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During exercise there is an exceptionally high demand for energy in the body. Nerves have to carry impulses, these signals need to be transferred to muscle fibres which in turn need to contract. All these processes need to happen at millisecond second speeds all the while all the other normal cell processes, also needing energy, need to be carried out. As a massive energy consumer, various pathways exist to supply the muscle cells with the required energy in the form of ATP including glycolysis, the citric acid cycle and fatty acid oxidation .
Two other mechanisms also exists to facilitate the production of ATP. These are the purine nucleotide cycle  and the breakdown of amino acids as an energy source . Besides the benefits they bring in terms of ATP production, the both have one disadvantage. The production of ammonia.
Ammonia is a corrosive base and considered a waste product in the body. In large quantities is is toxic for the body and contributes to central fatigue . It is therefore important to get rid of ammonia to avoid these negative effects.
Various mechanisms exist for the transport of ammonia from the muscle cells to the liver, where it is detoxified in the urea cycle. Other mechanisms for the removal of ammonia from the body also exist.
In this seminar we will discuss the mechanisms whereby ammonia is produced as well as the various transport, detoxification and excretion mechanisms.
The Purine Nucleotide Cycle
The purine nucleotide cycle (PNC) is a major source of ammonia production during exercise. Studies suggest that during intense, short-duration exercise the PNC is most active and mostly responsible for ammonia production. This cycle has the important function of helping to maintain the [ATP]/[ADP] at a high level during exercise. It does this by removing AMP from the cell by deamination, thereby favouring the production of ATP through the adenylate kinase reaction. The purine nucleotide cycle also provides citric acid cycle intermediates through the production of fumarate . The one great disadvantage of this cycle is the production of ammonia in the first reaction of the cycle.
The PNC consists of three reactions that occur in the cytoplasm of all cells with nuclei. This includes the muscle cells where it is particularly active during exercise.
The first reaction in the cycle involves the deamination of AMP to IMP and is also responsible for the production of ammonia. The reaction is catalysed by the enzyme AMP deaminase. This enzyme is activated by AMP and acidosis of the muscles, while being inhibited by inorganic phosphate and GTP during rest . Therefore one can deduce that as ATP is being hydrolysed at a rapid rate during exercise, the increase increase in proton concentration  in the muscles leading to higher levels of acidosis will increasingly stimulate this reaction. This leads to increased ammonia production rate as exercise continues and as exercise intensity increases.
The Second reaction of the PNC converts IMP and aspartate to adenylosuccinate. It uses GTP as an energy source and is catalysed by the enzyme adenylosuccinate synthase.
Finally adenylosuccinate is recycled to AMP via the enzyme Adenylosuccinate lyase. This reaction also leads to the formation of fumarate, an Citric acid intermediate. This reaction therefore fulfils the second function of the PNC by supplementing the CAC with this intermediate. Fumarate is also an important intermediate in the urea cycle, which will be discussed later on in this seminar.
This cycle may seem somewhat futile as its main function is to reduce AMP levels, but one must remember that not all the reactions in the cycle will take place at the same rate as they depend on different substrates. The second reaction, for example, requires both GTP and aspartate in addition to IMP to continue. Therefore it may continue against a much slower rate than the reaction catalysed by AMP deaminase. AMP deamination therefore probably takes place at a faster rate than AMP regeneration. This has been suggested by previous reports of a relationship between IMP accumulation and increases in ammonia concentration in the muscles .
The reaction that benefits from the removal of AMP is the adenylate kinase reaction. This reaction involves the conversion of two molecules of ADP to ATP and AMP. It is important that the [ATP]/[ADP] ratio is kept high, as this is the function of this reaction, but this is obviously unfavourable for the production of ATP through this reaction. Therefore the only way to favour the production of ATP through this reaction without affecting the [ATP]/[ADP] ratio is by keeping the [ADP]/[AMP] ratio high as well . Keeping this in mind, the benefit of the PNC is very clear as it facilitates this goal.
