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PubMed1982

Modulation of methylenetetrahydrofolate reductase activity by S-adenosylmethionine and by dihydrofolate and its polyglutamate analogues.

Methylenetetrahydrofolate reductase catalyzes the reduction of methylenetetrahydrofolate to methyltetrahydrofolate. This reaction commits one carbon units to the pathways of adenosylmethionine-dependent methylation in mammalian cells. We have purified the pig liver enzyme to homogeneity and shown that it contains FAD as a non-covalently bound prosthetic group. Methylenetetrahydrofolate is not only a substrate for the reductase, but also for thymidylate synthase and for methylenetetrahydrofolate dehydrogenase. The latter reaction leads to utilization of one carbon units in de novo purine biosynthesis. A priori, one might expect that methylenetetrahydrofolate reductase activity would be modulated by cellular requirements for de novo biosynthesis of purines and pyrimidines, as well as by cellular levels of adenosylmethionine. Methylenetetrahydrofolate reductase is inhibited by dihydrofolate and its polyglutamate analogues. The Ki is 6.5 microM for dihydrofolate and decreases with each additional glutamyl residue to a minimum value of 0.013 microM for dihydropteroylhexaglutamate. The I50 for dihydropteroylhexaglutamate inhibition of reductase activity in the presence of 0.5 microM methylenetetrahydropteroylhexaglutamate is 0.07 microM. We propose that stimulation of thymidylate synthase activity (as in the replicating cell) may lead to elevations in the steady state levels of cellular dihydrofolate derivatives and to resultant inhibition of methylenetetrahydrofolate reductase activity. Thus methylenetetrahydrofolate derivatives would be spared for purine and pyrimidine biosynthesis. We have also examined the inhibition of methylenetetrahydrofolate reductase by adenosylmethionine, which serves as an allosteric effector of the enzymatic activity. Adenosylmethionine induces a slow transition in the enzyme, and leads to the inhibition of NADPH-menadione, NADPH-methylenetetrahydrofolate and methyltetrahydrofolate-menadione oxido-reductase activities.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed1983

Investigations of tissue folates in normal and malignant tissues.

The folates present in liver, gut and tumour tissue were examined before and after autolysis. Before autolysis 10-formylfolate tetraglutamate (10-CHOFA(glu)4), 5-methyltetrahydrofolate triglutamate (5-CH3THF(glu)3) and possibly tetrahydrofolate polyglutamate(s) (THF(glu)n) were detected. Liver contained all 3 species whereas no 5-CH3THF(glu)3 was present in the tumours; gut showed an intermediate situation. After autolysis the predominant monoglutamates formed were 5-CH3THF in the liver, 10-formylfolates in the gut and possibly tetrahydrofolate (THF) in the tumour extracts. These differences illustrate changes in tissue folates with the proliferation rate of the tissue and suggest an explanation for the methionine auxotrophy of Walker 256 carcinosarcoma cells.

Animals↗
PubMed1981

Changes in tissue folates accompanying nitrous oxide-induced inactivation of vitamin B12 in the rat.

The anesthetic gas, nitrous oxide, oxidizes cob(I)alamin and thus inactivates methionine synthetase which requires cobalamin as a coenzyme. The effect on folates in liver, kidney, marrow, plasma, and brain in rats breathing a 1/1 nitrous oxide/oxygen mixture is described. There is loss of folate from tissues, most marked in liver, that affects folate polyglutamates to a greater extent than folate monoglutamates. Both methyl- and nonmethyl-analogues are affected. There is a transient rise in the levels of 5-methyltetrahydropteroylpolyglutamate in all tissues 8 h after starting nitrous oxide, which falls thereafter. In marrow and brain there is also a transient rise in methyltetrahydropteroylmonoglutamate. Plasma folate increased markedly throughout the period of exposure to nitrous oxide. It is suggested that these changes are due to the action of nitrous oxide in depressing tissue uptake of folate from plasma, in promoting loss of folate into urine and in inhibiting folate polyglutamate synthesis.

Animals↗
PubMed1981

Recovery of tissue folates after inactivation of cobalamin by nitrous oxide. The significance of dietary folate.

The anesthetic gas, nitrous oxide (N2O), oxidizes the cobalt moiety in the vitamin B12 molecule and in this way inactivates methionine synthetase which requires reduced cobalamin. In rats this is followed by a disappearance of folates from the tissues, this loss being most marked in the liver. Returning the animals to a normal atmosphere leads to restoration of most of the pre-N2O folate levels within 5 days. The plasma folate, which rises on exposure to N2O, falls within several hours. The restoration of tissue folates does not take place if the rats are placed on a low folate diet after withdrawal from an N2O environment. Thus the fall in tissue folate levels is due to loss from the body either by excretion or increased catabolism and not to redistribution of folate. Return of normal folate levels requires a dietary source of folate.

