 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.
 Alanine (glucogenic)
 Acetoacetyl CoA (ketogenic)
 Formyl group (One-carbon unit)
 Niacin & NAD+
 Serotonin
 Melatonin
 Hydroxy indole acetic acid (excretory
product)
 Kynurenine (kynurenine-anthraniIate)
pathway.
 Serotonin pathway.
 Kynurenine (kynurenine-anthraniIate)
pathway:
 Mostly occurs in liver leading to oxidation of
tryptophan & the synthesis of NAD+ & NADP+
 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.
 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.
 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.
 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.
 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.
 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.
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.
 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.
 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.
 Matabolism of
Tryptophan-
Kynurenine pathway
 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.
 QPRT
Synthesis of niacin
tryptophan
 Tryptophan undergoes deamination &
decarboxylation to produce indolepyruvate
& tryptamine.
 Both these compounds are converted to
indoleacetate & excreted in urine.
 Tryptophan

Deamination
NH3

Indole 3-pyruvate

Decarboxylation
CO2

Indole acetate

Urine
 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.
 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.
 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.
 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.
 Serotonin &
melatonin synthesis
 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).
 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).
 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.
 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.
 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.
 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.
 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.
 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.
 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.
 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.
 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.
 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.
 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.
 Textbook of Biochemistry-U Satyanarayana

 Textbook of Biochemistry-DM Vasudevan