Ammonia Detoxification: From Muscle to Liver

 

Answer to Biochemistry Question AM-04

 

Answer:  (a) alanine and glutamine

 

 

 

 

                                                  

 

At cellular pH NH3 exists as NH4⁺ ion. If the concentration of ammonium ions is very high, coma may result ( “Hepatic coma”).

 

There are mechanisms in our body to avoid hyperammonemia. Those mechanisms allow the transport of ammonia from muscle and other peripheral tissues to the liver and the kidneys.

 

 

 

 

                                                             

 

 In the liver, the ammonia delivered by these mechanisms will form UREA, while in the kidneys these mechanism will allow the direct excretion of NH4⁺  in urine.

 

These mechanisms are:

 

– Glucose-alanine cycle (transport of  NH3 from muscle to liver).

 

– Glutamine synthase/glutaminase system (transport of NH3 from different tissues to kidney and liver)

 

  Ammonia Detoxification in Muscle:

 

 Alanine transaminase has an important function in the delivery of skeletal muscle carbon and nitrogen (in the form of alanine) to the liver. In the glucose-alanine cycle ammonium ion is transported from muscle cells to the liver in the form of alanine.

 

Through glycolysis, glucose becomes pyruvate in the muscle. The participation of this ketoacid (pyruvate) in transamination reactions produce the corresponding amino acid: alanine. Alanine is then transported to the liver, where it can be transaminated again producing pyruvate that can be used for gluconeogenesis yielding glucose that can be send again to the muscle for producing energy (glucose-alanine cycle).

 

The other mechanism for transporting nitrogen in a non toxic form from the muscle to the liver is in form of glutamine. The enzyme glutamine synthase (also present in the liver) catalyses the following reaction:

 

Glutamate + NH3 + ATP ———-à glutamine +ADP + (P)

 

This reaction allows the transportation of nitrogen in a non toxic form to the liver and kidney (this reaction is important for other things, also!). Glutamine is the major amino acid found in the circulatory system, followed by alanine. The role of glutamine in the blood is to carry ammonia to and from various tissues but principally from peripheral tissues like the muscle, to the kidney and liver, where the amide nitrogen is hydrolyzed by the enzyme glutaminase and the ammonia is released, forming H4+ ion. In the kidney, it can be excreted in the urine by direct renal excretion, while in the liver the ammonia released by glutaminase will be used mainly for the synthesis of urea.

 

Note that ammonia arising in muscle and other peripheral tissues is carried in a nonionizable form as alanine or glutamine from to the liver. In these forms, ammonia does not have the toxic properties of free ammonia.

 

 More information ca be found in:

 

Brosnan, J.T.: Interorgan Amino Acid Transport and its Regulation

 

 The medical biochemical page: Nitrogen metabolism

 

 Vey good graphics about the glucose-alanine cycle, can be found in this link.