Animals↗
PubMed1991

Bacterially synthesized folate in rat large intestine is incorporated into host tissue folyl polyglutamates.

Unlike mammalian tissues, certain intestinal microflora are capable of de novo synthesis of folate. To explore the availability of bacterially synthesized folate to the host organism, we used [3H] p-aminobenzoic acid (3H PABA) to label folate newly synthesized by the intestinal microflora. Labeled folates were isolated by affinity chromatography and identified by ion-pair HPLC. In this study [3H]PABA was injected into rat cecum to determine whether the [3H]folate synthesized by bacteria appeared in rat liver and other tissues. Rats were kept in sling suits to prevent coprophagy. Ion-pair chromatography of the purified liver folate demonstrated that bacterially derived [3H]folate was incorporated into all host liver-specific folate polyglutamates, mostly penta- and hexaglutamyl derivatives. Similar results were observed in kidney folates. These data provide direct evidence that some of the folate synthesized by the microflora in the rat large intestine is incorporated into the tissue folate of the host.

4-Aminobenzoic Acid↗
PubMed1983

Regulation of folylpoly-gamma-glutamate synthesis in bacteria: in vivo and in vitro synthesis of pteroylpoly-gamma-glutamates by Lactobacillus casei and Streptococcus faecalis.

Lactobacillus casei and Streptococcus faecalis accumulated labeled folic acid and metabolized this compound to poly-gamma-glutamates of chain lengths of up to 11 and 5, respectively. Octa- and nonaglutamates predominated in L. casei, and tetraglutamates predominated in S. faecalis. The most effective monoglutamate substrates for the L. casei and S. faecalis folylpoly-gamma-glutamate (folylpolyglutamate) synthetases were methylene- and formyltetrahydrofolate, respectively. Methylenetetrahydropteroylpoly-gamma-glutamates were the preferred poly-gamma-glutamate substrates for both enzymes and, in each case, the highest activity was observed with the diglutamate substrate. The final distribution of folylpolyglutamates in these bacteria appeared to reflect the ability of folates with various glutamate chain lengths to act as substrates for the bacterial folylpolyglutamate synthetases. The proportions of individual folylpolyglutamates were markedly affected by culturing the bacteria in medium containing adenine, whereas thymine was without effect. Adenine did not affect the level of folylpolyglutamate synthetase in either organism but caused a large increase in the proportion of intracellular folates containing one-carbon units at the oxidation level of formate, folates which are substrates for enzymes involved in purine biosynthesis. The folates with shorter glutamate chain lengths in bacteria cultured in the presence of adenine resulted from primary regulation of the de novo purine biosynthetic pathway, regulation which caused an accumulation of formyltetrahydropteroyl-poly-gamma-glutamates (folate derivatives that are ineffective substrates for folylpolyglutamate synthetases), and did not result from regulation of folylpolyglutamate synthetase per se.

Adenine↗
PubMed1981

Dual functions of bacteriophage T4D gene 28 product: structural component of the viral tail baseplate central plug and cleavage enzyme for folyl polyglutamates. I. Identification of T4D gene 28 product in the tail plug.

The T4D bacteriophage gene 28 product is a component of the central plug of the tail baseplate, as shown by the following two independent lines of evidence. (i) A highly sensitive method for radioactive labeling of only tail baseplate plug components was developed. These labeled plug components were incorporated by a complementation procedure into new phage particles and were analyzed by radioautography after sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Three new structural proteins were found in addition to the three known tail plug proteins (i.e., gP29, gP27, and gP5). One of the three newly identified components had a molecular weight of 24,000 to 25,000 and appeared to be a product of T4D gene 28. (ii) Characterization of mutants of Escherichia coli bacteriophage T4D which produced altered gene 28 products also indicated that the gene 28 product was a viral tail component. T4D 28(ts) phage particles produced at the permissive temperature had altered heat labilities compared with parent T4D particles. We isolated a single-step temperature revertant of T4D 28(ts) and found that it produced phage particles which phenotypically resembled the original T4D particles. Since the properties of the phage baseplate components usually determine heat lability, these two changes in physical stability after two sequential single mutations in gene 28 supported the other evidence that the gene 28 product was a viral baseplate component. Also, compared with parent T4D particles, T4D 28(ts) and T4D 28am viral particles adsorbed at different rates to various types of host cells. In addition, T4D 28(ts) particles exhibited a different host range than parent T4D particles. This T4D mutant formed plaques with an extremely low efficiency on all E. coli K-12 strains tested. We found that although T4D 28(ts) particles adsorbed rapidly and irreversibly to the E. coli K-12 strains, as judged by gene rescue experiments, these particles were not able to inject their DNA into the E. coli K-12 strains. On the other hand, the T4D 28(ts) revertant had a plating efficiency on E. coli K-12 strains that was quite similar to the plating efficiency of the original parent, T4D. These properties of phage particles containing an altered gene 28 product supported the analytical finding that the gene 28 product is a structural component of the central plug of the T4D tail baseplate. They also indicated that this component plays a role in both host cell recognition and viral DNA injection.

