Nitrogen disposal and excretion
While this reaction is straightforward, it produces free ammonia, which is quite toxic and must be kept at low (micromolar) concentrations in the systemic circulation at all times. Therefore, free ammonia is not a suitable medium for ultimate disposal of nitrogen; instead, elimination occurs mostly in the form of urea. The sequence of reactions that incorporates nitrogen into urea is the urea cycle.In liver cirrhosis, one of the main problems is the lacking capability of the liver to detoxify ammonia derived from bacterial metabolism in the large intestine. paromomycin) are used in this condition to reduce bacterial growth and ammonia formation.
Some ammonia is excreted with the urine as well, where it serves to buffer surplus protons also destined for excretion. However, this ammonia is not extracted from the circulation but is formed from glutamine directly in the kidneys.
The glutamate dehydrogenase reaction is reversible in principle, but the affinity of the enzyme for ammonia is low. Interestingly, this enzyme can utilize both NAD+ and NADP+ as cosubstrates. The former is present in the cell most hermes uk ly in the oxidized form, which would favor the release of ammonia, whereas the latter is mostly found as NADPH, which would favor ammonia fixation. It begins with the incorporation of ammonia into carbamoylphosphate by the corresponding synthetase. This reaction occurs in three successive steps. The first step uses ATP to activate bicarbonate to carbonylphosphate, which then captures free ammonia to form carbamate. Another ATP dependent step activates that intermediate to carbamoylphosphate. This reaction yields citrulline.
Citrulline and aspartate form argininosuccinate, catalyzed by argininosuccinate synthetase. This reaction again requires ATP, which is converted to AMP in the process.
Argininosuccinate is cleaved to fumarate and arginine by argininosuccinase.
Urea is released from arginine by arginase, which regenerates ornithine and closes the cycle.
You will have noticed that only one of the nitrogens in urea is accounted for by carbamoylphosphate and, therefore, ammonia. The overall reaction of the urea cycle is
To answer this question, we just need to pull together our previous knowledge about transamination as well as the citric acid cycle. Fumarate is turned into malate and then oxaloacetate in the citric acid cycle, so we can just borrow those reactions. Oxaloacetate can be transaminated to aspartate using glutamate (slide 6.9.2), which in turn acquired its nitrogen by transamination of some other amino acid destined for degradation. In other words, the aspartate simply serves as an intermediate carrier of nitrogen en route from amino acid degradation to urea synthesis.
The network of reactions shown in this slide accounts for the disposal of nitrogen that accrues in amino acid degradation in the liver. As stated at the outset, other tissues also break down amino acids; for example, skeletal muscle metabolizes the lion’s share of branched chain amino acids. Therefore, a mechanism is needed to ferry the nitrogen produced in the peripheral organs to the liver. Ammonia cannot be used as a carrier, since it is too toxic; amino acids are a better alternative. The two most important nitrogen carriers are alanine and glutamine.
is an interorgan cycle that piggybacks on the Cori cycle and accomplishes a net transport of nitrogen from muscle and other peripheral tissues to the liver. Here, pyruvate that is produced from glucose in the periphery is not reduced to lactate as is the case in the Cori cycle, see slide 8.5.3 but instead transaminated to alanine, which is th hermes uk en transported to the liver. There, transamination is reversed, and pyruvate is converted again to glucose by gluconeogenesis. Release of glucose into the bloodstream and renewed glycolysis in the periphery close the cycle.
It can bring about a net transfer of nitrogen from peripheral tissues to the liver in exchange for glutamate. The enzymes involved in the overall scheme are transaminases (1), glutamate dehydrogenase (2), glutamine synthe hermes uk tase (3), and glutaminase (4). The latter two reactions are shown in detail in slide .
If we summarize the network of reactions in nitrogen elimination, we find that glutamate has a very central place in it. Glutamate collects nitrogen from other amino acids through transamination and either releases it as ammonia or transfers it to aspartate in order to feed the urea cycle. Together with glutamine, it also controls the level of free ammonia and accomplishes the transport of nitrogen between organs.
As shown in this scheme, glutamate is formed from glutamine by glutaminase, and it can be turned back into glutamine by glutamine synthetase.The mechanism of glutamine synthetase is shown in slide 2.4.1.
Evidently, both enzymes together would create a futile cycle that would accomplish nothing except ATP hydrolysis. In most organs, only one or the other enzyme has significant activity; for example, glutamine synthetase predominates in skeletal muscle (see slide ), whereas glutaminase is abundant in the kidneys, which use it to secr hermes uk ete ammonium chloride into the urine when eliminating excess acid.