Abbreviated Posting on Carbamoyl Phosphate Synthetase II and Nucleotides

This is a really good article [Shambaugh, 1979: (http://www.ajcn.org/cgi/reprint/32/6/1290.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/35970)], and the author cites research showing that the administration of either exogenous purines (nucleotides of adenosine, guanosine, or inosine) or exogenous pyrimidines (nucleotides of uridine or cytidine or both), given separately, has been shown to suppress carbamoyl phosphate synthetase II in various cell types (discussed on the last two pages). The author also goes over other mechanisms by which an excess of purines could produce depletion of pyrimidine nucleotides, such as uridine, by inhibiting uridine biosynthesis in the de novo pathway (which is dependent on glutamine and can be influenced by glutamine availability). This would be beneficial, to a certain extent, because an excess of carbamoyl phosphate, which is known to be exported from the mitochondrial pool (which is usually compartmentalized, in liver cells, so as to only be available for entry into the urea cycle) when the urea cycle cannot dispose of ammonia rapidly enough, tends to lead to an increase in the production of orotate. Orotate (a.k.a. the conjugate base of orotic acid) is normally a precursor of uridine, but inhibition of mitochondrial respiration is known to prevent uridine formation from dihydroorotate and to be associated with orotate accumulation. Orotate is well-known to be capable of inducing ATP depletion and fatty liver disease, and there are countless articles showing that dietary arginine depletion can, over the long term or under conditions of metabolic stress or glucocorticoid resistance (chronically-elevated glucocorticoid production tends to increase the activities of the urea cycle enzymes, and this eventually can put a strain on the capacity of the liver to maintain its arginine pool from dietary sources and endogenous biosynthesis from glutamate, via arginase and ornithine delta-aminotransferase), lead to fatty liver disease by elevating orotate levels (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=arginine+orotate+OR+orotic). That second article in the list is a bad one, in my opinion, but I don't have time to go through it. I actually don't have time to finish this posting now.