Proteins & Amino Acids / How the Liver Works

Nitrogen Metabolism

In our discussion of amino acid metabolism we concentrated on the use of amino acids in synthesis of new cellular proteins and the way in which the various carbon skeletons derived from amino acids could be used to support energy production in the peripheral tissues and the synthesis of glucose in the liver.

I. Overview

Recall that in addition to the carbon structures, as indicated by their name, amino acids also contain an amino group (NH2.) During the breakdown of amino acids, this amino group raises certain problems for the cell.

The simplest way to deal with the amino group would be to remove it from the amino acid directly, releasing the nitrogen as free ammonia (NH3). Unfortunately, ammonia is extremely toxic and would quickly kill the organism if not promptly removed. Fish are the only members of the animal kingdom to excrete nitrogen in this way. Since they are surrounded by water, they can convert the amino acid amino group to ammonia, release ammonia to the blood, and excrete the ammonia into the surrounding water. Fish circulate blood through the delicate structures of the gills where the blood and water come into close contact. The gills simultaneously carry out two processes. One is obtaining oxygen from the water, the other is releasing ammonia to the water.

Land dwelling animals must deal with nitrogen in a completely different way. Mammals avoid the production of toxic ammonia by converting the amino group into a water soluble non-toxic compound known as urea. Urea is a compound in which two amino groups are attached to a single oxidized carbon atom (CO).

Again the liver plays a central role in metabolism because the synthesis of urea occurs only in liver cells. Once synthesized, urea is released from the liver to the blood and transported to the kidneys where it is concentrated and released from the body in the urine.

II. Nitrogen Metabolism in the Fed State

As described above, free amino acids are obtained by breaking down dietary protein and enter the blood for transport throughout the body. We have seen that the carbon skeletons of excess amino acids are used either as fuel or are converted to fat.

The first step in the breakdown of excess amino acids involves the removal of the amino group and the production of the first intermediate. Since there are 20 different amino acids, there are twenty different compounds that result from removal of the amino group. These are each degraded through a series of reactions unique to that compound.

If excess amino acid is being degraded in a peripheral cell or tissue, the amino acid must be transferred to the liver so that the nitrogen can be converted to urea and excreted from the body. The removal of the amino group from an amino acid is achieved by first transferring the group to an acceptor molecule. There are several possible acceptors, but the bulk of the nitrogen is transferred to a three carbon intermediate formed during the breakdown of glucose.

Here you can see that, once again, glucose is playing a central role in whole body metabolism. This intermediate, pyruvate, is converted to a three carbon compound known as alanine. Alanine is released to the blood and transferred to the liver. In the liver, the nitrogen is moved to another acceptor molecule, regenerating pyruvate. Pyruvate can be used as a precursor for glucose (can enter gluconeogenesis.) It is easy to see a cyclical process (known as the Alanine Cycle) in which the newly synthesized glucose is released from the liver to the blood, transported to the peripheral tissue where the glucose is reconverted to pyruvate, the pyruvate converted once again to alanine and released to the blood to carry nitrogen to the liver where pyruvate is formed, supporting the production of glucose. The net effect of the alanine cycle is to move amino groups from peripheral tissue to the liver with the regeneration of the intermediates needed to carry more amino groups.

Excess amino acid can also be metabolized by liver cells. In this instance there is no need for nitrogen transport since the liver cells can make urea themselves. In the fed state, the carbon skeletons derived from the amino acids enter the TCA cycle (directly or indirectly) where they are either used as fuel (oxidized to CO2) or the excess calories they provide are stored as fat (converted to citrate and then to triglyceride - see above).

III. Nitrogen Metabolism in the Fasting State

Most of the nitrogen in the body is in the form of amino groups on amino acids making up protein molecules. We have seen that the bulk of the bodyÕs protein, particularly the protein that is broken down during fasting, is contained in peripheral tissues.

Once again, if amino acids are to be used as fuel, or to support the TCA cycle so that fat can be used as fuel, it is essential to transport the amino groups to the liver so that toxic nitrogen can be converted to non-toxic urea, released to the blood and then concentrated and excreted by the kidneys.

Transport is achieved by two mechanisms. The first, of central importance to the peripheral tissue itself, is the Alanine Cycle described above. The second, of central importance to the whole body, is the release of free amino acids from the peripheral tissues to the blood. Once in the blood, these amino acids can serve the full range of functions that we have discussed. They can be used directly to support the synthesis of needed protein by all of the body's tissues. They can be taken up by other cells and converted to TCA cycle intermediates (nitrogen transport from these cells to liver will be required, the Alanine Cycle again being significant.) Finally, they can be taken up by the liver and excess amino acid converted to glucose (gluconeogenesis) for release to the blood and the support of whole body metabolism.