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PubMed1977

Mutants of formyltetrahydrofolate interconversion pathway of Saccharomyces cerevisiae.

Thirteen mutants of Saccharomyces cerevisiae that lack one or more of the three enzyme activities of the pathway for interconversion of tetrahydrofolate coenzymes at the formate level of oxidation have been isolated. They do not require adenine. All fail to complement mutations in the ade3 locus. Mutations that greatly reduce activity for the other two interconversion enzymes. The three enzyme activities cochromatograph on TEAE-cellulose columns. A mutation that eliminates synthetase activity also alters the chromatographic behavior of the remaining cyclohydrolase and dehydrogenase activities. It is suggested that the three activities reside in an enzyme complex encoded by the ade3 locus.

Adenine↗
PubMed1996

Formyltetrahydrofolates associated with mitochondria have longer polyglutamate chains than the methyltetrahydrofolates associated with cytoplasm in rat brain.

The subcellular distribution of folate coenzymes in the brain is unknown. Brain folate concentrations are low and hence require a sensitive assay to determine the subcellular distribution. Rat brain was fractionated by differential centrifugation into cytoplasmic, mitochondrial and crude synaptosomal fractions. The compositions of the folate pools in these subcellular fractions were determined by differential conversion of one-carbon forms enzymatically to 5,10-methylenetetrahydrofolate (5,10CH2H4PteGlu(n)) followed by reaction of the 5,10CH2H4PteGlu(n) with thymidylate synthetase and [3H]fluorodeoxyuridylate to form ternary complexes, which were then separated as a function of polyglutamate chain length by isoelectric focusing, visualized by fluorography and quantified by densitometry. The distribution of the pteridine derivatives in brain was very similar to the distribution of these derivatives in liver. Cytoplasm contained primarily 5-methyltetrahydropteroylpolyglutamates with smaller amounts of unsubstituted tetrahydropteroylpolyglutamates, whereas mitochondria contained approximately equal concentrations of unsubstituted and formyl-substituted tetrahydropteroylpolyglutamates. The subcellular distribution of polyglutamate derivatives in brain, however, was different from that in liver. In the brain, the mitochondrial folates exhibited longer polyglutamate chains than did the cytoplasmic folates, a pattern opposite to that in the liver. Whereas the brain cytoplasmic pteroylpolyglutamates were primarily penta and hexa glutamates, the brain mitochondrial pteroylpolyglutamates were primarily hexa and hepta glutamates. The brain also contained small but measurable levels of oxidized folates, which were seen in crude synaptosomal fractions but not in cytoplasmic or mitochondrial fractions.

Animals↗
PubMedDate not supplied

Red blood cell partitioning of the [6S]- and the [6R]-isomer of N5-formyltetrahydrofolic acid.

The in vitro interaction of the [6S]- and [6R]-stereoisomers of CHO-THFA with human RBCs was investigated in the (therapeutically comparable) concentration range from 1.0 to 12.5 micrograms/ml. Both compounds are bound to RBCs with a kRBC ranging from 0.13 to 0.75 for [6S]-CHO-THFA and from 0.06 to 0.33 for [6R]-CHO-THFA, respectively. The interaction of the [6S]-form with RBCs is about two times higher than of the [6R]-form. Incubation of CHO-THFA with RBCs over 24 h showed an accelerated disappearance from the test solution for [6R]-CHO-THFA with a mean t1/2 of 49.9 h in compare to t1/2 = 58.2 h for the [6S]-enantiomer. The results indicate that RBCs may play a major role for the pharmacokinetics and metabolism of CHO-THFA and may act as an intravasal depot especially for [6S]-CHO-THFA.

Binding Sites↗
PubMed1989

Studies on the mechanism of methanol poisoning: purification and comparison of rat and human liver 10-formyltetrahydrofolate dehydrogenase.

Methanol poisoning in primates and humans is due to formate accumulation as a result of low rates of formate oxidation. This toxicity is not seen in rats, where formate oxidation rates are high. Formate oxidation in vivo is dependent on hepatic tetrahydrofolate levels and on the activity of the enzyme 10-formyl-tetrahydrofolate (10-formyl-H4folate) dehydrogenase (EC 1.5.1.6). Because hepatic 10-formyl-H4folate dehydrogenase activity is lower in human liver than in rat liver, studies were performed investigating the properties of this enzyme in rat and human liver. 10-Formyl-H4folate dehydrogenase was purified to homogeneity from rat and human liver and was found to possess similar subunit molecular weights on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (96,000). N-Terminal amino acid analysis of the pure proteins showed an identical sequence for the first 16 amino acids. Antibodies raised in rabbits against the rat liver enzyme were inhibitory toward the activity of both rat and human liver enzymes and appeared to recognize only the 10-formyl-H4folate dehydrogenase in cytosolic preparations of rat and human liver. Immunoblots of pure rat and human liver 10-formyl-H4folate dehydrogenase showed similar staining intensity. It is concluded that rat and human liver 10-formyl-H4folate dehydrogenase possess very similar properties and that the activity of the enzyme in human liver is lower than that of rat liver, due to a reduced amount of enzyme protein in human liver. This may be an important factor in regulating formate oxidation in humans and may explain, in part, the accumulation of formate and the mechanism of toxicity of methanol in humans.

Amino Acid Sequence↗
PubMed1980

Folate metabolism in filariae. Enzymes associated with 5,10-methenyltetrahydrofolate and 10-formyltetrahydrofolate.

Adult Dirofilaria immitis and Brugia pahangi were found to possess the following folate-related enzymes that catalyze the formation of 5,10-methenyltetrahydrofolate (methenylFH4) or 10-formylFH4 (f10FH4): f10FH4 synthetase, methenylFH4 cyclohydrolase, f5FH4 cyclodehydrase, and a bifunctional complex composed of formiminoglutamate: FH4 formiminotransferase and 5-fomiminoFH4 cyclodeaminase. The properties of these filarial enzymes were generally similar to those of their counterparts from invertebrate and vertebrate sources, although each possessed one or more distinctive characteristics.

Aminohydrolases↗
PubMed1993

Sequence and expression of the gene for N10-formyltetrahydrofolate synthetase from Clostridium cylindrosporum.

Sau3 A and Hind III restriction fragments of Clostridium cylindrosporum genomic DNA were used to isolate clones containing 80% of the N10-H4folate synthetase gene in a 5' fragment and the remaining 20% of the gene in the 3' fragment. These fragments were joined at a common SnaB I restriction site and expressed in Escherichia coli at a level equivalent to what is normally found in C. cylindrosporum. Sequence comparisons show a large degree of homology with genes from two other clostridial species, including a thermophile. Certain conserved sequences found in the three clostridial proteins and in the N10-H4folate synthetase portion of eukaryotic C1-H4folate synthases may represent consensus sequences for nucleotide and H4folate binding.

Amino Acid Sequence↗