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.

Synthesis of niacin tryptophan

QPRT

Tryptophan undergoes deamination &

decarboxylation to produce indolepyruvate

& tryptamine.

Both these compounds are converted to

indoleacetate & excreted in urine.

Tryptophan

Indole 3-pyruvate

Indole acetate

Urine

Deamination NH3

Decarboxylation

CO2

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