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At least 19 recordsLinked to original sources
PubMed1979

Folate metabolism and in vivo radiofolate binding in normal, folate-deficient and folate-saturated subjects.

After ingestion of 14C-CH3H4Pte Glu by folate-deficient and folate-saturated subjects, and 14C-CH3H4PteGlu as well as 3H-PteGlu by a normal control subject, the dialysis-resistant (bound) plasma radiofolate fraction appeared increased in folate saturation and decreased in folate deficiency (compared with normal folate status). This suggests that absorbed radiofolate does not admix with the total folate pool before complexing with the plasma binder. As the bound plasma fractions appeared later than did the total biofolate peaks, in vivo plasma folate binding probably occurs independently of the intestinal folate absorption process. It also appears unrelated to postabsorption storage folate displacement, as this biofolate fraction is unbound. A bound radiofolate fraction persisting in plasma for 72 hours in spite of a normal food intake indicates a relatively inert binder complex.

Adolescent↗
PubMed1976

Regulation of folate reductase synthesis in sensitive and methotrexate-resistant sarcoma 180 cells. In vitro translation and characterization of folate reductase mRNA.

A highly specific assay for folate reductase mRNA activity from Sarcoma 180 cells was developed using the rabbit reticulocyte lysate protein synthesizing system. Quantitation of in vitro folate reductase synthesis was accomplished by direct immunoprecipitation from lysate reactions. The in vitro labeled folate reductase was synthesized in a linear response to a wide range of RNA concentrations, migrated as a single prominent radioactive species upon polyacrylamide gel electrophoresis, and was indistinguishable from authentic 14C-labeled folate reductase on the basis of molecular weight and immunotitration with anti-folate reductase gamma-globulin. The assay was used to quantitate folate reductase mRNA activity in various cell lines and under several conditions known to affect folate reductase synthesis. These included (a) sensitive and methotrexate-resistant Sarcoma 180 cells, (b) two lines of resistant cells having different relative rates of folate reductase synthesis, (c) growth of methotrexate-resistant cells in the absence of methotrexate, and (d) growth phase. The results indicate that the relative rate of folate reductase synthesis in each case can be explained solely by the level of translatable folate reductase mRNA. The use of poly(U)-Sepharose and sucrose gradient fractionation procedures indicated that folate reductase mRNA contains poly(A) and has a sedimentation coefficient of approximately 14 S. These two fractionation steps were combined to achieve an approximately 90-fold purification of folate reductase mRNA over total cytoplasmic RNA.

Animals↗
PubMed1979

Folates of rat tissue. Bioassay of tissue folylpolyglutamates and a relationship of liver folypolyglutamates to nutritional folate sufficiency.

The folate content of young rat tissues extracted into boiling ascorbate was assayed by Lactobactillus casei both without and after treatment by a folate-free preparation of conjugase. The total folate content of various tissues was: liver, 8.9 microgram/g; kidney, 2.6; adrenal, 2.6; bone marrow, 2.4; spleen, 0.9; erythrocytes, 0.8; small intestinal mucosa, 0.7; small intestinal smooth muscle, 0.8; heart, 0.6; brain, 0.4, and skeletal muscle, 0.1 microgram/g tissue. For most tissues, with the exception of muscle and kidney, approximately 80% of the total folates assayed as longer chain length folylpolyglutamates. When liver folates were analyzed from rats fed folate-supplemented, control and folate-deficient diets, a relationship was found between folate nutrition and distribution of folylpolyglutamates. The proportion of total folates in the form of longer chain length folylpolyglutamates was greatest in the livers of folate-deficient rats and least in the livers of folate-supplemented rats.

Animals↗
PubMed1979

Role of serum folate binders in the delivery of folate to tissues and to the fetus.

Specific folate binding protein (FBP) and non-specific binding protein have been prepared from pooled serum from patients in late pregnancy. The two classes of folate binder were labelled with 75Se-selenofolate and injected into non-pregnant and pregnant rabbits. Selenofolate bound to specific FBP was delivered predominantly to the liver, in both pregnant and non-pregnant animals. Fetal tissue took up selenofolate from non-specific FBP only. Specific FBP thus functions to deliver folate to stores and represents a storage pool of folate. The non-specific FBP are responsible for the delivery of folate to the fetus, and probably also to sites of utilization.

