Methylfolate Trap

I'll try to post my 40-page paper on folic acid in purine and pyrimidine metabolism, but one unresolved issue in relation to folic acid is the differences between reduced folates and folic acid. There's a prescription form of (6S)-5-methyltetrahydrofolate (sold under the brand name Deplin), the biologically-"active" enantiomer of 5-methyltetrahydrofolate, that was approved awhile back for treating psychiatric disorders. There's a lot of research showing that reduced folates, including leucovorin, which is a prescription precursor of 5-formyltetrahydrofolate and has been used as a "rescue" for toxicity due to methotrexate and, I think also, 5-fluorouracil. I still don't have a good handle on why it would be so much different, but I've seen a lot of in vitro and in vivo studies showing that it is. There probably is an effect of mitochondrial function on one-carbon metabolism, and the reduced folates bypass the steps in the folate coenzyme network that are sensitive to the cytoplasmic NADPH/NADP+ ratio and the intramitochondrial NADH/NAD+ ratio.

One thing that is probably not true is this notion that methylfolate can bypass the deficient activity of methionine synthase that characterizes vitamin B12 (cobalamin) deficiency. The methylfolate trap hypothesis of B12 deficiency/depletion says that the reduction in cobalamin-dependent methionine synthase activity leads to 5-methyltetrahydrofolate (5-MTHF) accumulation and that 5-MTHF inhibits serine hydroxymethyltransferase and other enzymes of the network of folate coenzyme-dependent enzymes, producing so-called "network disruptions." The idea that methylfolate can bypass this is more or less exactly wrong. It is true that reduced folates, as either 5-MTHF or 5-formyltetrahydrofolate, or folic acid can temporarily support cell proliferation in the absence of cobalamin, but this is basically a temporary and undesirable effect. This article shows some of that, but I remember seeing another one that showed it more clearly for 5-MTHF (this "Deplin" is 5-MTHF, a.k.a. methylfolate). The greater effectiveness of 5-formyltetrahydrofolate has to do with the fact that thymidylate synthase activity and de novo purine biosynthesis, folate-dependent processes that are required for nucleotide formation and hence DNA replication and cell division, can operate somewhat independently of methionine synthase activity. There's also an effect of very high levels of 5-MTHF that can artificially activate methionine synthase, by providing more of its cofactor (namely, 5-MTHF). But this is not desirable in the long term, and this article shows the diminishing returns after a certain number of cell divisions. Note that they have to use concentrations as high as 10 or higher micromolar, which is extremely high as an extracellular folate concentration:

http://www.jbc.org/cgi/content/abstract/256/20/10329
(pubmed unique id: http://www.ncbi.nlm.nih.gov/pubmed/6974730?dopt=Abstract)

So the upshot is that methylcobalamin would be more, not less, necessary, in the long term, as far as the use of this Deplin would go. There may be an effect of bypassing cobalamin depletion in the short term (and that's part of the basis for using leucovorin and other reduced folates, like 5-MTHF, as rescue therapies in the short term, to temporarily support cell division in the face of methotrexate toxicity or "overdose"), but who's to say how long this would last in a normal person.