Tryptophan MetabolismDr. Ashok Kumar J

International Medical SchoolManagement and Science University

Malaysia

Tryptophan

•Aromatic amino acid•Essential amino acid•Glucogenic and ketogenic

Dr Ashok Kumar J Professor: Department of Biochemistry 2

Indole group

CH2

CH

COO-

NH3

OHNH

Tryptophan

AlanineGlucogenic

SerotonineNeurotransmitter

Melotonin Neurotransmitter

Tryptophan

N- Formyl kynurenine

Kynurenine

3- OH Kynurenine

O2

Tryptophan Pyrrolase

THFA

Formyl THFA

Kynureninase; PLP

3-OH Anthranilic acid

Acetoacetyl CoA

Alanine

NAD+(Co-enzyme form of Niacine)

Dr Ashok Kumar J Professor: Department of

Biochemistry

Kynurenine Formylase

Kynurenine Hydroxylase

O2

4

3- OH Kynurenine

Kynureninase; PLP

3-OH Anthranilic acid

Xanthurenic acid

Dr Ashok Kumar J Professor: Department of

Biochemistry

Tryptophan

Coenzyme form of water soluble vitamin niacin is PLP

Deficiency of niacin leads to decreased - PLP

Acetoacetyl CoAAlanineNAD+

Xanthurenic acid excreted in urine

Vitamin B6 deficiency

Kynureninase function defective

3 – OH kynurenine accumulates

3 – OH kynurenine is converted to

XANTHURINIC ACID -Excreted in urine

Normal person excretes 1 to 3 mgs of xanthurenic acid

in urine/day

2 to 11 mg in 24 hour urine after

taking a 2 gram load of tryptophan

In pyridoxine deficiency much higher amount of xanthurenic acid is excreted after

loading with tryptophan – up

to 60 mgs/day

Pellagra like symptoms in maize eating population is due to tryptophan deficiency

Dr Ashok Kumar J Professor: Department of Biochemistry 7

60 mg of tryptophan forms 1 mg of niacin

Tryptophan rich diet has sparing effect on niacin requirement

Tryptophan

Indolpyruvic acid

Indoleacetic acid

Sketol

Transaminase

Intestinal bacterial putrifaction of tryptophan Produce various indole compounds

Excreted in feces as sketoxyl

In urine as indoxyl and and indican

Dr Ashok Kumar J Professor: Department of

Biochemistry

8

IndicanIndoxyl sulfateIndoxyl

Indole

Degradation of tryptophan

Synthesized from tryptophan (1% of tryptophan converted to serotonin)

SERETONIN

Present in Gastric mucosa

IntestineBrain

Mast cellsPlatelets

Synthetic reaction is similar to synthesis of dopamine

Tryptophan

5-OH Tryptophan

5-OH Tryptamine(Serotonine)

O2

H2O

Tryptophan Hydroxylase

Decarboxylase :PLP

TetrahydobiopterinDihydobiopterin

CO2

Dr Ashok Kumar J Professor: Department of Biochemistry 10

Synthesis of serotonin from

tryptophan

Serotoni

n

serotoni

n

serotoni

n

Serotonin FunctionsNeurotransmitter : Regulation of cerebral

activity (Stimulate), Controls the behavioral pattern, sleep, blood pressure and body

temperatureEvokes release of peptide hormones from

GIT: Increases gastric motility

Powerful vasoconstrictor – smooth muscle constriction in bronchioles and arterioles

Sensitivity to pain is reduced

Serotonin

When protein rich diet taken – all amino acids are available in blood

Cause traffic jam I the amino acid transport system in brain

Tryptophan bulkiest amino acid - taken very slowly

When carbohydrate rich diet is taken – insulin secretion is increased

Lower the amino acid concentration in the blood

Tryptophan easily enters the brain – serotonin production increased – induce

sleep

5-OH Indole acetic acid(5HIAA)

Monoamine Oxidase (MAO)

5-OH Tryptamine(Serotonine)

5 – OH Indole acetic acid excreted in urine

Inhibitors of MAO : decrease the degradation of

serotonin: Serotonin concentration increases

Levels of serotonin have been linked to mood, many antidepressant drugs were developed that affect serotonin levels

Excess production of Serotonine – Increased

excretion of 5-HIA

Iproniazide• Inhibits MAO• Elevates serotonin concentration• Psychic stimulation

Lysergic acid diethylamide (LSD)

•Competes with serotonin•Acts as depressant

• Increases degradation of serotoninReserpine

• Part of the serotonin released is again taken up

• Selective serotonin reuptake inhibitors (SSRI) – used in the treatment of psychiatric disorders

fluoxetine

Carcinoid Syndrome

Uncontrolled growth develops – tumor called malignant carcinoid

( argentaffinoma)

Argentaffin cellsSerotonin producing cells of

intestine

Normally 1% of Tryptophan converted to serotonin

Carcinoid syndrome – 60% of tryptophan diverted to serotonin

production

Normal tryptophan metabolism is affected

Synthesis of NAD+ is impaired – symptoms of Pellegra

Serotonin synthesis increase (>40mg/dl)

Cutaneous flushingRespiratory distress

BronchospasmRight sided heart failureFluctuating hypertension

Urinary excretion of 5 HIAA is increases

Urine collected after stopping all medications for 72 hours

Dietary sources of 5-HIAA like • banana• red plum• pineapple• tomatoes• cough syrup with glycerol guaiacolate• drugs like indomethacin should be avoided for few days before urine collection

Random fresh urine sample collected

• Normal excretion is 2 – 7 mg/day

• If urine level is > 25 mg/ day diagnosis of carcinoid tumor

• In metastatic carcinoid tumor - up to 350mg/day

•

First described in the Harnup’s family – so the name

Impaired transport of tryptophan and neutral amino

acids in intestine, renal tubules

Mental retardationIntermittent cerebellar ataxia

Pellegra like skin rashes

Plasma level of tryptophan is decreased

Urine excretion of tryptophan, indole compounds increased

Decreased synthesis of serotonin and niacin are responsible for

neurological symptoms and pellagra like rash

Hartnup’s Disease

Acetyl Serotonine

Acetyl CoA

CoA

SAM

SAH

Melatonin

Methyl transferase

Acetyalse

Acetylated and methylated to form melatonin

Serotonine

Functions of Melatonin

Produced in Pineal gland

in response to the light–dark cycle

level in the blood rising in a dark environment

Action is thought to be mediated via c AMP

Connected with the diurnal variations, sleep wake cycles

involved in regulating reproductive functions.

Dr Ashok Kumar J Professor: Department of Biochemistry 23

Thank You