Amino Acid Breakdown
Branched chain amino acids are another source of ammonia during exercise. In 1995, van Hall et al  concluded that, as ammonia production exceeded IMP production during prolonged moderate exercise, the PNC is not always the main producer of ammonia.
Branched chain amino acids can be deaminated. Deamination takes place during a transaminase reaction, which will be discussed later on. The BCAAs' carbon skeletons can be converted into citric acid cycle intermediates or substrates such as Succinyl CoA and Acetyl CoA. This process of converting carbon skeletons into CAC intermediates require several reactions. The first reaction, after deamination, being oxidative decarboxilation of the Î± keto acid to produce Acyl CoA. Branched chain amino acid breakdown can therefore be considered anaplerodic.
Ammonia is transported out of the cell and into the blood in a few different forms. Ammonia can be transported as the amino groups of amino acids, specifically alanine and glutamine. It can also be transported without any modification as ammonia or as ammonium ions.
Amino Acid transport
The amino acids alanine and glutamine are particularly important for the transport of ammonium in the the blood. Glutamine has two nitrogen atoms in its structure, both potentially originating from ammonium produced during exercise. Alanine, on the other hand, only has one amino group. Both alanine and glutamine arise though reactions where glutamate plays a central role.
As glutamate plays such a central role in the removal of ammonia we will first briefly discuss the production of glutamate, which also involves the utilisation of ammonia. Î± Ketoglutarate and an ammonium ion are involved in a reaction that produces one molecule of glutamate. This reaction is catalysed by the enzyme glutamate dehyrogenase. This is potentially the first reaction in the amino acid transport mechanism of ammonia where ammonia is incorporated into another molecule.
Glutamine can be produced through two different reactions, both involving glutamate. In the first reaction glutamate and an ammonium ion react to produce one molecule of glutamine in a reaction catalysed by the enzyme glutamate synthase. One can clearly see that this reaction is superficially similar to the glutamate dehydrogenase reaction as it involves the simple incorporation of an ammonium ion into another molecule to produce an "ammonium carrier".
The second mechanism whereby glutamine can be produced is through the reaction catalysed by glutamate synthase. During this reaction, which involves two molecules of glutamate, the amino group of one molecule of glutamate is transferred to the other. This leads to the production of glutamine and Î± ketoglutarate.
Alanine is also an important ammonia carrier. It only carries one nitrogen atom, but it has one advantage and that is the abundance of substrate for its production. Pyruvate is the Î± keto acid of alanine and during both aerobic and anaerobic glycolysis an abundance of pyruvate will be produced. A simple transaminase reaction between pyruvate and glutamate catalysed by the enzyme alanine transaminase is responsible for the transfer of an amino group from the glutamate to pyruvate. It produces alanine and Î± ketoglutarate, which is now free to undergo another glutamate dehydrogenase reaction.
Glutamine and alanine are now transported out of the muscle cells and into the blood.
Ammonia and Ammonium Ion Transport
Ammonia (NH3) is a highly soluble molecule and can easily pass through cellular membranes to end up in the blood. It is, however, also a weak base with a pK of 9.3. This means that at pH values in the physiological range, ammonia will mostly exist as ammonium ions (NH4+). These can not pass the cell membranes as readily as they are charged.
In red blood cells the Rh complex is responsible for the transport of ammonium ions out of the red blood cells. Rh homologues have also been implicated as transporters for ammonium in other tissues as well. This may indicate a possibility of an Rh complex homologue being responsible for the transport of NH4+ out of exercising muscle cells.
The easy transport of NH3 out of the muscle cells may also shift equilibrium slightly in favour of ammonia instead of ammonium ions. This means when ammonia moves out of the cells into the blood, where there is a low concentration of ammonia, a few ammonium ions in the cells will convert to ammonia to fill the void left by the exit of the ammonia. These ammonia molecules will in turn also exit from the cells via the membrane, so continuing the cycle. This theory is, however, purely speculative.
