Folic Acid, Phosphate Sequestration, and Glycolysis and Gluconeogenesis

In my last posting, I meant to say that ZMP acts as an AMP analog, not "as an AMP." I think that phosphate sequestration in nucleotides and nucleotide analogs could be a double-edged sword and either buffer phosphate levels or promote the phosphate-depletion-induced ATP depletion. ZMP probably could have either effect, too, depending on its concentration in relation to other nucleotides and nucleosides. The phosphate sequestration concept is really interesting and may also help explain the opposing influences of folic acid and methotrexate on glycolysis and gluconeogenesis. I mention gluconeogenesis because one study shows that folic acid can be used to promote gluconeogenesis, and this effect may only emerge at higher doses. Here's that article (note that they used 15 mg/d, a high dose that may have the opposite effect, on some of the pathways associated with glycolysis and gluconeogenesis, that the lower doses have):

http://www.ncbi.nlm.nih.gov/pubmed/207269

I actually just found this one, and I haven't read it (it looks similar):

http://www.ncbi.nlm.nih.gov/pubmed/4341454

And here's some obscure abstract in a U.S. Army publication about folic acid's effects on gluconeogenesis and glycolysis:

http://oai.dtic.mil/oai/oai?verb=getRecord&metadataPrefix=html&identifier=AD0750325

There's actually other research showing that adequate phosphate availability activates and is necessary for PRPP formation, particularly in the context of folate depletion (http://www.ncbi.nlm.nih.gov/pubmed/7687143), but that doesn't mean that adding phosphate or taking it would somehow enhance PRPP levels. Extra phosphate wouldn't selectively enhance PRPP formation. But I think this phosphate sequestration concept is really relevant to understanding the mysterious effects of folic acid on purine metabolism and carbohydrate metabolism. No one knows how folic acid protects against damage from ischemia or causes this phosphodiesterase-inhibitor-like vasodilation (that effect is especially pronounced in response to reduced folates, such as (6S)-5-methylfolate). There are hypotheses about the mechanisms, but none of them is convincing to me.

I talked in that old paper of mine about the elusive qualities of the opposing effects of folic acid and methotrexate. It's really mind-bending, because both methotrexate and folic acid can increase the extracellular adenosine concentrations, but they do so by sort of opposite and sort of just different mechanisms. Some of the elusiveness has to do with the ways in which nucleotide metabolism is regulated at so many levels and is so extremely dynamic. AICAR, for example, can have some beneficial effects, under certain conditions, but can then be harmful under other conditions. The same thing is probably true for exogenous purines and pyrimidines, even though I think their beneficial effects are likely to be fairly "durable."

What really needs to be done is more research on the regulation of purine metabolism, by folic acid, in postmitotic cells or cells that are not actively dividing (i.e. nonmitotic, not proliferating). Because in proliferating cells, the DNA synthesis and progression through the cell cycle makes the changes in ATP levels and purine nucleotide levels so dynamic as to be almost impossible to interpret. I'll post a link to one of those articles that shows that, and I cited it in my paper. It shows the way methotrexate initially increases ATP levels and then gradually decreases them, etc.