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Nitrogen Transport (Glutamine Synthesis, Glucose/Alanine Cycle)

Nitrogen Transport (Glutamine Synthesis, Glucose/Alanine Cycle)

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  • Now, let's learn how the body transports and delivers nitrogenous waste (ie, ammonia) to the urea cycle in the liver:
    • Glutamine synthesis
    • Glucose alanine cycle.

First, let's address glutamine synthesis.

  • So let's add a few key organs (clearly not to scale) to our diagram:
    • Brain, where we'll show the glutamine synthesis reaction.
    • Liver
    • Kidneys
  • Draw-out glutamine so we can remind ourselves that its functional group involves an amino group to underscore that it's an important carrier of nitrogen.
  • Denote that for nitrogen transport (in the periphery), glutamine synthetase is necessary for the creation of glutamine.
  • Denote that for nitrogen liberation (in the liver), glutaminase is necessary (specifically for amide nitrogen (not amino-nitrogen) release.

Let's see how this works with glutamine synthesis and the brain.

  • Show that glutamate is an excitatory neurotransmitter found in high levels in the brain.
    • In too high of levels, however, it can be toxic.
  • So, show that ammonium combines with glutamate to produce glutamine.
  • Indicate that glutamine synthetase catalyzes this reaction with the addition of ATP and that ADP is released along with a phosphate ion.
  • Next, indicate that typically this management involves astrocyte to neuron recycling (remaining within the brain).
    • Astrocyte/Neuron Recycling
  • Glutamate is taken up by astrocytes, converted to glutamine by glutamine synthetase, released, then, taken up by neurons and converted glutamate, and used once again for neurotransmission.

Or it can involve peripheral deamination as follows:

  • Draw the urea cycle in the liver.
  • We include a mitochondrion because the urea cycle involves both mitochondrial and cytosolic compartments of hepatocytes.
  • Include a representation of systemic circulation and show that glutamine is safely transport to the liver via systemic circulation where glutaminase hydrolyzes the its conversion to glutamate and the liberation of ammonium.
  • Show that ammonium enters the urea cycle.

Now, let's focus on the Glucose/Alanine Cycle.

  • Denote that for nitrogen transport (in the periphery), alanine carries nitrogen and is formed as follows: in muscle, glucose converts to pyruvate, which converts to alanine – it carries nitrogen in systemic circulation to the liver.
  • Denote that for nitrogen liberation (in the liver), glutamate dehydrogenase (GDH) acts via oxidative deamination to liberate nitrogen.

Begin in the muscle, where alanine is formed.

  • Start with glycogen, which is the main storage form of glucose.
  • Show that via glycogenolysis, glycogen converts to glucose.
  • Show that via glycolysis, glucose converts to pyruvate.
  • Show that via transamination with ALT as the transaminase, pyruvate receives an amino group from glutamate and becomes alanine.
    • The deaminated glutamate, then, becomes alpha-ketoglutarate.
  • Next, show that alanine leaves muscle to enter systemic circulation and is picked up by the liver.
  • Show that, here, alanine undergoes the standard two-step reaction:
  • Thus, alanine gives up its amino group to alpha-ketoglutarate to become pyruvate.
  • Show that the urea cycle produces urea that exits the body via the kidneys as urine.
  • Finally, show that to make the glucose/alanine cycle a true "cycle", the pyruvate formed in the hepatic transamination converts to glucose via gluconeogenesis, which again is NOT simply the opposite of glycolysis.
    • That glucose, then, enters systemic circulation and can be picked up by muscle and converted to alanine via the aforementioned pathway.
  • Lastly, consider that branched chain amino acids are particularly interesting because they skip first pass hepatic metabolism – meaning they retain their nitrogen.
    • Thus, they are a good source of nitrogen to create alanine and can fuel the glucose/alanine cycle when necessary.