Animals↗
PubMed1978

Comparison between the unsaturated plasma folate binder and in vivo labelled plasma folate binder.

Endogenous plasma folate binder denuded of folate by dialysis at pH 3, subsequently bound more methylfolate than folic acid, in contrast with the minor unsaturated plasma binder which bound folic acid in preference to methylfolate. On Sephadex DEAE-A50 chromatography 14C-CH3H4PteGlu bound to acid-denuded endogenous binder, eluted like the endogenous binder-radioactivity, labelled in vivo after oral 14C-CH3H4PteGlu. It is suggested that the endogenous plasma folate binder is not identical with the unsaturated binder.

Blood Proteins↗
PubMed1979

Characterization of endogenous folate and incorporation of labelled folates into the brain of the South African fruit bat.

Folate in the brain of the South African fruit bat consists of 10-formyltetrahydropteroyglutamic acid and the tri-, tetra- and penta- forms of 5-methyltetrahydropteroylglutamic acid. Following parenteral injection, only 5-[3H]-methyltetrahydropteroylglutamic acid was taken up by the brain, but none of a dose of 14C-labelled tetrahydropteroylglutamic acid was detectable. Only trace smounts of the 5-methyltetrahydropteroylglutamic acid were converted into the formyl compounds and a small amount of methyltetrahydropteroyltriglutamic acid appeared after 96 h. There was no significant difference in vitamin B-12-deficient animals.

Animals↗
PubMed1975

pH dependence of the binding of folates to milk binder in radioassay of folates.

We compare the binding of folic acid and N-5-methyltetrahydrofolic acid to milk binder in the pH range 7.4 to 10.1. At pH 7.4 the relative affinities are quite disparate, with folic acid showing the greater affinity for milk binder. As the pH is increased from 7.4 to 9.3, the difference in affinities becomes smaller, and at pH 9.3 the affinities are nearly the same. As the pH is increased from 9.3 to 10.1, the relative affinities again begin to differ, with N-5-methyltetrahydrofolic acid displaying the greater affinity. These results indicate that at a pH of 9.3 the more stable folic acid may be used as the standard in radioassay of endogenous folates.

Dose-Response Relationship, Drug↗
PubMed2026

Isolation of folate-producing probiotic candidates and their effects on homocysteine metabolism and gut microbiota composition.

BACKGROUND: Folate deficiency is a global nutritional problem associated with multiple adverse health outcomes, including impaired one-carbon metabolism and elevated homocysteine levels (hyperhomocysteinemia). Gut microbiota-mediated folate biosynthesis has emerged as a promising strategy for improving the host's folate status. This study aimed to isolate folate-producing probiotic strains, clarify their folate synthesis mechanisms, and evaluate their regulatory effects on folate metabolism and gut microbiota. METHODS: High-throughput cultivation and screening were performed to isolate folate-producing candidate probiotics. Whole-genome sequencing analysis, pathway reconstruction, and metabolite profiling in fermented milk were performed to explore folate biosynthesis pathways and microbial cross-feeding interactions. A folate-deficient mouse model was established to evaluate the effects of a candidate probiotic cocktail on serum folate, homocysteine (Hcy) levels, and gut microbiota composition using quantitative PCR (qPCR) and 16S rRNA gene sequencing. RESULTS: High-throughput screening identified 8 high-folate-producing candidate probiotic strains, including Lactiplantibacillus plantarum and Heyndrickxia coagulans, from over 1,000 isolates. Genomic analysis revealed that most commonly used probiotics lacked para-aminobenzoic acid (pABA) biosynthesis genes but retained downstream modules, suggesting a reliance on cross-feeding with pABA-producing gut commensals such as Bacteroides. Metabolite profiling of fermented milk demonstrated that selected strains significantly increased bioactive 5-methyltetrahydrofolate (5-MeTHF) and tetrahydrofolate levels. In vivo, only a high-dose candidate probiotic cocktail significantly elevated serum folate (p&#x202f;<&#x202f;0.05) and reduced homocysteine levels (p&#x202f;<&#x202f;0.05) in deficient mice. Fecal qPCR confirmed dose-dependent transient persistence of the administered bacterial species. Consistent with the qPCR data, 16S rRNA gene sequences demonstrated significant enrichment of these administered species observed in the high-dose group. Furthermore, beta-diversity analysis found that high-dose candidate probiotic supplementation promoted a shift in the gut microbiota composition toward a normal profile, partially mitigating the dysbiosis induced by the folate-deficient diet. This effect was accompanied by a significant enrichment of potential short-chain fatty acid producers (e.g., Lachnospiraceae and Oscillospiraceae) and the depletion of potential opportunistic pathogens. CONCLUSION: This study screened high-folate-producing candidate probiotic strains and demonstrated their ability to synthesize the active form of 5-MeTHF. Moreover, folate-producing candidate probiotic cocktail treatment significantly improved folate status and Hcy metabolism and modulated the gut microbiota by enriching potential beneficial bacterial taxa. These findings suggested that folate-producing probiotics may serve as a promising microbiota-based strategy to improve folate availability and homocysteine metabolism.

