketogenic
pathway).
 Tryptophan is both glucogenic & ketogenic.
 The remaining 3 carbons are removed as 3
CO2 molecules.

7.  Formamidase hydrolyses formylkvnurenine,
Iiberates formate & kynurenine.
 Kynurenine formed in this reaction is a
branch point with different fates.
 In the prominent pathway, kynurenine
undergoes NADPH-dependent hydroxylation
by kynurenine hydroxylase to give 3-
hydroxykynurenine.

8.  Kynureninase, a PLP - dependent enzyme
acts on the 3-hydroxykynurenine & splits off
alanine.
 kynureninase is sensitive to vitamin B6
deficiency.
 Due to the lack of PLP, kynureninase reaction
is blocked & 3-hydroxykynurenine is
diverted to form xanthurenate.

9.  EIevated excretion of xanthurenate serves
as an indication of B6 deficiency.
 Administration of isoniazid, an
antituberculosis drug-induces B6 deficiency &
results in xanthurenate excretion in urine.
 Defects in the activity of kynureninase (in B6
deficiency) cause reduced synthesis of NAD+
& NADP+ from tryptophan & manifestations
of pellagra.

10.  Kynurenine hydroxylase is inhibited by
estrogen.
 Women are more susceptible to Pellagra.
 3-Hydroxyanthranilate is cleaved by an
oxidase (Fe2+ dependent) to form an
unstable intermediate, 2-amino 3-carboxy
muconate semialdehyde.
 This compound has three fates.

11. 1. It undergoes spontaneous cyclization to
form quinolinate for NAD+ synthesis.
2. Picolinate carboxylase decarboxylates the
intermediate which cyclizes to produce
picolinate.
 This enzyme competes with the formation of
quinolinate.

12.  High activity of picolinate carboxylase in
some animals (e.g. cat) deprives them of
NAD+ synthesis from tryptophan.
 Cat is exclusively dependent on niacin for its
coenzymes (NAD+, NADP+).
3. The intermediate undergoes decarboxylation,
catalysed by amino carboxysemialdehyde
decarboxylase to produce 2-aminomuconate
semialdehyde that enters glutarate pathway.

13.  Semialdehyde is converted to 2-
aminomuconate by a dehydrogenase.
 The aminomuconate, in a series of reactions
involving reduction, deamination,
decarboxylation etc., is converted to glutaryl
CoA & finally to acetyl CoA.
 Acetyl CoA is either completely oxidized via
TCA cycle or converted to fat.

14. Matabolism of
Tryptophan-
Kynurenine pathway

15.  Tryptophan is not a precursor for the
synthesis of free niacin.
 Quinolinate undergoes decarboxylation & is
converted to nicotinate mononucleotide by
the enzyme quinolinate phosphoribosyl
transferase (QPRT).
 From nicotinate mononucleotide NAD+ &
NADP+ are synthesized.

16. Synthesis of niacin
tryptophan
QPRT

17.  Tryptophan undergoes deamination &
decarboxylation to produce indolepyruvate
& tryptamine.
 Both these compounds are converted to
indoleacetate & excreted in urine.

18. Tryptophan
Indole 3-pyruvate
Indole acetate
Urine
Deamination
NH3
Decarboxylation
CO2

19.  Serotonin or 5-hydroxytryptamine (5HT) is a
neurotransmitter, synthesized from
tryptophan.
 About 1% of the tryptophan is converted to
serotonin.
 The production of 5HT occurs in the target
tissues.

20.  Serotonin is synthesized in the brain, mast
cells, platelets, gastrointestinal tract mucosa &
intestinal cells.
 Tryptophan is first hydroxylated at 5th carbon
by tryptophan hydroxylase.
 Tryptophan hydroxylase requires
tetrahydrobiopterin as a cofactor.

21.  5-Hydroxytryptophan is decarboxylated by
aromatic amino acid decarboxylase (PLP-
dependent) to give serotonin.
 Platelets contain high concentration of 5HT.
 Platelets do not carry out the synthesis of
serotonin.

