Specific Learning Objectives
Outline formation and transport of ammonia
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Describe importance of reactions catalyzed by glutamine synthetase,
glutaminase, and glutamate dehydrogenase
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Role of Glutamine in Nitrogen metabolismAmmonia Intoxication
List causes for hyperammonemia, its consequences, and treatments
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to reduce blood ammonia levels
Sources of Ammonia
1. From glutamine
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2. From bacterial action in intestine
3. From amines
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4. From purines and pyrimidinesRole of Glutamine in Nitrogen Metabolism
1. When muscle degrades branched chain aa, it exports their nitrogen
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as part of glutamine
2. In liver, hepatocytes use glutamine synthetase catalyzed reaction to
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remove ammonia from blood3. In brain, astrocytes use glutamine synthetase reaction to remove
neurotransmitter and recycle a precursor of it to neurons as part of a
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glutamate/GABA cycle
Glutamine Transport Ammonia in Bloodstream
? Free ammonia produced in tissues is
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combined with glutamate to yield glutamine
by glutamine synthetase and it requires ATP
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? Glutamate and ATP react to form ADP and-glutamyl phosphate intermediate which
reacts with ammonia to produce glutamine
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and inorganic phosphate (Pi)
? Glutamine is a nontoxic transport form of
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ammonia?
Fig18.8: Lehninger Principles of Biochemistry by David L Nelson, 6th Ed
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Cont--
Free ammonia converted to non toxic compounds before export from
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extrahepatic tissues into blood and transport to liver or kidneysFor this transport function, glutamate critical to intracellular amino
group metabolism, is replaced by glutamine
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Free ammonia produced in tissues combined with glutamate gives
glutamine by glutamine synthetase, this requires ATP
Glucose-Alanine Cycle: Alanine transport ammonia from skeletal muscle to liver
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Two mechanisms are available in humans for transport
of ammonia from peripheral tissues to liver for its
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ultimate conversion to urea1) Combine ammonia with glutamate to form glutamine
(nontoxic transport form of ammonia) by glutamine
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synthetase
? Glutamine is transported into blood and then to liver
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where it is cleaved by glutaminase to produceglutamate and free ammonia which is converted to
urea
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Fig 19.13. Alanine serves as a carrier of ammonia and of the carbon skeleton of
pyruvate from skeletal muscle to liver. The ammonia is excreted and the pyruvate
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is used to produce glucose, which is returned to the muscle.Lippincott's Illustrated Reviews, Biochemistry, 6th Ed
2) Formation of alanine by transamination of pyruvate produced from
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both aerobic glycolysis and metabolism of succinyl CoA generated by
catabolism of branched-chain aa
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Alanine is transported by blood and then to liver, where it is convertedto pyruvate by transamination
Pyruvate is used to synthesize glucose by gluconeogenesis, which
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can enter blood and be used by muscle
Ammonia Toxicity
Emptying cytosol of excess ammonia require reductive amination of
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-ketoglutarate to glutamate by glutamate dehydrogenase and
conversion of glutamate to glutamine by glutamine synthetase
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Both enzymes present at high levels in brain, although glutaminesynthetase reaction pathway imp for removal of ammonia
Cont--
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High level of ammonium ions leads to increased level of glutamine,
which acts as osmotically active solute in brain astrocytes of CNS
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provides nutrients, support to neuronsThis triggers uptake of water into astrocytes to maintain osmotic balance
leads to swelling of cells and brain, which lead to coma
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Cont--Hyperammonemia: Blood ammonia level must be low because even slight
elevation leads hyperammonemia (toxic to CNS)
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Normal blood ammonia is 30-60M
Elevated levels of ammonia in blood cause symptoms of ammonia
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intoxication, which include tremor, slurring of speech, and blurring of visionThere are two types of conditions: Acquired and Hereditary
Cont--
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Acquired: Cirrhosis of liver may result in formation of collateral
circulation around liver
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As a result, portal blood is shunted directly into systemic circulationand does not have access to liver
Therefore, conversion of ammonia to urea is severely impaired,
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leading to elevated levels of ammonia.
Cont--
Hereditary: Genetic deficiency of each of five enzymes in urea cycle
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pathway
X-linked ornithine transcarbamoylase/ornithine carbomyl transferase
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deficiency is common of these disordersIn each case, failure to synthesize urea leads to hyperammonemia during
first weeks of birth
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Treatment included restriction of dietary protein in presence of sufficient
calories to prevent catabolism
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Two Clinical-cases discussed15
Reference Books
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1) Biochemistry, Lippincott's Il ustrated Reviews, 6th Ed2) Harper's Il ustrated Biochemistry-30th Ed
3) Lehninger Principles of Biochemistry-6th Ed
Thank you
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