The bio-inactive C-6 isomer, [6R]-5-formyl-tetrahydrofolate (5-HCO-H4F), is not found in Nature. An oral dose of 13.5µmol of [6R]-5-HCO-H4F in humans results in the appearance of the naturally occurring [6S]-5-methyl-tetrahydrofolate and relatively large amounts of other bioactive folates in plasma. The removal of the asymmetry at C-6 could account for these results. Two oxidized cytochrome c [cyt c (Fe3+)] molecules oxidize one 10-formyl-tetrahydrofolate (10-HCO-H4F) with second-order kinetics and a rate constant of 1.3×;104 M-1·s-1. The folate product of this oxidation reaction is 10-formyl-dihydrofolate (10-HCO-H2F), which has no C-6 asymmetric centre and is therefore bioactive. The folate-requiring bacterium, Enterococcus hirae, does not normally biosynthesize cytochromes but does so when given an exogenous source of haem (e.g. haemin). E. hirae grown in haemin-supplemented media for 3 days utilizes both [6R]- and [6S]-5-HCO-H4F in contrast to that grown in control medium, which utilizes only the [6S] isomer. Since known chemical reactions form 10-HCO-H4F from 5-HCO-H4F, the unusually large rate constant for the oxidation of 10-HCO-H4F by cyt c (Fe3+) may account for the unexpected bioactivity of [6R]-5-HCO-H4F in humans and in E. hirae grown in haemin-containing media. We used an unnatural C-6 folate isomer as a tool to reveal the possible in vivo oxidation of 10-HCO-H4F to 10-HCO-H2F; however, nothing precludes this oxidation from occurring in vivo with the natural C-6 isomer.

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