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PubMed2005

QscR-mediated transcriptional activation of serine cycle genes in Methylobacterium extorquens AM1.

QscR, a LysR-type regulator, is the major regulator of assimilatory C1 metabolism in Methylobacterium extorquens AM1. It has been shown to interact with the promoters of the two operons that encode the majority of the serine cycle enzymes (sga-hpr-mtdA-fch for the qsc1 operon and mtkA-mtkB-ppc-mclA for the qsc2 operon), as well as with the promoter of glyA and its own promoter. To obtain further insights into the mechanisms of this regulation, we mapped transcriptional start sites for the qsc1 and qsc2 operons and for glyA via primer extension analysis. We also identified the specific binding sites for QscR upstream of the qsc1 and qsc2 operons and glyA by DNase I footprinting. The QscR protected areas were located at nucleotides -216 to -165, nucleotides -59 to -26, and nucleotides -72 to -39 within the promoter-regulatory regions upstream of transcriptional starts of, respectively, qsc1, qsc2 and glyA. To examine the nature of the metabolic signal that may influence QscR-mediated regulation of the serine cycle genes, Pqsc1::xylE translational fusions were constructed and expression of XylE monitored in the wild-type strain, as well as in knockout mutants defective in a variety of methylotrophy functions. The data from these experiments pointed toward formyl-H4F being a coinducer of QscR and possibly the major signal in the regulation of the serine cycle in M. extorquens AM1. The ability of formyl-H4F to enhance the binding of QscR to a specific region upstream of one of the serine cycle operons was demonstrated in gel retardation experiments.

5' Flanking Region↗
PubMed1988

In vivo oxidation of the methyl group of hepatic 5-methyltetrahydrofolate.

Methionine given parenterally to rats caused rapid disappearance of methyltetrahydrofolate from the liver and a corresponding rise in tetrahydrofolate and formyl-tetrahydrofolate concentrations. When [14C]H3--H4folate was given, methionine caused an increased [14C]0(2) excretion, indicating that oxidation of the methyl group had occurred. Methionine was more effective than S-adenosylmethionine at causing oxidation, but serine was ineffective. The lowest dose of methionine to produce an effect was 0.5 mumol, which is less than the daily dietary intake in a rat. The data suggest that the concentration of methylfolate in rat livers is controlled by the concentrations of methionine.

Adenosine↗
PubMed1987

Effect of methotrexate on intracellular folate pools in purified myeloid precursor cells from normal human bone marrow.

We investigated the effects of the antifolate methotrexate on intracellular folate pools of human myeloid precursor cells (MPCs). Immature MPCs, representing 3.2% of the original marrow population, were selected from normal human bone marrow by immune rosetting. The intracellular folate pools were labeled by incubation with 5 X 10(-8) M [3H]5-formyl-FH4 and were quantitated by high performance liquid chromatography. The predominant folates were 5-methyl-tetrahydrofolate (5-methyl-FH4) (36%), 10-formyl-FH4 (41.4%), 5-formyl-FH4 (12.3%), and FH4 (10.3%). A 12-h exposure to 1 microM methotrexate (MTX) resulted in a 34% reduction in the intracellular concentration of 10-formyl-FH4, a 61% decrease in 5-formyl-FH4, and a 62% decrease in 5-methyl-FH4, as well as the appearance and progressive expansion of the FH2 and 10-formyl-FH2 pools. These changes were maximal after 4 h of incubation with MTX. Paralleling the changes in folates, particularly the increase in FH2, were a 64% reduction in myeloid colony formation and a 77% depression of de novo purine synthesis after 4 h of MTX. We conclude that MTX does not produce quantitative depletion of 10-formyl-FH4 and that its antipurine effect may be mediated by direct inhibition of de novo purine synthesis by FH2 and, at later time points, by MTX polyglutamates.

Bone Marrow Cells↗
PubMed1977

Cytochemical demonstration of 5-formyl tetrahydrofolate cyclodehydrase and 5,10-methenyl tetrahydrofolate cyclohydrolase activity.

