Transcript Urea

Amino Acids Metabolism:
Disposal of Nitrogen
No Storage
of Amino Acids
in the body
• So, amino acids must be obtained from
1. Diet
2. De novo synthesis (of non-essential aa)
3. Degradation of protein (normal turnover)
De novo
synthesis
Amino Acids
Pool
Other Nitogencontaining comp.
Protein Turnover
Simultaneous
synthesis & degradation
of protein molecules
Protein turnover
Most proteins in the body are constantly being
synthesized & then degraded, permitting the
removal of abnormal or unneeded proteins
Protein Degradation
By Two Major Enzyme Systems
1- Ubiquitin-proteasome mechanism
• Energy-dependent
• Mainly for endogenous proteins
(proteins synthesized within the cell)
2- Lysosomes
• Non-energy-dependent
• Primarily for extracellular proteins as:
- plasma proteins that are taken into cells by endocytosis
- cell surface membrane proteins: for receptor-mediated endocytosis
Amino Acids Catabolism
Amino Acids Catabolism - Overview
• Unlike glucose and fatty acids, amino acids are not stored by the
body
• Amino acids in excess of biosynthetic needs are degraded.
• Degradation of amino acids involves:
First Stage
Removal of α-amino group
Ammonia (NH3)
Second Stage
Remaining carbon skeleton
Energy metabolism
1st phase of catabolism of amino acids:
Removal of the α-amino groups
With
production
of
Free
Ammonia
In Liver
Small amount
excreted in urine
Urea
Amino Acids Catabolism - Overview
• Ammonia is produced by all tissues from the catabolism of amino
acids
• Ammonia is mainly disposed is via formation of urea in liver
• Blood level of ammoina must be kept very low, otherwise,
hyperammonemia & CNS toxicity will occur
• To solve this problem, ammonia is transported from peripheral
tissues to liver via formation of:
Glutamine (most tissues)
Alanine (muscle)
2nd phase of A. A. catabolism
Carbon skeletons of the α-ketoacids are converted to
common intermediates of energy producing, metabolic
pathways
• ATP, CO2 & H2O (by Citric acid cycle)
• Glucose (by gluconeogenesis)
• Fatty Acids (from acetyl CoA)
• Ketone Bodies (from acetyl CoA)
Amino Acids Metabolism
Removal of Nitrogen from Amino Acids
Removing the a-amino group
• Essential for producing energy from any amino acid
• An obligatory step for the catabolism of all amino acids
Deamination Pathways
Amino group (nitrogen) is removed from an amino acid
by either
1- Transamination : by transaminases
2- Oxidative Deamination: by glutamate dehydrogenase
1- Transamination
ALL Amino Acids (except lysine & threonine)
a-ketoglutarate accepts the
amino group from amino acids to
become glutamate by:
Transaminases (aminotransferases)
Transaminase
Glutamate:
Glutamate dehydrogenase
Ammonia
Energy, glucose, FAs or KB
2- Oxidative deamination
by Glutamate Dehydrogenase
Glutamate (from transamination steps)
by enzyme Glutamate Dehydrogenase
Ammonia
a-ketoglutarate
Urea
Cycle
Urea
used for transamination
of further amino acids
Diagnostic Value of Plasma Aminotransferases
• Aminotransferases are normally intracellular enzymes
• Plasma contains low levels of aminotransferases
representing release of cellular contents during normal cell
turnover
• Elevated plasma levels of aminotransferases
indicate damage to cells rich in these enzymes
(as physical trauma or disease to tissue)
• Plasma AST & ALT are of particular diagnostic value
Diagnostic Value of Plasma Aminotransferases
1- liver disease:
Plasma ALT & AST are elevated in nearly all liver diseases
but, particularly high in conditions that cause cell necrosis as:
viral hepatitis
toxic injury
prolonged circulatory collapse
ALT is more specific for liver disease than AST
AST is more sensitive (as liver contains a large amount of AST)
2- Nonhepatic disease:
as: Myocardial infarction
Skeletal muscle disorders
These disorders can be distinguished clinically from liver disease
Metabolism of Ammonia
•
Ammonia is produced by all tissues during metabolism of a variety of
compounds
• Ammonia is disposed of primarily by formation of urea in the liver
• The level of ammonia in blood must be kept very low
• Slightly elevated concentrations (hyperammonemia) are toxic to CNS
So,
There must be a mechanism by which
Ammonia is moved from peripheral tissues to the liver
for disposal as urea
While at the same time
Ammonia must be maintained at low levels in blood
Disposal of Ammonia
1-
Urea
in the liver
• is quantitatively the most important disposal route for
ammonia
• Urea is formed in the liver from ammonia (urea cycle)
• Urea travels in the blood from the liver to the kidneys
where it is filtered to appear in urine
Disposal of Ammonia
cont.
