Folic Acid and Glucose Metabolism

I've been looking into the potential regulation of both gluconeogenesis and glycolysis by folic acid, and this business about glutamate formiminotransferase playing a role is seeming uncertain. There seems to be very little information available on the ways in which changes in glutamate formiminotransferase activity affect glucose metabolism, but folic acid does appear to be able to affect, possibly in ways that are complex and depend on various cellular conditions, the activities of fructose 2,6-bisphosphatase, in particular, and also fructose 1,6-bisphosphate aldolase, phosphofructokinase, and pyruvate kinase. Part of the difficulty I'm having is the old names the researchers are using for the enzymes. The names for enzymes change over time or are referred to with different words, and I need to spend some time sorting through this stuff. The main points, though, are that there's this research showing that folic acid has significant effects on glucose metabolism, that the research was abandoned 25 years ago, like many avenues of basic research in many branches of medicine, and that it's likely to be relevant for understanding some of the effects of folic acid.

One might suggest that folic acid tends to reduce PRPP levels or influence the activities of glycolytic and gluconeogenic enzymes by an effect on DNA methylation, by increasing the availability of S-adenosylmethionine (SAM-e) and increasing the SAM-e/S-adenosylhomocysteine ratio (SAM-e/SAH). But the DNA methylation effects tend to be sort of inconsistent and not very strong. I also think the effects on glycolytic enzymes, effects that appeared after 24 hours, may have occurred too rapidly to be explainable in terms of an increase in the SAM-e/SAH ratio. The reductions in plasma homocysteine in response to folate supplementation require at least several days to manifest themselves completely, and the plasma homocysteine is in equilibrium with the enterocyte-derived homocysteine (locally-produced homocysteine in the enterocytes or colonocytes or whatever cells the Rosensweig group analyzed--see previous postings for the reference). I might be wrong about the time frame being too short to be explained in terms of changes in DNA methylation, though. In the case of PRPP, I really think it's some kind of metabolic effect and not the result of changes in gene expression due to changes in DNA methylation (folic acid and an increase in SAM-e/SAH does not always increase DNA methylation but tends to normalize it, increasing the degrees of methylation of some CpG islands and decreasing DNA methylation at other sites). The inverse relationship between intracellular total folates and PRPP, along with the magnitude of the inverse relationship, suggests to me that it's a metabolic effect.

The other main point is that there's no folate-derived-cofactor-dependent enzyme that is directly involved in either gluconeogenesis or glycolysis, and so the mechanism is mysterious. Serine hydroxymethyltransferase serves to sort of "follow up" on glycolysis, but the cytosolic and mitochondrial SHMT's are reversible and do not really seem to be likely candidates for the regulation of glucose metabolism. There is one article talking about SHMT having aldolase-like activity, but I doubt that could account for the effects of folic acid on glycolysis and gluconeogenesis.