Vitamin B12, Polyglutamylation, and Reduced Folates

This article is really interesting [Frater-Schroder et al., 1981: (http://www.springerlink.com/content/p5628601hv166950/)]. It's a case study, but the data the authors collected is consistent with a lot of other case reports, in particular, of people who have been treated for vitamin B12 (cobalamin) depletion. There's very little information on this type of thing, but the authors found that, in a person with transcobalamin II (TC-II) deficiency, the intracellular folates and, in particular, polyglutamylated folates did not return to normal, in red blood cells, until the person had taken folinic acid in addition to the usual, high doses of hydroxocobalamin (OH-Cbl) that are required to maintain serum cobalamin levels in a person with TC-II deficiency. There was no increase until the reduced folate was added, and the usual assumption is that cobalamin repletion will automatically replenish the pools of polyglutamylated folates intracellularly. There's an activation of folylpolyglutamate synthetase in response to cobalamin repletion [Smulders et al., 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16445837)], and polyglutamylation of folates helps in the retention of intracellular folates and probably in the coupling of reactions by folate-cofactor-dependent enzymes (the polyglutamate tail acts as a "tether," as the explanation goes, allowing folates to be transferred between enzymes without diffusing away). After the researchers had diagnosed the defect and begun using the high-dose OH-Cbl, the person began getting infections and demonstrating abnormalities in her circulating granulocytes.

The point of the article is basically that, after cobalamin depletion has been recognized and treated, this does not guarantee that everything will be "pristine," in terms of intracellular folate levels. Also, the implication is that cobalamin repletion, which tends to produce a decrease in the ratio of intracellular 5-methyltetrahydrofolate/(non-MTHF reduced folates), thereby overcoming the so-called "methylfolate trap" can accelerate folate turnover or just not fix the underlying deficits in the reductase steps in the folate cycle that are sensitive to the cellular redox state. This is relevant to the use of higher doses of cobalamins, though, because, in the context of pernicious anemia and subacute combined degeneration, there tends to be a fear of using folates. There can be worsening of neurological symptoms, if the person is still cobalamin deficient. But this article and others suggest that, as long as the cobalamin status of the person is adequate, the use of reduced folates may be necessary, at least temporarily, to replenish the intracellular, polyglutamylated folate stores. A lot is not known about the effects of cobalamins on the folate cycle.