As exercise continues and ammonia is transported out of the muscle cells, the concentration of ammonium ions, glutamine and alanine in the blood rises. Unless these substances are removed by some mechanism, they could still have a toxic effect for the body. This will mean that all the effort of transporting ammonia out of the muscle cells would have been an exercise in futility.
Therefore the body has a method for the detoxification of ammonia by the urea cycle in the liver. Ammonia can also be excreted through the skin and in urine.
The Urea Cycle
The urea cycle was discovered by Hans Krebs and Kurt Henseleit in 1932. It takes place chiefly in the liver and uses ammonia and bicarbonate as substrates and produces urea as an end product. This cycle also has quite a few intermediates and has some reactions taking place in the mitochondria and some in the cytoplasm.
The ammonia needed for the cycle is produced from the amino acids glutamine and alanine. Glutamine is hydrolytically cleaved by the enzyme glutaminase to produce glutamate and ammonia. This reaction is not unlike the reverse of the glutamine synthase reaction previously described. The alanine on the other hand undergoes the exact reverse of the transaminase reaction that produced it in the muscle cells. The pyruvate produced by this reaction can now undergo gluconeogenesis, providing the body with with glucose that can either be used or stored in the form of glycogen. The glutamate produced by these reactions can now undergo the reverse of the glutamate dehydrogenase reaction, producing ammonia and Î± ketoglutarate .
The first reaction in the urea cycle produces carbomyl phosphate. This reaction requires the investment of two molecules of ATP as well as one carbon in the form an bicarbonate ion. This illustrates how important the removal of ammonia is as the body is willing to make a relatively large sacrifice in terms of energy and carbon to detoxify ammonia.
Carbomyl phosphate combines with ornithine to form citrulline to enter the urea cycle. This reaction is catalysed by the enzyme ornithine transcarbamoylase. The exact specifics of this cycle is not of importance for this seminar, but it is important to note that another ammonia gets incorporated into this cycle in the form of aspartate. Aspartate is formed from a transaminase reaction between oxaloacetate and glutamate. Oxaloacetate can be produced by a series of reaction from fumarate.
The urea produced contains two nitrogen atoms and is very soluble. It can therefore easily enter the bloodstream and be transported to the kidneys where it is excreted.
With high levels of ammonia in the bloodstream on body the urea cycle takes place at a rate that is too slow to detoxify ammonia fast enough. Ammonia, being soluble can be dissolved in sweat and be excreted through the skin. It can also be excreted though the kidneys and end up in urine.
After exercise the PNC will again be inhibited as the demand for energy decreases. The same counts for BCAA breakdown, as the CAC will turn at a slower rate as there is a lower demand for energy in the muscles. There will, however, still be large amounts of ammonia, glutamine and alanine in the blood.
The urea cycle will still be active to remove the excess ammonia from the body, but because amino acids were used during exercise as ammonia carriers and to supplement the CAC they will have to be regenerated. Pyruvate, produced through the deamination of alanine, can be used as a precursor for branched chain amino acid synthesis. Glutamate that was lost from the muscle cells will be replaced . AMP will be regenerated to pre-exercise levels as well.
The body has a high energy demand during exercise. The fulfilment of this demand is achieved through complex supply systems that are optimised for instant satisfaction, but that are not without their flaws. These systems create a logistics nightmare of having to transport large amounts of waste products, processing these wastes and eventually having to completely remove them from the body. This is not simplified by the fact that after exercise has ceased, the body needs to restore what was lost during its energy spending spree. Amino acids and purine nucleotides, both essential for human life have to be restored.
The body is, however, not ill-equipped for these tasks. It handles it with great resilience, allowing itself to return to normal not long afterwards. This is another great example of how the human body is fine-tuned to meet its own needs under a variety of circumstances.