Amino Acids Metabolism : Disposal of Nitrogen
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Amino Acids MetabolismAmino Acids Metabolism::
Disposal of NitrogenDisposal of Nitrogen
NoNo Storageof Amino AcidsAmino Acids
in the body
• So, amino acids amino acids must be obtained from
1.1.Diet Diet
2.2.DeDe novo synthesis novo synthesis (of non-essential aa)
3.3.DegradationDegradation of protein (normal turnover)
• So, amino acids amino acids must be obtained from
1.1.Diet Diet
2.2.DeDe novo synthesis novo synthesis (of non-essential aa)
3.3.DegradationDegradation of protein (normal turnover)
Amino Acids Amino Acids PoolPool
Degradation
Degradation
Protein
Protein
synthesis
synthesis
Protein
Protein
synthesis
synthesis Other NitogenOther Nitogen-containing compcontaining comp..Other NitogenOther Nitogen-
containing compcontaining comp..
SimultaneousSimultaneous
synthesis & degradationsynthesis & degradation
of protein moleculesof protein molecules
SimultaneousSimultaneous
synthesis & degradationsynthesis & degradation
of protein moleculesof protein molecules
Protein TurnoverProtein Turnover
Protein turnoverProtein turnover
Most proteins in the body are constantly being synthesizedsynthesized & then degradeddegraded,
permitting the removal of abnormal or unneeded proteins
Protein DegradationProtein Degradation
By Two Major Enzyme SystemsBy Two Major Enzyme Systems
1-1- Ubiquitin-proteasome mechanismUbiquitin-proteasome mechanism
• Energy-dependent• Mainly for endogenous proteins (proteins synthesized within the cell)
2- 2- LysosomesLysosomes
• 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 CatabolismAmino Acids Catabolism
• Unlike glucose and fatty acids, amino acids amino acids are notnot stored by the body
• Amino acids Amino acids in excess of biosynthetic needs are degraded.
• Degradation of amino acids amino acids involves:
First Stage First Stage
Removal of α-amino group AmmoniaAmmonia (NH3)
Second Stage Second Stage
Remaining carbon skeleton Energy metabolism
Amino Acids Catabolism - OverviewAmino Acids Catabolism - Overview
1st phase of catabolism of amino acids:1st phase of catabolism of amino acids:
RRemoval of the α-amino groupsemoval of the α-amino groups
1st phase of catabolism of amino acids:1st phase of catabolism of amino acids:
RRemoval of the α-amino groupsemoval of the α-amino groups
With production
of
Free Free AmmoniaAmmonia
In Liver
Small amount excreted Small amount excreted in urinein urine
UreaUrea
• AmmoniaAmmonia is produced by all tissues from the catabolism of amino acids
• AmmoniaAmmonia is mainly disposed is via formation of ureaurea in liver
• Blood level of ammoina ammoina must be kept very low, otherwise, hyperammonemia hyperammonemia & CNS toxicity CNS toxicity will occur
• To solve this problem, ammoniaammonia is transported from peripheral tissues to liver via formation of:
Glutamine (most tissues)
Alanine (muscle)
Amino Acids Catabolism - OverviewAmino Acids Catabolism - Overview
22ndnd phase of A. A. catabolism phase of A. A. catabolism CCarbon skeletons of the α-ketoacids arbon skeletons of the α-ketoacids are converted to are converted to
common intermediates of energy producing, metabolic common intermediates of energy producing, metabolic pathwayspathways
22ndnd phase of A. A. catabolism phase of A. A. catabolism CCarbon skeletons of the α-ketoacids arbon skeletons of the α-ketoacids are converted to are converted to
common intermediates of energy producing, metabolic common intermediates of energy producing, metabolic pathwayspathways
• ATP, CO2 & H2O (by Citric acid cycle) • Glucose (by gluconeogenesis)• Fatty Acids (from acetyl CoA)• Ketone Bodies (from acetyl CoA)
• ATP, CO2 & H2O (by Citric acid cycle) • Glucose (by gluconeogenesis)• Fatty Acids (from acetyl CoA)• Ketone Bodies (from acetyl CoA)
Amino Acids MetabolismAmino Acids MetabolismRemoval of Nitrogen from Removal of Nitrogen from Amino AcidsAmino Acids
