This article [Yamauchi et al., 2002: (http://www.ncbi.nlm.nih.gov/pubmed/11934546)] is interesting, and the authors found that exogenous arginine supplementation only increased cell proliferation, in cultured epithelial cells, when extra glutamine was also added. The effects of arginine+glutamine occurred largely through the capacity of glutamine to serve as a precursor for purine and pyrimidine nucleotides formed by their respective de novo biosynthetic pathways. Glutamine has been shown to specifically enhance de novo purine biosynthesis in the same cell line that Yamauchi et al. (2002) used (Caco-2 colonic epithelial cells) [Boza et al., 2000: (http://www.ncbi.nlm.nih.gov/pubmed/10900556)]. The influence of glutamine availability on de novo uridine (pyrimidine) biosynthesis is more well-known, but the main point of Yamauchi et al. (2002) is that glutamine alone was less effective in supporting cell proliferation than was the combination of glutamine and arginine together. The authors found that the presence of extra arginine reduced the conversion of glutamine into arginine, via the conversion of arginine into glutamate. Glutamate did not substitute for glutamine in these experiments, and that's what one would expect (given, in my opinion, the ATP requirement for the conversion of large amounts of glutamate into glutamine, as discussed by researchers). There could be some ATP buffering in response to exogenous glutamate, under some circumstances, given its potential to be converted into alpha-ketoglutarate, for example, and help to maintain the pools of tricarboxylic acid cycle intermediates. But the glutamate would have to be converted into glutamine to serve as a precursor of purines or pyrimidines.
Yamauchi et al. (2002) also found that exogenous nucleotides "spared" glutamine, as would be expected, by reducing its incorporation into nucleotides formed by the de novo pathways. This glutamine-sparing effect of exogenous nucleotides has been shown in other articles, and researchers would usually attribute this to the standard mechanisms by which purines or pyrimidines suppress their respective de novo biosynthetic pathways, by allosteric effects. But the author of that article I cited in my last posting was referring to "nonstandard" mechanisms by which exogenous purine nucleotides could deplete pyrimidines from different cell types. Two mechanisms that Shambaugh (1979) [(http://hardcorephysiologyfun.blogspot.com/2009/02/abbreviated-posting-on-carbamoyl.html)] mentioned are the inhibition of uridine kinase by purines and the inhibition of the cell-cycle-associated upregulation of carbamoyl phosphate synthetase II (CPSII) by purines. Traditionally, only uridine nucleotides have been thought to exert feedback suppression of de novo uridine formation, by inhibiting CPSII activity.
The interesting point that shows up in one of the graphs in Yamauchi et al. (2002) and in the results of Boza et al. (2000) is that exogenous nucleotides can't substitute for glutamine in some cell types, and the enhancement of cell proliferation that occurs in response to exogenous nucleotides tends to "plateau" in some cell types. One might suppose that it's the high rate of de novo nucleotide biosynthesis that accounts for this, but Yamauchi et al. (2002) note that Caco-2 cells have a low capacity to produce nucleotides by the de novo pathways. But Boza et al. (2000) found that glutamine (or, more specifically, if one takes the results of Yamauchi et al. (2002) into account, glutamine+arginine) could increase the retention of exogenous nucleotides by enhancing the activities of nucleotide salvage enzymes (presumably by providing tricarboxylic acid cycle intermediates or by conversion into glucose, etc.). One way of explaining that is the fact that nucleotide biosynthesis increases dramatically at specific points in the cell cycle, and exogenous nucleotides could enter cells in one part of the cell cycle and then be exported and act, extracellularly, on plasma membrane adenosine or purinergic receptors and regulate the cell cycle in aberrant ways (or be converted into uric acid, etc.). I have an article that talks about that, the fact that glutamine is used as a source of glucose or tricarboxylic acid cycle substrates most of the time, in proliferating lymphocytes, but then becomes crucially important for pyrimidine biosynthesis at specific points in the cell cycle. The toxic effects of excessive amounts of purines on lymphocytes used to be explained in terms of the conversion of adenosine into deoxyadenosine, which can inhibit ribonucleotide reductase (thereby inhibiting DNA replication) and S-adenosylhomocysteine hydrolase (thereby interfering with one-carbon metabolism and nucleotide metabolism in other ways). But, in the context of supplementation in humans without known genetic defects in adenosine deaminase activity (as in severe combined immunodeficiency), other mechanisms could produce undesirable effects, in my opinion, at high doses, and some of the effects could be independent of hyperuricemia.
But one key point that comes out of these articles is that glutamine and arginine could be used, in my opinion, to reduce the therapeutic dosages of nucleotides, in the context of the conditions that exogenous purines or pyrimidines have been used or researched in the treatment of. The suppression of CPSII by purines would not be completely undesirable, however, given that the excessive activation of de novo pyrimidine biosynthesis can lead to orotate accumulation, and orotate tends to exert many toxic effects. It's used in one animal model of fatty liver disease and can produce ATP depletion in other cell types. Orotate is an intermediate in uridine biosynthesis. Glutamine could also increase AICAR levels, and reduced folates, in combination with methylcobalamin, could be useful as strategies to ensure that AICAR does not accumulate in the presence of exogenous glutamine and arginine. Folates have also been shown to reduce orotate accumulation [Van der Weyden et al., 1979, cited here: (http://hardcorephysiologyfun.blogspot.com/2009/01/purines-and-orotic-acid-in-porphyrias.html)] in proliferating cells, but I don't know what the mechanism is. Another implication is that some of the neuroprotective effects of uridine or purines, such as guanosine and adenosine or inosine, may be due to the "sparing" of the intracellular glutamine pools in cells in the brain (via the suppression of CPSII and via the standard mechanisms exerted by purines, which are the suppression of PRPP synthetase and amidophosphoribosyltransferase activities), thereby maintaining the pool of tricarboxylic acid cycle intermediates or supporting glycolysis by ribose-5-phosphate-independent mechanisms, etc.
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