Another explanation for ammonia inhibition comes from detailed studies on various ribonucleotides by Ryll and Wagner (128) and Ryll et al. (129). The intracellular pools of UDP-A-actylglucosamine (UDP-GlcNAc) and UDP-A-actylgalactosamine (UDP-GalNAc) have been shown to be responsible for inhibition of protein, DNA, and RNA synthesis (129-132). The pool of UDP-GNAc refers to both UDP-GlcNAc and UDP-GalNAc collectively, and it was demonstrated to be elevated in response to increased ammonia levels for a variety of cell lines. Ammonia is incorporated into the glycolytic pathway in cytosol (Fig. 7). Fructose-6-phosphate and ammonia combine to form glucosamine-6-phosphate, a direct precursor for the UDP-GNAc pool in the cytosol. In the mitochondria, ammonium leads to formation of carbamoylphosphate. When the ammonia concentration is high in the mitochondria, then subsequently up-regulated carbamoylphosphate can enter the cytoplasm. Carbamoylphosphate in the cytosol stimulates de novo synthesis of UMP and UTP. Finally, UTP and glucosamine-6-phosphate are combined to supplement the UDP-GNAc pool.
Figure 7. Biosynthesis of UDP-GNAc pool after ammonia application. Source: Adapted from Ryll et al. (129).
Ryll et al. (129) studied the biochemistry of the UDP-GNAc pool formation and regulation of the enzymes involved. The formation of the UDP-GNAc pool was observed to be dependent on both glucose and ammonia. Ammonia increases the size of the UDP-GNAc pool, which has been correlated with growth inhibition. It is also important to note that the UDP-GlcNAc is also known as a precursor substrate for glycosylation processes in the endoplasmic reticulum and Golgi. Thus, the effects of ammonia on glycosylation could also be explained by this mechanism (101,102).
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