Tryptophan Metabolism Dr. Ashok Kumar J International Medical School Management and Science University Malaysia
Jun 12, 2015
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