PubMed · 48789
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G Tisman, S J Wu, G E Safire, E Rodriguez. 1975-05-24. Letter: The methylfolate-trap hypothesis.. https://doi.org/10.1016/s0140-6736(75)93154-2
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The interaction between plasma homocysteine levels and vitamins B6, B12, and folate is an exciting field and one that has gathered great momentum over the past few years, with the recognition that homocysteine probably plays an important role in occlusive vascular disease. Our understanding in this field is greatly advanced compared to just a few years ago. There are a number of important issues, however, that will need to be addressed in the future if we are to develop a sufficient knowledge base to effectively minimize the risk of occlusive vascular disease ascribable to hyperhomocysteinemia. These include (1) definitive evidence that homocysteine is the actual agent that mediates accelerated occlusive vascular disease and the mechanism by which this occurs; (2) an understanding of what constitutes a pathologic elevation in homocysteine (is there a threshold concentration in the plasma below which no vascular injury occurs? is the peak concentration achieved the critical determinant of injury, or is the area under the curve, or some other feature, more important?); (3) understanding what synergies might exist by adding B6 or B12 to a regimen of folate supplementation (what doses are most appropriate? will toxologic issues limit the utility of supplementation?); and (4) determining the circumstances where reduction of plasma homocysteine will retard or reverse the process of occlusive vascular disease.
The partial characterization of the modified folate present in Sulfolobus solfataricus has been carried out. Separation of ethanol-water extracts of these cells on a DEAE-Sephadex column led to the isolation of a small amount of intact oxidized cofactor, which, when subjected to reductive cleavage with Zn-HCl, produced 6-methylpterin. This indicated that the modified folate in these cells contained a nonmethylated pterin linked, via a methylene group at the C-6 position of the pterin, to an arylamine, as is found in folate. Oxidative cleavage of intact reduced cofactor produced pterin and a single arylamine. The azo dye derivative of this arylamine was prepared and purified by chromatography on a Bio-Gel P-6 column. The resulting purified compound was shown to be readily hydrolyzed in dilute acid to the azo dye derivative of 5-(p-aminophenyl)-1,2,3,4-tetrahydroxypantane, which was, in turn, readily cleaved to 5-(p-aminophenyl)-1,2,3,4- tetrahydroxypentane by Zn-HCl reduction. The stereochemistry of the resulting 5-(p-aminophenyl)-1,2,3,4-tetrahydroxypentane was shown to be ribo, the same as that of the 5-(p-aminophenyl)-1,2,3,4- tetrahydroxypentane moiety found in methanopterin. The complete arylamine side chain of the modified folate thus contains 5-(p-aminophenyl)-1,2,3,4-tetrahydroxypentane attached, via an acid-labile bond, to a currently unidentified substituent. The modified folate present in S. solfataricus thus contains structural features common to both folates and methanopterin.
A new process for (6S)-tetrahydrofolate production from dihydrofolate was designed that used dihydrofolate reductase and an NADPH regeneration system. Glucose dehydrogenase from Gluconobacter scleroides KY3613 was used for recycling of the cofactor. The reaction mixture contained 200 mM dihydrofolate, 220 mM glucose, 2 mM NADP, 14.4 U/ml dihydrofolate reductase, and 14.4 U/ml Glucose dehydrogenase, and the reaction was complete after incubation at pH 8.0, and 40 degrees C for 2.5 hr. With (6S)-tetrahydrofolate as the starting material, l-leucovorin was synthesized via a methenyl derivative. The purity of the l-leucovorin was 100%, and its diastereomeric purity was greater than 99.5% d.e. as the (6S)-form.