9/7/2010

Amino Acid Metabolism

Dr Madhav Gautam
BCM 121
Pharmacy

Amino Acid Metabolism

Overview
Protein Turnover,Amino Acid Pool
,Catabolism and Anabolism

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Protein Turnover
• 1
1. Adult (70kg) degrade about 400g of body
protein daily
• Principally muscle protein liberated amino acid
1. 300-400g –reutilized in new protein
synthesis(about 75%) 2. 30g converted to
specialized products 3.Rest of them are
catabolized: nitrogen-urea and carbon
• Excess AA are degraded ,not stored

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Specialized Products
• Prophyrin from glycine
• Creatine from glycine,Arginine and Methainine
• Glutathionine from glycine,cysteine and glutamate
• Histamine from Histidine
• Serotonin from tryptophan
• Catecholamine from phenylalanine and Melanin
from Tyrosine, thyroxine from tyrosine,
• Purine from Glutamine ,Glycine,Aspartate
• Pyrimidine from Aspartate.

coned
• Amino Acid Pool: Amino acid released by the
hydrolysis of dietary or tissue protein mix with
other free amino acids distributed throughout the
body ,collectively called amino acid pool.
• Catabolism : - First Phase of amino acid
Catabolism-the removal of the alpha-amino group
Transamination Deamination : oxidation or non-
Transamination,Deamination non
oxidation and Urea Formation
Second Phase of Amino acid Catabolism-
Catabolism of the Carbon Skeletons –Ketogenic
and Glycogenic amino acid.

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Removal of Amino Group

• Tansamination
• Deamination: 1 Oxidative Deamination -
Alternate route L-amino oxidase results
FMNH2/NADH2 and NH4+and D-amino
oxidase will have more NH4+ found as
leftover 2. Non-oxidative Deamination
• Urea Synthesis

Metabolism of Ammonia
• Sources of Ammonia
• 1 Amino Acids :- Many tissues ,particularly in the
liver Aminotransferase and Glutamate
Dehydrogenase .
• 2.Glutamine (source :muscle,liver and brain) -
Renal Glutaminase –hydrolysis
hydrolysis of glutamine
Ammonia –excreted into urine as NH4+
Intestine Glutaminase – from blood or dietary
protein.

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cont
• Bacterial Action in the Intestine-
Ammonia formed by the bacterial
degradation of urea absorbed from the
intestine by way of the portal vein removed
by the liver by converted to urea
• Amines – Amine oxidase – amine from
diet ,monoamines (Hormones).
• Purines and Pyrimidines

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Transport of Ammonia in the

Circulation
• A very low level of ammonia in the blood is
maintained by
• 1.Glutamine – Tissues esp., muscle release
amino acid nitrogen in the form of glutamine or
alanine ,rather than as free ammonia.
• 2.Urea
2 Urea - Ammonia is rapidly removed from the
blood by the liver by forming urea. And Urea
travels in the blood from the liver to the kidneys

coned
3.Hyperammonemia and Ammonia Intoxication-
1.Liver cirrhosis –shunting of blood through
collateral 2. Hereditary Hyperammonemia-
G ti deficiencies
Genetic d fi i i off eachh off the
th Five
Fi off the
th
urea cycle enzyme
• Mechanism of Ammonia Toxicity:-A shift in the
equilibrium of the glutamate dehydrogenase
reaction toward the direction of glutamate
formation
• 1. Change in cellular pH: NH4 + Å---Æ NH4
+H+ (pK= 9.5) 2. Depletion of citric acid cycle
intermediates –Alpha ketoglutrate + NADPH +
H+ + NH3 Å-----Æ glutamate +NADP+

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coned
• 4.
4 Urea Cycle
• Fate of Urea

Disorder of Amino Acid

Metabolism
• Glutamate and Ammonia removal from Brain- Brain
The brain’s uptake of glutamine is approximately
balanced by its output of glutamine
• The glutamate –glutamine conversion in the brain
• kidney that produces some of the ammonia
entering the tubules –probably serves as a
d
detoxifying
if i mechanism
h i to keep
k the
h brain
b i free
f off
ammonia.
• Ammonia is very toxic to the nerve cells ,and
ammonia intoxication is believed to be a
neurological symptoms in hepatic coma.

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coned
• Ammonia Secretion in the Kidney
• The principal reaction producing NH4 + in the
cells is conversion of glutamine to glutamate ,and
the reaction is catalyzed by glutaminase, and is
abundant in the renal tubular cells
• Glutamic dehydrogenase catalyzes the
conversion
i off glutamate
l to Alpha
Al h –ketoglutarate,
k l
and produces more NH4+
• In chronic acidosis ,the amount of NH4+ excreted
at any given pH also increases ,because more NH3
enters the tubular urine.

coned
• The process by which NH3 is secreted into the
urine and then changed to NH4 ,maintaining ,the
concentration gradient for diffusion of NH# ,is
called nonionic diffusion.
• Ammonia Production in Colon:-
• Ammonia is also produced in the colon and
absorbed
b b d bbut iin the
h liver
li disease
di ammoniai is
i not
removed from the blood and hyperammonemia
can cause neurological symptoms.
• Administration of osmotic cathartics such as
lactulose decreases the ammonia production.

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Urea Cycle Enzymes

• The urea cycle,
cycle which consists of a series of
five biochemical reactions ,has two roles.
• It prevents the accumulation of toxic
nitrogenous compounds,excreted as urea as
the waste nitrogen.
• Five
Fi well-documented
ll d t d disease
di (each
( h with
ith
considerable genetic and phenotypic
variability) have been observed.

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coned
• Deficiencies of carbamoyl phosphate synthetase
(CPSD),ornithine transcarbamoylase (OTCD),
argininosuccinic acid synthetase (ASD),and
arginosuccinase (ALD) ,are the characterized by
sign and symptoms.
• Induced by the accumulation of precursors of urea
,principally
principally ammonia and glutamate
glutamate.
• Disease occurs in full term infants ,risk start
appearing from 24 to 48 hrs.
• Increase very high ammonia levels

coned
• Brain edema
• Swollen caused due to accumulation of glutamine
resulting in osmotic shifts of water into the cells.
• These four disease may continue in
infancy,childhood,and adulthood
• Fifth disease ,arginase
g deficiency
y causes mental
retardation .
• Less hyperammoniea compare to other four
disease.

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coned
• Diagnosis is available by a number of methods
such as enzyme analysis of fibroblasts ,culture
culture
from aminocytes, liver biopsy and DNA technique
.
• Treatment requires restriction of dietary protein
intake or phenyl butyrate –glutamine
• For argininosuccinase, supplementation of diet
with
i h arginine
i i ,promotes the
h synthesis
h i off citrulline.
i lli
• Elevated ornithine levels due to deficiency of
ornithine delta-aminotransferase.Causes atrophy
of vision,progressive degeneration of retina and
blindness.

Other Disorder of Amino Acids

Metabolism
• Disorders of Phenylalanine:
Phenylalanine:-
Hyperphenylalaninemias characteristic of PKU
:- Elevated Phenylalinine,CNS symptoms,
Hypopigmentation.
• Tyrosine:- tyrosinemia type –
I,II,III,Alkaptonuria,Albinism.
• Branched
B h d –Amino
A i A Acid:-
id Maple
M l Syrup
S Ui
Urine
Disease (branch chain Ketonuria)
• Methionine:- Homocystinuria

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