Principles of Biochemistry, Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
Oxidative Degradation of Amino Acids. The Urea Cycle
Ammonia is toxic to animals

Earlier we interrupted our Structure/133.html">Discussion of Amino Group METABOLISM to examine The breakdown of deaminated Amino Acids acting as an energy source. Let us now return to where we left off and examine The Fate of ammonia, which is produced by the Oxidative Deamination of glutamate catalyzed by Glutamate dehydrogenase—a process taking place in virtually all Tissues. Here we encounter a serious biochemical problem, because ammonia is an extremely toxic substance, particularly hazardous to the Brain. Ammonia is so toxic that injecting even a very dilute solution into an animal can induce coma.

The reason for such a drastic effect of ammonia on the brain is not yet fully understood. The explanation likely lies in two main factors. 1) Ammonia has a very high pK' value; consequently, at Blood pH, it exists almost entirely as the ammonium ion (NH⁺₄). NH₄ ions cross plasma and mitochondrial membranes with great difficulty. In contrast, neutral free ammonia molecules (NH₃) readily diffuse across these membranes. Although at a blood pH of 7.4 free ammonia accounts for only about 1% of the total amount, this free ammonia crosses the membranes and enters brain Cells, as well as their Cell/35.html">Mitochondria. 2) Once inside the mitochondria of brain cells, ammonia reacts with a-ketoglutarate to form glutamate; this reaction is simply the reverse of the glutamate dehydrogenase reaction:

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The ultimate result is a depletion of a-ketoglutarate from the pool of Citric Acid Cycle intermediates in brain mitochondria, leading to a decreased rate of glucose oxidation, which serves as the primary fuel for brain cells. Both of these factors are undoubtedly very important, but there are clearly other, as yet insufficiently understood reasons for the brain's high sensitivity to ammonia.