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Tryptophan Metabolism

Tryptophan MetabolismGandham.RajeevEmail:gandhamrajeev33@gmail.comTryptophan is aromatic & essential amino acid. It contains an indole ring & chemically it is -amino -indole propionic acid. Tryptopan is both glucogenic & ketogenic. Tryptophan MetabolismSubstances produced from tryptophanAlanine (glucogenic)Acetoacetyl CoA (ketogenic)Formyl group (One-carbon unit)Niacin & NAD+SerotoninMelatoninHydroxy indole acetic acid (excretory product)Metabolism of tryptophan 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. 7Kynureninase, 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.It undergoes spontaneous cyclization to form quinolinate for NAD+ synthesis.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 pathwayNAD+ 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 tryptophanQPRTConversion of tryptophan to indole acetateTryptophan undergoes deamination & decarboxylation to produce indolepyruvate & tryptamine.Both these compounds are converted to indoleacetate & excreted in urine.Tryptophan Indole 3-pyruvateIndole acetateUrine Conversion of tryptophan to indole acetateDeamination NH3 Decarboxylation CO2 Serotonin pathway 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.Synthesis of serotonin 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.Degradation of serotoninMonoamine 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 synthesisFunctions of serotoninSerotonin 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).

Serotonin & brain 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.Effect of drugs on serotoninThe 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.Malignant carcinoid syndromeSerotonin 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.DiagnosisThe excretion of 5-hydroxyindole acetate in urine is tremendously elevated (upto 500 mg/day against normal