The enzyme 5-formyl tetrahydrofolate cyclodehydrase plays an important role in the conversion of 5-formyl tetrahydrofolate to 5,10-methenyl tetrahydrofolate. A second enzyme, cyclohydrolase, converts 5,10-methenyl tetrahydrofolate to 10-formyl tetrahydrofolate. These folate derivatives play a significant part in the biosynthesis of purines. A method has been devised for the cytochemical demonstration of 5-formyl tetrahydrofolate cyclodehydrase and 5,10-methenyl tetrahydrofolate cyclohydrolase activity which uses 5-formyl tetrahydrofolate or 5,10-methenyl tetrahydrofolate as substrate respectively, blocking possible interferences by other enzymes, and allows the nonenzymatic reduction of nitro-blue tetrazolium by 5,10-methenyl tetrahydrofolate formed by the action of the cyclodehydrase on the substrate 5-formyl tetrahydrofolate, and by 10-formyl tetrahydrofolate formed by the action of cyclohydrolase on the substrate 5,10-methenyl tetrahydrofolate, thus revealing intracellular sites of enzyme activity. The methods appear to show only intracellular localization of the blue formazan deposits of reduced tetrazolium. The distribution of positivity in cells of human blood and bone marrow is described.

Aminohydrolases↗
PubMed1976

Metabolism of dihydroaminopterin and the influence of aminopterin and related derivatives on the metabolism of (-)-5-formyl-tetrahydrofolic acid in Pediococcus cerevisiae.

[3H]Dihydroaminopterin, but not [3H]methotrexate or [3H]aminopterin, was rapidly taken up by resting cell of Pediococcus cerevisiae and inhibited the uptake of (-)-5-formyl-tetrahydrofolic acid to more than 90% at a concentration of 25 muM. On the other hand 5-formyl-tetrahydrofolic acid inhibited the uptake of dihydroaminopterin to a similar extent. Dihydroaminopterin was metabolized by Pediococcus cerevisiae, but not by Lactobacillus casei, to a compound tentatively identified as dihydroaminopterin diglutamate. Methotrexate or aminopterin at a concentration of 25 muM did not inhibit the uptake of 5-formyl-tetrahydrofolic acid in Pediococcus cervisiae, but inhibited the conversion of this compound to polyglutamate forms almost completely at a level of 2.5 mu M.

Aminopterin↗
PubMed1986

The effect of methotrexate on intracellular folate pools in human MCF-7 breast cancer cells. Evidence for direct inhibition of purine synthesis.

This report details the effects of methotrexate on the intracellular folate pools of the MCF-7 human breast cancer cell line. To achieve this goal, we designed a high-pressure liquid chromatography system capable of separating the physiologic folates. The folate pools were quantitated following growth and equilibration in 2.25 microM radiolabeled folic acid. Each of the intracellular folates was identified by coelution with standard folates and by chemical/biochemical tests unique to each of the various folates. The 10-formyl-H4PteGlu (where H4PteGlu represents dl-tetrahydrofolic acid) pool accounted for 20.5% of the total intracellular folate pool in untreated cells, whereas 5-formyl-H4PteGlu and H4PteGlu accounted for 6.5 and 10.6%, respectively. The levels of these three folates remained stable throughout cell growth. The 5-methyl-H4PteGlu pool accounted for less than 10% in early growth phase cells but assumed greater than 60% of the total pool by the mid- and late-log phases of cell growth. When the MCF-7 cells were exposed to 1 microM methotrexate, de novo purine synthesis and de novo thymidylate synthesis were rapidly inhibited to less than 20% of control within 3 h. During this time period, rapid alterations in the folate pools also occurred such that dihydrofolic acid levels rose from less than 1% in untreated cells to greater than 30% of the total pool. This rise was accompanied by a parallel fall in 5-methyl-H4PteGlu. H4PteGlu and 5-formyl-H4PteGlu were undetectable following 2 h of methotrexate exposure, but 10-formyl-H4PteGlu, the required cosubstrate for de novo purine synthesis, was preserved at greater than 80% of pretreatment values following a 1 microM methotrexate exposure of up to 21 h. The rapid inhibition of de novo purine synthesis in these cells following methotrexate exposure coupled with a relatively preserved 10-formyl-H4PteGlu pool suggests direct inhibition of this synthetic pathway by the temporally coincident accumulation of dihydrofolic acid and/or methotrexate polyglutamates. This inhibition cannot be ascribed to depletion of the folate cofactor 10-formyl-H4PteGlu.

