Folic Acid, Ribose, Megaloblastic Anemia, and Neuroprotective Effects of Nucleotides

Here's an article on thiamine-responsive megaloblastic anemia:

http://bloodjournal.hematologylibrary.org/cgi/content/full/102/10/3464-a

This is interesting because there may be some relationship to the effects of folic acid on glucose metabolism. The most well-studied abnormality in folate deficiency is megaloblastic anemia. Thiamine (vitamin B1) (more specifically thiamine diphosphate) is a cofactor for transketolase, which is part of the nonoxidative pentose cycle that cycles ribose-5-phosphate with other pentose sugars. The low transketolase activity in people with this genetic disorder is due to an impairment in thiamine transport (their cells can't transport thiamine normally, and this decreases transketolase activity) that can sometimes be overcome by taking extra thiamine. This would not be true in a normal person, however, and transketolase activity wouldn't keep increasing as one increased the dose. One key point that tends to be neglected in superficial treatments of the nonoxidative pentose cycle is that transketolase is reversible, and it's the transketolase-dependent formation of ribose-5-phosphate that's abnormally low in this genetic disorder.

This stuff on transketolase and ribose is relevant to a lot of things related to nucleotide and folate metabolism. There's all this research showing that exogenous nucleotides can be neurotrophic and neuroprotective, and many of these effects are, to some extent, due to the ribose-1-phosphate, which is interconverted with ribose-5-phosphate, that is liberated from the nucleotides by purine nucleoside phosphorylase or uridine phosphorylase. The more important point is that the cytoprotective effects of exogenous nucleotides are augmented when ribose is added with the nucleotides. Here's a representative article, and the same concept has been found to hold for neuroprotection by purine nucleotides (purine nucleoside phosphorylase-mediated phosphorolysis of purines into the purine base and the ribose sugar is required for neuroprotection): (http://www.ncbi.nlm.nih.gov/pubmed/16839635). The authors of that article suggest that ribose-1-phosphate is converted into glycolytic intermediates and would thereby act as a source of "fuel." This actually is probably not the primary mechanism, in part because of these striking effects of ribose in people with this group of acquired or inherited myopathies, collectively known as myoadenylate deaminase deficiency. Essentially, the researchers found that the improvements in exercise tolerance produced by ribose were too large to be accounted for by the "consumption" of ribose, as "fuel," in glycolysis. There's reason to think this concept of glycolytic activation, possibly by the conversion of ribose-5-phosphate into ribose 1,5-bisphosphate (an activator of phosphofructokinase in the brain), is a more potent and complete explanation, both for the neuroprotection by nucleotides + ribose and for the effects of ribose on the purine nucleoside cycle or glycolysis in myoadenylate deaminase deficiency. There's a series of articles on the use of ribose in myoadenylate deaminase deficiency, and there are many articles showing that exogenous ribose, with or without exogenous nucleotides, augments nucleotide salvage. There's reason to think that the elevation of intracellular folate would make that type of thing safer, given that folate repletion tends to decrease poly(ADP-ribose) polymerase activity and augment purine salvage and would potentially limit AICAR accumulation induced by exogenous ribose. Another concern with ribose, either in the absence or presence of exogenous nucleotides, would be its conversion into histidine.