Biological Chemistry - Berezov T. T., Korovkin B. F. 1998

Metabolism of Simple Proteins
Detoxification of Ammonia in the Body

In The Human Body, approximately 70 g of Amino Acids undergo breakdown daily. This process releases a large amount of ammonia—a highly toxic compound—As a result of deamination and The oxidation of biogenic amines. Therefore, the concentration of ammonia in the body must be kept at a low level. Indeed, the normal Blood ammonia concentration does not exceed 60 µmol/L (which is nearly 100 times lower than blood glucose levels). Experiments on rabbits have shown that an ammonia concentration of 3 mmol/L is lethal. Consequently, ammonia must be bound in Tissues to form non-toxic compounds that are readily excreted in the urine.

One of the pathways for binding and detoxifying ammonia in the body—specifically in the Brain, retina, Kidneys, Liver, and Muscles—is The Biosynthesis of glutamine (and possibly asparagine). Glutamine and asparagine are excreted in the urine in small quantities. It has been suggested that they primarily serve a transport function, carrying ammonia in a non-toxic form. The chemical reaction for glutamine synthesis, catalyzed by Glutamine Synthetase*, is shown below.

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The Mechanism of this synthetase reaction, studied in detail by A. Meister, involves several stages. The Synthesis of Glutamine in the presence of glutamine synthetase can be represented as follows:

The biosynthesis of asparagine proceeds somewhat differently, depending on The Nature of the Enzymes and the ammonia donor. Specifically, a specific ammonia-dependent asparagine synthetase has been discovered in microorganisms and animal tissues, which catalyzes the synthesis of asparagine in two stages:

a) Asp + E + ATP -> E-aspartyl~AMP + PP_i;

б) E-aspartyl~AMP + NH₃ -> Asn + E + AMP.

In addition, animal tissues contain a glutamine-dependent asparagine synthetase, which utilizes the amide group of glutamine for synthesis In the second stage:

б) E-aspartyl~AMP + Gln -> Asn + E + AMP + Glu.

The overall enzymatic reaction of asparagine synthesis can be represented as follows:

Asp + ATP + NH₃ (or Gln) —> Asn + AMP + PP_i + (Glu).

* The End products of glutamine METABOLISM (Histidine, glucose-6-phosphate, AMP, cAMP, etc.), as well as Gly and Ala, have been shown to be allosteric inhibitors of glutamine synthetase. The enzyme also undergoes covalent modification via adenylylation-deadenylylation (Tyr residue), which makes it more sensitive to allosteric inhibitors. The cumulative inhibitory effect exceeds the action of any single inhibitor. This type of regulation is known as concerted inhibition.

It is evident that, energetically, the synthesis of asparagine is more costly to the Organism, since the resulting PP_i subsequently breaks down into orthophosphate.

Part of the ammonia is readily bound to α-ketoglutaric acid due to the reversibility of the Glutamate dehydrogenase reaction. Taking into account the binding of a single ammonia molecule during glutamine synthesis, it is easy to see that the body possesses a well-functioning system that binds two molecules of ammonia:

Furthermore, glutamine is utilized by the kidneys as a reserve source of ammonia (formed from glutamine through the action of glutaminase), which is necessary to neutralize acidic metabolic products during acidosis, thereby protecting the body from the urinary loss of Na⁺ ions used for these purposes.