Removing the Removing the -amino group-amino group • Essential for producing energy from any amino acidEssential for producing energy from any amino acid
• An obligatory step for the catabolism of all amino acidsAn obligatory step for the catabolism of all amino acids
Deamination PathwaysDeamination Pathways
Amino group (nitrogen) is removed from an amino acid Amino group (nitrogen) is removed from an amino acid by eitherby either
1- TransaminationTransamination : by transaminases
2- Oxidative DeaminationOxidative Deamination: by glutamate dehydrogenase
-ketoglutarate-ketoglutarate accepts the
amino group from amino acids to become glutamate glutamate by :
Transaminases Transaminases (aminotransferases)(aminotransferases)
GlutamateGlutamate: Glutamate dehydrogenaseGlutamate dehydrogenase
AmmoniaAmmonia
1- TransaminationTransamination
ALL Amino Acids ALL Amino Acids ((exceptexcept lysine & threonine))
Energy, glucose, FAs or KBEnergy, glucose, FAs or KB
TransaminaseTransaminase
GlutamateGlutamate (from transamination stepsfrom transamination steps)
by enzyme Glutamate Dehydrogenaseby enzyme Glutamate Dehydrogenase
AmmoniaAmmonia -ketoglutarate
Urea Urea CycleCycle
Urea used for transamination
of further amino acids
2- Oxidative deamination Oxidative deamination by Glutamate Dehydrogenaseby Glutamate Dehydrogenase
Diagnostic Value of Plasma Diagnostic Value of Plasma AminotransferasesAminotransferases
• 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
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
ALTALT is more specificmore specific for liver disease than AST ASTAST is more sensitivemore 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
Diagnostic Value of Plasma Aminotransferases
Metabolism of AmmoniaMetabolism of Ammonia
• AmmoniaAmmonia is produced by all tissuesall tissues during metabolism of a variety of compounds• AmmoniaAmmonia is disposed of primarily by formation of ureaurea in the liver• The level of ammonia in bloodlevel of ammonia in blood must be kept must be kept very lowvery low• Slightly elevated concentrations (hyperammonemiahyperammonemia) are toxic to CNS
So,There must be a mechanism by whichThere must be a mechanism by which
Ammonia is moved from peripheral tissues to the liver Ammonia is moved from peripheral tissues to the liver for disposal as ureafor disposal as urea
While at the same timeWhile at the same timeAmmonia must be maintained at low levels in bloodAmmonia must be maintained at low levels in blood
1- Urea Urea in the liverin the liver
• is quantitatively the most important most important disposal route for ammonia
• Urea is formed in the liver liver from ammonia (urea cycle)
• UreaUrea travels in the blood from the liver to the kidneyskidneys where it is filtered to appear in urineurine
Disposal of AmmoniaDisposal of Ammonia
2- GGlutamine lutamine in in most peripheral tissues most peripheral tissues especiallyespecially brain, sk.ms. & liver brain, sk.ms. & liver
• In most peripheral tissues, glutamate binds with ammoniaammonia by action of glutamine synthase glutamine synthase
• in the brainbrain, it is the major mechanism of removal of ammonia from the brain
• This structure provides a nontoxic storage & transport form of ammonia 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 glutaminaseglutaminase.
Disposal of Ammonia Disposal of Ammonia contcont . .
3- Alanine Alanine in skeletal musclesin skeletal muscles
• AmmoniaAmmonia + Pyruvate form alanine alanine in skeletal muscles• Alanine is transported in blood to liver• In liver, alanine is converted to pyruvate & ammoniaammonia • Pyruvate can be converted to glucoseglucose (by gluconeogenesis)• GlucoseGlucose can enter the blood to be used by skeletal muscles
(GLUCOSE - ALANINE PATHWAY)(GLUCOSE - ALANINE PATHWAY)
Disposal of Ammonia Disposal of Ammonia contcont . .
Disposal of Ammonia Disposal of Ammonia contcont . .