2- Glutamine
in most peripheral tissues especially brain, sk.ms. & liver
• In most peripheral tissues, glutamate binds with ammonia by action of
glutamine synthase
• in the brain, it is the major mechanism of removal of ammonia from the
brain
• This structure provides a nontoxic storage & transport form of ammonia
• Glutamine is transported to blood to other organs esp. liver & kidneys
• In the liver & Kidney, glutamine is converted to ammonia & glutamate
by the enzyme glutaminase.
Disposal of Ammonia
3-
cont.
Alanine
in skeletal muscles
• Ammonia + Pyruvate form alanine in skeletal muscles
• Alanine is transported in blood to liver
• In liver, alanine is converted to pyruvate & ammonia
• Pyruvate can be converted to glucose (by gluconeogenesis)
• Glucose can enter the blood to be used by skeletal muscles
(GLUCOSE - ALANINE PATHWAY)
Disposal of Ammonia
Glutamine
in Most Tissues
Esp. brain & Kidneys
Urea
in Liver
Alanine
in Skeletal Muscles
cont.
Urea Cycle
• Urea is produced in the liver
• From the liver, it is transported in the blood to the kidneys for
excretion in urine
Urea is composed of:
Two nitrogen atoms
• First nitrogen atom is from free ammonia
• Second nitrogen atom is from aspartate
Carbon & oxygen atoms are from CO2
Reactions of the Urea Cycle
• First two reactions occur in the mitochondria
• Remaining reactions occur in the cytosol
Ammonia + Aspartate + CO2 + 3 ATP
UREA + Fumarate + 2 ADP + AMP + 2 Pi + PPi + 3 H20
• Synthesis of urea is irreversible
• 4 high-energy phosphates are consumed for synthesis of one molecule of
urea
Overview of Urea Cycle
Fate of Urea
Urea
(synthesized in the liver)
Blood
Kidney
intestine
Urine
cleaved by bacterial urease
Ammonia
In stool
CO2
Reabsorbed in blood
Hyperammonemia
= Increase of ammonia level of blood
• Blood Ammonia
•
Normal level of blood ammonia is 5-50 mmol/L
• Hyperammonemia
A medical emergency as ammonia has a direct neurotoxic effect on CNS
• Ammonia intoxication:
•
•
It is defined as toxicity of the brain due to increase in ammonia level in the systemic blood.
This increased ammonia will be directed to α ketoglutarate to form glutamic acid then glutamine
leading to interference with citric acid cycle  so decrease ATP production in the brain cells.
Clinical manifestations:
Tremors, slurring of speech, somnolence, vomiting, cerebral edema & blurring of vision
At high concentrations, ammonia can cause coma & death
Types of Hyperammonemia
1-
Acquired Hyperammonemia
1- Liver diseases: are common causes in adults
1- Acute causes:
viral hepatitis, ischemia, hepatotoxins
2- Chronic causes:
liver cirrhosis due to alcoholism, hepatitis, biliary obstruction…etc may
result in the formation of collateral circulation around the liver
So, portal blood is shunted directly into systemic circulation & detoxication
of ammonia to urea is markedly impaired
2- Gatrointestinal Bleeding
By action of bacteria of GIT on blood urea with production of big amounts of
ammonia that is absorbed to blood.
Types of Hyperammonemia cont.
1- Hereditary
Hyperammonemia
Genetic deficiencies can occur for each of the five enzymes of the urea cycle
(overall prevalence 1:300,000 live births)
Ornithine transcarbamoylase deficiency
• X-linked
• Most common deficiency among all 5 enzymes
• Males are predominantly affected
• Females carriers are clinically affected
All other urea cycle disorders are autosomal recessive
•
•
In each case, failure to synthesize urea leads to hyperammonemia during the
first weeks following birth
All inherited disorders of the urea cycle enzymes result in mental retardation
Treatment of Hyperammonemia
• Limiting protein in diet
• Administration of compounds that bind covalently to amino
acids
To produce nitrogen-containing molecules that are excreted in the
urine for example:
Phenylbutyrate given orally converted to phenylacetate that
condenses with glutamine to form phenylacetylglutamine which is
excreted in urine
Hyperammonemia in Renal Failure
Rena Failure
blood urea levels are elevated
Transfer of urea to intestine is increased
Much amounts of Ammonia is formed by bacterial urease
Absorbed to blood
Hyperammonemia
• To reduce hyperammonemia:
Oral neomycin reduces the amount of intestinal bacteria
responsible for ammonia production