Download MBBS Biochemistry PPT 59 Formation And Transport Of Ammonia Lecture Notes

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Formation and transport of Ammonia and its

associated disorders

Department of Biochemistry

Specific Learning Objectives

Outline formation and transport of ammonia

Describe importance of reactions catalyzed by glutamine synthetase,

glutaminase, and glutamate dehydrogenase

Role of Glutamine in Nitrogen metabolism

Ammonia Intoxication

List causes for hyperammonemia, its consequences, and treatments

to reduce blood ammonia levels
Sources of Ammonia

1. From glutamine

2. From bacterial action in intestine

3. From amines

4. From purines and pyrimidines

Role of Glutamine in Nitrogen Metabolism

1. When muscle degrades branched chain aa, it exports their nitrogen

as part of glutamine

2. In liver, hepatocytes use glutamine synthetase catalyzed reaction to

remove ammonia from blood

3. In brain, astrocytes use glutamine synthetase reaction to remove

neurotransmitter and recycle a precursor of it to neurons as part of a

glutamate/GABA cycle
Glutamine Transport Ammonia in Bloodstream

? Free ammonia produced in tissues is

combined with glutamate to yield glutamine

by glutamine synthetase and it requires ATP

? Glutamate and ATP react to form ADP and

-glutamyl phosphate intermediate which

reacts with ammonia to produce glutamine

and inorganic phosphate (Pi)

? Glutamine is a nontoxic transport form of

ammonia

?

Fig18.8: Lehninger Principles of Biochemistry by David L Nelson, 6th Ed

Cont--

Free ammonia converted to non toxic compounds before export from

extrahepatic tissues into blood and transport to liver or kidneys

For this transport function, glutamate critical to intracellular amino

group metabolism, is replaced by glutamine

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

Two mechanisms are available in humans for transport

of ammonia from peripheral tissues to liver for its

ultimate conversion to urea

1) Combine ammonia with glutamate to form glutamine

(nontoxic transport form of ammonia) by glutamine

synthetase

? Glutamine is transported into blood and then to liver

where it is cleaved by glutaminase to produce

glutamate and free ammonia which is converted to

urea

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

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

both aerobic glycolysis and metabolism of succinyl CoA generated by

catabolism of branched-chain aa

Alanine is transported by blood and then to liver, where it is converted

to pyruvate by transamination

Pyruvate is used to synthesize glucose by gluconeogenesis, which

can enter blood and be used by muscle
Ammonia Toxicity

Emptying cytosol of excess ammonia require reductive amination of

-ketoglutarate to glutamate by glutamate dehydrogenase and

conversion of glutamate to glutamine by glutamine synthetase

Both enzymes present at high levels in brain, although glutamine

synthetase reaction pathway imp for removal of ammonia

Cont--

High level of ammonium ions leads to increased level of glutamine,

which acts as osmotically active solute in brain astrocytes of CNS

provides nutrients, support to neurons

This triggers uptake of water into astrocytes to maintain osmotic balance

leads to swelling of cells and brain, which lead to coma
Cont--

Hyperammonemia: Blood ammonia level must be low because even slight

elevation leads hyperammonemia (toxic to CNS)

Normal blood ammonia is 30-60M

Elevated levels of ammonia in blood cause symptoms of ammonia

intoxication, which include tremor, slurring of speech, and blurring of vision

There are two types of conditions: Acquired and Hereditary

Cont--

Acquired: Cirrhosis of liver may result in formation of collateral

circulation around liver

As a result, portal blood is shunted directly into systemic circulation

and does not have access to liver

Therefore, conversion of ammonia to urea is severely impaired,

leading to elevated levels of ammonia.
Cont--

Hereditary: Genetic deficiency of each of five enzymes in urea cycle

pathway

X-linked ornithine transcarbamoylase/ornithine carbomyl transferase

deficiency is common of these disorders

In each case, failure to synthesize urea leads to hyperammonemia during

first weeks of birth

Treatment included restriction of dietary protein in presence of sufficient

calories to prevent catabolism

Two Clinical-cases discussed
15

Reference Books

1) Biochemistry, Lippincott's Il ustrated Reviews, 6th Ed
2) Harper's Il ustrated Biochemistry-30th Ed
3) Lehninger Principles of Biochemistry-6th Ed

Thank you

This post was last modified on 05 April 2022