There are lots of interesting articles that have shown the roles that glutamine (GLN)-mediated increases in the O-glycosylation, with beta-N-acetylglucosamine, of serine and threonine residues on proteins can play in mediating either the protective effects or undesirable effects of GLN (http://scholar.google.com/scholar?q=glutamine+hexosamine+ischemia&hl=en). GLN is a substrate of glutamine: fructose-6-phosphate amidotransferase (GFAT), and that enzyme forms glucosamine-6-phosphate and glutamate [Broschat et al., 2002: (http://www.jbc.org/content/277/17/14764.full)(http://www.ncbi.nlm.nih.gov/pubmed/11842094?dopt=Abstract)]. In any case, the overall point is that some of the GLN-mediated protection against damage due to ischemia have been shown to be a result of the augmentation of hexosamine formation by GLN (see that first search), but I've also seen articles showing that GLN can sometimes worsen the course of experimental fatty liver disease or the courses of other disease states, in animals, in which insulin resistance features prominently. There's a large amount of research showing that glucosamine can cause insulin resistance in animals (http://scholar.google.com/scholar?hl=en&q=glucosamine+liver+OR+insulin+OR+ATP) and other undesirable effects, but, under normal circumstances, I remember reading that only about 3 percent of the intracellular GLN in cells in the liver is metabolized into glucosamine. As I've discussed in past postings, the formation of uridine diphosphohexosamines can sometimes sequester large amounts of uridine in ways that is undesirable, in animal models of liver disease, and GLN can also serve as a substrate for de novo uridine biosynthesis. That's not generally something that one wants to accelerate in an unregulated way. But my point would be that, at reasonable dosages, the formation of glucosamine or carbamoyl phosphate, as a precursor of orotate and uridine, from GLN would be processes that would be subject to substantially more regulation than the formation of hexosamines and orotate from exogenous glucosamine and...orotate would be.
Another important point is that it's necessary to take into account the potential for GLN-mediated decreases in glutamine synthetase (GS) activity, with regard to the supposed ATP-sparing effects of that suppression, to occur and to consider the effects of GLN-derived 2-oxoglutarate on mitochondrial ATP formation. One can say that the effects of GLN are mediated by glycosylation during ischemia, but how was the uridine pool preserved during ischemia? The GLN-mediated preservation of ATP could indirectly preserve the UDP-N-acetylglucosamine and overall UDP-hexosamine pools during ischemia, given that ATP depletion tends to lead to loss of pyrimidine nucleosides, either by export or degradation. That's only one example. Not surprisingly, there's actually some research showing that some of the protective effects of uridine in cultured astrocytes, or something like that, are mediated by glycosylation of various proteins, and I remember downloading a paper that shows that glycosaminoglycan formation is more sensitive to increases in uridine availability than other UDP-sugar-dependent or UDP-hexosamine-dependent glycosylation reactions are. Again, however, one has to consider the increases in glucose uptake that exogenous uridine can produce. Did the uridine-induced increases in protein glycosylation exert protective effects by increasing the glucose uptake, or did the uridine-induced increases in glycogen formation, in the face of increase in glucose uptake by other mechanisms, buffer ATP levels and thereby maintain the normal, relative amounts of different UDP-hexosamines that are required for glycosylation reactions that produce other protective effects? Similarly, one can't look at an article on GFAT overexpression in mice, see a lot of adverse effects, and conclude that GLN is going to produce the same effects as GFAT overexpression will (for the reasons I discussed above, involving energy metabolism, primarily). But another important point is that, in some of those articles using high doses of GLN, one has to consider the cumulative, potentially-depleting effects of GLN-induced hexosamine and UDP-hexosamine formation on the intracellular and even plasma inorganic phosphate pools. I have at least one article showing that exogenous uridine can deplete the inorganic phosphate pool, and I'll try to put it up. Another thing to consider would be the use of uridine, glutamine, and inorganic phosphate in some sort of combination approach. The uridine could suppress de novo pyrimidine biosynthesis and avoid some of the undesirable effects of a high rate of de novo pyrimidine (uridine) formation (as discussed in past postings, orotate has tended to lead to ATP depletion in animal experiments) and also prevent the sequestration of uridine, some of which is obviously required for glycogen formation, in UDP-hexosamines. But the goal, in my opinion, should really be to normalize the availability of GLN to the brain or skeletal muscles, in order to prevent unnecessary exercise-induced ATP depletion, etc. There can be a significant increase in ATP turnover in the brain and, obviously, skeletal muscles during high-intensity exercise. That's separate, to a large extent, from the issue of ischemia.
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