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Lecture title: 12.09.08: Amino Acid Metabolism (Nitrogen Metabolism)
Lecture author: Robert Lyons

Powerpoint here

Handout:

I. Protein degradation/Nitrogen balance

A. Cells constantly turn over proteins

It's a normal process, balanced by protein intake.
Proteins can be degraded if they are:
damaged by free radicals
oxidative damage
misfolded
no longer needed.

B. "Nitrogen Balance" expresses the balance between anabolism and catabolism

1. Measured by assessing dietary N intake vs urinary N output (as urea)

2. "Positive" nitrogen balance (net storage of nitrogenous compounds):

childhood growth
pregnancy
muscle building
healing

3. "Negative" nitrogen balance (net breakdown of stored nitrogenous compounds):

illness
uterine resorption
starvation
amino acid deficiency
wounding

4. In negative nitrogen balance, the liver may be taxed in handling excess nitrogenous waste. We will revisit this when we discuss pathologies of the nitrogen disposal pathways.

II. AA catabolism - Separate the amino moiety, carbon skeleton:

A. Dealing with the amine: convert to urea or re-utilize:

1. transaminated to a-ketoglutarate forming an a-keto acid and glutamate.

In peripheral tissues, catabolism of amino acids tends to form glutamate (i.e. a-ketoglutarate is the preferred N-acceptor)

2. The amino group on glutamate can be transferred back to another keto-acid if needed by reversing the above reactions. A specific enzyme in liver mitochondrial matrix (Glutamate-aspartate aminotransferase) catalyzes exchange of amine groups between glutamate and aspartate. (Reaction depicted further down)

3. To discard, the amino group in glutamate is transported to the liver via glutamine:

a. Release amino group as ammonia (enzyme: glutamate dehydrogenase, oxidative deamination):

b. Incorporate the ammonia on a separate glutamate to form glutamine (enzyme: glutamine synthetase):

c. Glutamine passes through cell membranes via a variety of transports mechanisms, and into the bloodstream, to be taken up by other tissues, most notably (for the purposes of the current discussion) the liver.

d. In the liver, the enzyme glutaminase releases ammonia by hydrolysis of glutamine, leaving glutamate (also occurs in kidney and intestine).

The glutamate can go on to form aspartate, via glutamate-aspartate aminotransferase:

e. The urea cycle (only in liver) makes amine moieties into urea for excretion

Executive Summary: Amine groups are assembled onto ornithine (which essentially acts as a 'handle'), and they are ultimately cleaved off as Urea (releasing the ornithine again). This occurs in the liver, partly in the mitochondrial matrix and partly in the cytoplasm.

Key amino compounds entering the Urea Cycle:

Aspartate (typically from transamination of oxaloacetate; see IIA2 and IIA3d, above)

Ammonia, which may come from many sources, especially hydrolysis of glutamine (see IIA3a, above) and oxidative deamination of glutamate (see IIA3d, above). See also breakdown of purines, in a later lecture.