Dependence of Antiapoptotic Effects of Glutamine on de novo Uridine Biosynthesis

Evans et al. (2005) [Evans et al., 2005: (http://ajpgi.physiology.org/cgi/reprint/289/3/G388)(http://www.ncbi.nlm.nih.gov/pubmed/15878985?dopt=Abstract)] found that the antiapoptotic effects of physiological concentrations of glutamine (GLN) (500 uM) in cultured, colonic epithelial cells were mediated, at least in part, by the capacity of GLN to serve as a precursor for pyrimidine (uridine and the other pyrimidine nucleosides and nucleotides derived from it) biosynthesis. One thing that's interesting is that the GLN-induced maintenance of pyrimidine nucleotide concentrations did not depend on transcription or on DNA replication, and it's possible that the maintenance of the pyrimidine pool maintained glucose uptake by maintaining UDP-hexosamine-dependent glycosylation reactions, etc. These results don't mean that GLN didn't partially prevent apoptosis by serving as a precursor of 2-oxoglutarate and the TCA cycle intermediates that are formed from the entry of 2-oxoglutarate into the TCA cycle. The results just mean that the maintenance of a pyrimidine pool can be an obligatory condition for the prevention of apoptosis in response to certain apoptotic stimuli. The fact that inosine, at millimolar concentrations, could prevent apoptosis in those experiments shows that ribose-5-phosphate and hypoxanthine, derived from inosine, can help maintain the ATP and PRPP, etc., that are required for pyrimidine salvage and de novo pyrimidine formation and for other antiapoptotic effects.

One interpretation of that article is that glutamine, taken at excessive dosages in people who have chronic liver disease or other inflammatory conditions, could exacerbate liver disease or other disease processes that are characterized by impairments in mitochondrial functioning. Orotate, an intermediate in uridine biosynthesis, can be used to induce fatty liver disease in animals, in part by depleting ATP and purine nucleotide levels [see here: (http://hardcorephysiologyfun.blogspot.com/2009/08/some-more-old-papers-of-mine.html)]. GLN is a substrate of type II (cytosolic) carbamoyl phosphate synthase ["glutamine-utilizing carbamoyl phosphate synthase (CPS-II)], and there would mainly be an accumulation of cytosolic carbamoyl phosphate (CP) in people exhibiting impairments in the overall activity of the urea cycle, such as in chronic liver disease. In the context of a trauma or other acute injury that can increase glutamine turnover, there probably wouldn't be the kind of damage to the mitochondria that would cause mitochondrial CP to be exported to the cytosol and cause orotate formation to increase pathologically. But mitochondrial dysfunction could be expected to cause orotate and dihydroorotate to accumulate, given that dihydroorotate dehydrogenase is a mitochondrial enzyme whose activity can be impaired in mitochondrial disorders. Szondy and Newsholme (1989) [Szondy and Newsholme, 1989: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1138925&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/2803258)] noted, however, that only something like 0.4 percent of the glutamine that's utililzed (the Km of GLN for glutamine utilization overall, by all pathways, is 2.5 mM) in proliferating lymphocytes goes toward pyrimidine biosynthesis, and the Km of glutamine for binding to CPS-II is 16 uM. That implies that the rate of pyrimidine biosynthesis is unlikely to be sensitive to increases in GLN availability. Also, Evans et al. (2005) used 500 uM GLN to prevent apoptosis, and the plasma GLN concentration and, hence, extracellular fluid GLN concentrations are around 400-600 uM in humans. But the regulation of pyrimidine biosynthesis may not always be normal or comparable in other tissues or individuals, and that's another reason not to use excessive dosages. Ammonia derived from GLN deamidation could also contribute to adverse effects in some cases, but one would mainly expect to see that in some disease states.