Alanine Alanine in Skeletal Musclesin Skeletal Muscles
GlutamineGlutaminein Most Tissuesin Most Tissues
Esp. brain & KidneysEsp. brain & Kidneys
UreaUreain Liverin Liver
Urea CycleUrea Cycle
• Urea is produced in the Urea is produced in the liverliver• From the liver, it is transported in the blood to the From the liver, it is transported in the blood to the kidneyskidneys for excretion in for excretion in
urine urine
Urea is composed of:Urea is composed of:
Two nitrogen atomsTwo nitrogen atoms• First nitrogen atom is from free ammoniafree ammonia• Second nitrogen atom is from aspartateaspartate
Carbon & oxygen atoms are from CO2Carbon & oxygen atoms are from CO2
Reactions of the Urea CycleReactions of the Urea Cycle
• First two reactionsFirst two reactions occur in the occur in the mitochondriamitochondria• RemainingRemaining reactions occur in the reactions occur in the cytosolcytosol
Ammonia + Aspartate + CO2 + 3 ATP
UREA + Fumarate + 2 ADP + AMP + 2 Pi + PPi + 3 H20
• Synthesis of urea is Synthesis of urea is irreversibleirreversible• 4 high-energy phosphates4 high-energy phosphates are consumed for synthesis of are consumed for synthesis of one one molecule of molecule of urea urea
Overview of Urea CycleOverview of Urea Cycle
Fate of UreaFate of Urea
Urea Urea (synthesized in the liver) (synthesized in the liver)
BloodBlood
KidneyKidney intestine
Urine cleaved by bacterial urease
AmmoniaAmmonia CO2
In stool Reabsorbed in blood
HyperammonemiaHyperammonemia= Increase of ammonia level of blood
• Blood Ammonia Blood Ammonia • Normal level of blood ammonia is 5-50 mmol/L Normal level of blood ammonia is 5-50 mmol/L
• Hyperammonemia Hyperammonemia A medical emergency as ammonia has a direct neurotoxic effect on CNSA medical emergency as ammonia has a direct neurotoxic effect on CNS
• Ammonia intoxicationAmmonia 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:Clinical manifestations: Tremors, slurring of speech, somnolence, vomiting, cerebral edema & blurring of vision At high concentrations, ammonia can cause coma & death
Types of HyperammonemiaTypes of Hyperammonemia
1- Acquired HyperammonemiaAcquired Hyperammonemia
1- Liver diseasesLiver diseases: are common causes in adults 1- Acute causes: Acute causes: viral hepatitis, ischemia, hepatotoxins
2- Chronic causes: 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 BleedingGatrointestinal Bleeding By action of bacteria of GIT on blood urea with production of big amounts of
ammonia that is absorbed to blood.
1- Hereditary HyperammonemiaHereditary Hyperammonemia Genetic deficiencies can occur for each of the five enzymesfive enzymes of the urea cycle
(overall prevalence 1:300,000 live births)
Ornithine transcarbamoylase deficiencyOrnithine 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 All other urea cycle disorders are autosomal recessiveautosomal 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 retardationmental retardation
Types of Hyperammonemia Types of Hyperammonemia cont.
• Limiting protein in dietLimiting protein in diet
• Administration of compounds that bind covalently to amino Administration of compounds that bind covalently to amino acids acids
To produce nitrogen-containing molecules that are excreted in the urine for example: Phenylbutyrate Phenylbutyrate given orally converted to phenylacetate that condenses with glutamine to form phenylacetylglutamine which is excreted in urine
Treatment of HyperammonemiaTreatment of Hyperammonemia
Hyperammonemia in Renal FailureHyperammonemia in Renal Failure Rena FailureRena Failure
blood ureaurea levels are elevated
Transfer of ureaurea to intestine is increased
Much amounts of AmmoniaAmmonia is formed by bacterial ureasebacterial urease
Absorbed to blood
HyperammonemiaHyperammonemia
• To reduce hyperammonemia:To reduce hyperammonemia: Oral neomycin reduces the amount of intestinal bacteria Oral neomycin reduces the amount of intestinal bacteria responsible for ammonia productionresponsible for ammonia production