More on the Regulation of Carbohydrate Metabolism by Folic Acid: Guanosine Nucleotides and Formylmethionyl-tRNAs

This is a really interesting and insightful article:

http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abstract&artid=297456 (Norton Rosensweig et al., 1969)

Those are some brilliant suggestions, by the authors, about potential mechanisms. I think the authors' suggestion about guanosine triphosphate potentially being a mediator of the effect of folic acid is especially interesting. There has, in fact, tended to be a conspicuously prominent effect of methotrexate on guanosine nucleotides, in cell culture studies. Here's an example, showing that guanosine nucleotide depletion, at least as is reflected in the dGTP levels in response to methotrexate, occurs to a more significant extent adenosine nucleotide depletion. As a result, the depletion of guanosine-based nucleotides limits DNA replication (the authors found that dGTP levels were very low, lower than dATP levels, in both methotrexate-exposed and non-methotrexate-treated cells):

http://cancerres.aacrjournals.org/cgi/content/abstract/35/6/1427 (pubmed: http://www.ncbi.nlm.nih.gov/pubmed/1055632?dopt=Abstract) (William Hryniuk et al., 1975)

Here's an article showing a variety of effects of folates on GTPase activities and guanine nucleotide binding:

http://www.ncbi.nlm.nih.gov/pubmed/2118600 (Hartley and Snodgrass, 1990)

The authors of this article discuss some of the implications of the Hartley and Snodgrass (1990) article on neuronal second messenger systems. Some of the GTPase effects might also have relevance to the whole tetrahydrobiopterin thing with folates. GTP is involved in BH4 synthesis, but I forget all the details. The authors of this article also discuss problems with radioimmunoassays for serum folate (variability between labs and differences due to the handling of samples) and note that red blood cell folate (intracellular folate in red blood cells) may be more sensitive to folate status than serum folate:

http://www.ncbi.nlm.nih.gov/pubmed/15378677 (Paul et al., 2004)

I'll try to dissect some of the effects of folic acid on glycolysis and gluconeogenesis.

The articles and discussions by Rosensweig and colleagues talking about formylmethionyl-tRNA synthetase, in relation to folate metabolism, are also really brilliant. In one of them (and I'll link to it), the authors compare some of the specific metabolic changes, produced by some drug, in prokaryotes to the changes that occur in a human with glutamate formiminotransferase deficiency (a folate-dependent enzyme). The articles are really amazing. There actually is some evidence that formylmethionyl-tRNAs regulate protein synthesis in higher mammals and not just prokaryotes. I have at least one paper showing it in cows, I know, and there's probably been more research on it since those came out. I'm going to read more of the articles related to that, but the Rosensweig articles discuss that as a potential mechanism by which folates could regulate carbohydrate metabolism.

This is a great article that includes some discussion of the evidence that formylation of mammalian methionyl-tRNAs does play a role in regulating protein synthesis:

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=524296 (Angela Spencer and Linda Spremulli, 2004)

I think there's been controversy about this, and I think the formylation of methionyl-tRNAs is a really "primitive" process. That's a subjective statement, but the issue with the relationship between nucleic acids and protein synthesis, with histidine (the enzyme complex that has glutamate formiminotransferase-cyclodeaminase activity converts tetrahydrofolate into 5,10-methenyl-THF, which can then be converted into N10-formylTHF that can formylate methionyl-tRNAs, I think, and it's an enzyme that participates in the catabolism and recycling of histidine), is really primitive and goes back to issues with early prokaryotes, as far as I remember. In a related vein, the sarcosine and dimethylglycine/betaine metabolism is also primitive, and some of those methylated glycines have these osmoregulatory roles in plant cells.