Alteration of Ribonucleotide Pools

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.

CP Frc-6-P

UMP Uridine

UDP-GlcNAc t


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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