Adsorption↗
PubMed1979

Folate distribution in cultured human cells. Studies on 5,10-CH2-H4PteGlu reductase deficiency.

We have studied the distribution of folate coenzyme forms in cultured human fibroblasts from control lines and from lines derived from nine patients representing all of the published reports of 5,10-CH(2)-H(4)PteGlu reductase deficiency. Based on mobility on DEAE-Sephadex and differential microbiological assay the major folate fractions in extracts of human fibroblasts were 5-CH(3)-H(4)PteGlu, 10-CHO-H(4)PteGlu, and 5-CHO-H(4)PteGlu with smaller fractions, which included 5-CH(3)-H(2)PteGlu, 10-CHO-PteGlu, and H(4)PteGlu. Evidence that the 5-CHO-H(4)PteGlu may have been derived from 5,10-CH=H(4)PteGlu during extraction is presented. In most of the mutant fibroblasts the absolute concentration of 5-CH(3)-H(4)PteGlu was lower than in control cells but the proportion of intracellular folate which was 5-CH(3)-H(4)PteGlu was strikingly lower in mutant cells when determined by chromatography or differential microbiological assay. In both control and mutant cells most of the 5-CH(3)-H(4)-PteGlu was polyglutamate. The proportion of intracellular folate which was polyglutamate was similar in control and mutant cells. A direct relationship was observed between the proportion of cellular folate which was 5-CH(3)-H(4)PteGlu, and both the clinical severity of this disorder and the residual enzyme activity indicating that the distribution of different folates may be an important control of intracellular folate metabolism. These studies indicate that 5,10-CH(2)-H(4)PteGlu reductase is the only significant intracellular pathway for the generation of 5-CH(3)-H(4)PteGlu, that the activity of this enzyme regulates the level of this folate in control and mutant cells under conditions of culture used here, that the majority of intracellular folate is in the polyglutamate form, and that the relative distribution of folates may control folate metabolism by interaction in the various folate reactions.

Cells, Cultured↗
PubMed1990

DL-3,3-difluoroglutamate: an enhancer of folylpolyglutamate elongation.

The effect of 3,3-difluoroglutamate (F2Glu) on the reaction catalyzed by rat liver folypolyglutamate synthetase was investigated. F2Glu was a potent, concentration-dependent inhibitor of poly(gamma-glutamylation) using [3H]Glu and either methotrexate (4-NH2-10-CH3PteGlu) or tetrahydrofolate as substrates. It was determined that F2Glu acted as an alternate substrate, but in contrast to the previously characterized alternate substrate 4-fluoroglutamate (McGuire, J.J., and Coward, J.K. (1985) J. Biol. Chem. 260, 6747-6754), it did not terminate polyglutamate chain elongation. Instead, F2Glu promoted chain elongation. Thus, synthesis of products from [3H]methotrexate containing 1 and 2 additional amino acid residues occurred at a substantially higher rate in the presence of F2Glu when compared to identical reactions in the presence of Glu; this was more pronounced for the product containing 2 additional residues. Identities of the products were established by their respective chromatographic elution positions and by limit digestion with gamma-glutamyl hydrolases. Ligation of Glu to 4-NH2-10-CH3PteGlu-gamma-(3,3-difluoroglutamate) was also enhanced. These results are consistent with F2Glu enhancing the synthesis of poly(gamma-glutamate) metabolites at the level of either the incoming amino acid (glutamate analog) or the gamma-glutamyl acceptor species. F2Glu is thus the first glutamate analog which enhances chain elongation catalyzed by folypolyglutamate synthetase.

Animals↗
PubMed1984

Comparison of folylderivative biosynthesis in Ehrlich ascites carcinoma cells and in some organs of healthy and tumor-bearing mice.

Biosynthesis of folylderivatives derived from subcutaneously injected 2-[14C]folate was studied in Ehrlich ascites carcinoma (EAC) cells and in liver and kidneys of healthy and tumor-bearing mice. Retention of exogenous folate was followed by measurements of the total radioactivity of folylderivatives present in the EAC cells and organs examined. Identification of unconjugated and conjugated folylderivatives was done by means of column chromatography on Sephadex G-25, G-15 and cellulose sheets. The level of retained radioactivity in folyderivatives, being 5% in the liver and 1% in the kidneys of the radioactivity administered to mice, was similar in healthy and tumor-bearing animals. Moreover, no quantitative and qualitative differences were found in folylmono-and polyglutamates originated from the organs of healthy or tumor-bearing mice, although the content of folylpolyglutamates arose faster in liver and kidneys of EAC cells-bearing mice as well as in the tumor cells than in the organs of healthy mice.

Animals↗