22.  Monoamine oxidase (MAO) degrades
serotonin to 5-hydroxyindoleacetate (5 HIA)
which is excreted in urine.
 Small portion of serotonin is conjugated with
sulfate or with glucuronic acid & excreted
through urine.

23. Serotonin &
melatonin synthesis

24.  Serotonin is a neurotransmitter.
 Serotonin is a powerful vasoconstrictor &
results in smooth muscle contraction in
bronchioles & arterioles.
 It is closely involved in the regulation of
cerebral activity (excitation).

25.  Serotonin controls the behavioural patterns,
sleep, blood pressure & body temperature.
 Serotonin evokes the release of peptide
hormones from gastrointestinal tract.
 It is also necessary for the motility of GIT
(peristalsis).

26.  The brain synthesizes 5-HT, in a bound form.
 The outside serotonin cannot enter the brain
due to blood-brain barrier.
 Serotonin is a stimulator (excitation) of brain
activity.
 Its deficiency causes depression.
 Serotonin level is decreased in psychosis
patients.

27.  The drug, iproniazid (isopropyl isonicotinyl
hydrazine) inhibits MAO & elevates serotonin
levels.
 This drug is a psychic stimulant.
 Reserpine increases the degradation of
serotonin & acts as a depressant drug.
 Lysergic acid diethylamide (LSD) competes
with serotonin & acts as a depressant.

28.  Serotonin is produced by argentaffin cells of
gastrointestinal tract.
 When these cells undergo uncontrolled
growth, they develop into a tumor called
malignant carcinoid or argentaffinomas.
 The patients exhibit symptoms like respiratory
distress, sweating, hypertension etc.

29.  In carcinoid syndrome, very high amount (up
to 60%) of tryptophan is diverted for
serotonin production.
 This disturbs the normal tryptophan
metabolism & impairs the synthesis of NAD+
& NADP+.
 The patients of carcinoid syndrome develop
symptoms of pellagra.

30.  The excretion of 5-hydroxyindole acetate in
urine is tremendously elevated (upto 500
mg/day against normal <5 mg/day) in
carcinoid syndrome.
 The estimation of 5 HIA in urine is used for
the diagnosis of this disorder.

31.  Melatonin is a hormone.
 Synthesized by the pineal gland.
 Serotonin-produced from tryptophan-is
acted upon by serotonin N-acetylase to give
N-acetylserotonin.
 Serotonin N-acetylase is a rate limiting
enzyme.

32.  N-acetylserotonin undergoes methylation,
S-adenosylmethionine being the methyl
group donor to produce melatonin or N-
acetyl 5-methoxyserotonin.
 The synthesis & secretion of melatonin from
pineal gland is controlled by light.

33.  Melatonin is involved in circadian rhythms or
diurnal variations (24 hr cyclic process) of the
body.
 It plays a significant role in sleep & wake
process.

34.  Melatonin inhibits the production of
melanocyte stimulating hormone (MSH) &
adrenocorticotropic hormone (ACTH).
 It has some inhibitory effect on ovarian
functions.
 Melatonin also performs a neurotransmitter
function.

35.  It is an hereditary disorder.
 Symptoms - dermatitis, ataxia, mental
retardation.
 Characterized by low plasma levels of
tryptophan & other neutral amino acids &
their elevated urinary excretion.
 Increased urinary output of indoleacetic acid
& indolepyruvic acid.

36.  Pellagra like symptoms are very common.
 There is an impairment in the synthesis of
NAD+ & serotonin from tryptophan.
 Hartnup's disease is believed to be due to an
impairment in the absorption and/or transport
of tryptophan & other neutral amino acids
from the intestine, renal tubules & probably
brain.

37.  Textbook of Biochemistry-U Satyanarayana
 Textbook of Biochemistry-DM Vasudevan