Breast Neoplasms↗
PubMed1978

Thermal destruction of folacin in microwave and conventional heating.

Folacin derivatives were found to vary greatly in thermal stability. It is worth mention that pteroylmonoglutamic acid (PGA), the folate used therapeutically and in food supplementation, was extremely stable to heat under the experimental conditions, that is, at 100 degrees C. in neutral solution. Under these conditions, 5-formyl-THFA also exhibited marked stability; neither form was affected significantly by microwave radiation. In view of the increasing data indicating the abundance of 5-methyl-THFA and other derivatives of THFA in foods, the thermal lability of these forms was especially interesting. THFA was found to be an extremely labile folate, while 5-methyl-THFA had intermediate stability among the forms tested. Microwave heating of 5-methyl-THFA resulted in a faster rate of degradation than conventional heating at the same temperature. The mechanism of this action needs further research.

Cooking↗
PubMed1994

5-Formyltetrahydropteroylpolyglutamates are the major folate derivatives in Neurospora crassa conidiospores.

5-Formyltetrahydropteroylpolyglutamate (5-CHO-H4PteGlun) is the only reduced folate derivative that is stable to oxidation and alkaline pH. However, no metabolic role has been assigned to this folate derivative, and evidence for its existence in cells has been questioned. Recently, serine hydroxymethyltransferase was shown to catalyze the formation of 5-CHO-H4PteGlun from 5,10-methenyl-H4PteGlun (Stover, P., and Schirch, V. (1990) J. Biol. Chem. 265, 14227-14233). We have proposed that 5-CHO-H4PTeGlun may serve as a storage form of reduced folates and one-carbon groups in cells that are in a dormant stage. This hypothesis was tested by determining the levels of H4PteGlun derivatives in the mycelia and conidiospores of Neurospora crassa and a mutant strain that lacks cytosolic serine hydroxymethyltransferase. N. crassa serine hydroxymethyltransferase was purified to homogeneity and characterized with respect to kinetic constants, quaternary structure, stability, and reaction specificity. A new assay for determining the concentration of the polyglutamate forms of H4PteGlun derivatives was also developed. Using this assay, it was shown that 85% of the tetrahydropteroylpolyglutamates in conidiospores was 5-CHO-H4PteGlun. After adding the spores to growth media, the 5-CHO-H4PteGlun was reduced to less than 10% of the folate pool in 20 min. Mycelia had no detectable 5-CHO-H4PteGlun. Only 10-20% of the folate pool in conidiospores from the mutant strain lacking cytosolic serine hydroxymethyltransferase was in the form of 5-CHO-H4PteGlun.

Formyltetrahydrofolates↗
PubMed1977

The influence of folate antagonists on the metabolism of folic acid and its reduced derivatives in rat liver and kidney.

Uptake and conversion of [3H]folic acid to polyglutamate derivatives by rat liver and kidney were inhibited by methotrexate or aminopterin (15 mg/kg body weight) and DL-tetrahydromethotrexate (30 mg/kg body weight). In contrast, these antagonists did not influence the conversion of L-5-formyl-[3H]tetrahydrofolic acid or L-5-methyl[3H]tetrahydrofolic acid to polyglutamine derivatives and had little effect on the uptake of reduced folate derivatives. When [3H]methotrexate, [3H]aminopterin, and DL-[3H]tetrahydromethotrexate were administered in small amounts (15 mug/kg body wieght), no metabolites of these compounds were observed. However, at higher doses of [3H]methotrexate (300 mug/kg body weight), more than 30% of the radioactivity remaining in the tissue 24 hr after administration could be attributed to a metabolite of methotrexate. This metabolite was tentatively identified as methotrexate diglutamate.

Aminopterin↗