B vitamin↗
PubMed1976

Absorption and malabsorption of folates.

Folic acid is one of the 'younger' vitamins, yet it has attracted intensive study in the thirty years since the identification of pteroylglutamic acid and its polyglutamyl conjugates. The absorption and malabsorption of folates, natural, purified and synthetic, in disease has been studied more than any other vitamin and indeed folate absorption has become one clinical test of intestinal function. We know little about the release of folate from protein complexes, but we have learned, with the help of synthetic radiolabelled pteroylpolyglutamates that polyglutamyl folates are hydrolysed at or near the luminal border of the intestine and the released folate is efficiently absorbed. The rate limiting stage of folate absorption appears to be the transport of the monoglutamyl folate. In disease, and with drugs, folate malabsorption occurs primarily when monoglutamyl transport is depressed. The specific components of the folate transport system, listed in Table 4, are receiving increased attention. The mechanism of uptake is still a topic of controversy but a dual system including both a saturable and a diffusion component would explain most of the data. Reduction and methyl or formyl addition occur in the intestine but such metabolism is not obligatory for transport. The nature of folate binding within the cell and the function of specific folate binding proteins requires further study. At present we have little or no information about the mechanism of folate release from the epithelial cell to the circulation but this step also could influence the rate and specificity of overall process. The tools are now at hand to complete our understanding of the steps in folate absorption and metabolism. Such an understanding should facilitate the management of folate deficiency whenever it complicates gastrointestinal disease or drug therapy.

Alcoholism↗
PubMed1979

Mechanism of folate transport in Lactobacillus casei: evidence for a component shared with the thiamine and biotin transport systems.

Lactobacillus casei cells have been shown previously to utilize two separate binding proteins for the transport of folate and thiamine. Folate transport, however, was found to be strongly inhibited by thiamine in spite of the fact that the folate-binding protein has no measurable affinity for thiamine. This inhibition, which did not fluctuate with intracellular adenosine triphosphate levels, occurred only in cells containing functional transport systems for both vitamins and was noncompetitive with folate but competitive with respect to the level of folate-binding protein. Folate uptake in cells containing optimally induced transport systems for both vitamins was inhibited by thiamine (1 to 10 muM) to a maximum of 45%; the latter value increased to 77% in cells that contained a progressively diminished folate transport system and a normal thiamine system. Cells preloaded with thiamine could transport folate at a normal rate, indicating that the inhibition resulted from the entry of thiamine rather than from its presence in the cell. In a similar fashion, folate (1 to 10 muM) did not interfere with the binding of thiamine to its transport protein, but inhibited thiamine transport (to a maximum of 25%). Competition also extended to biotin, whose transport was strongly inhibited (58% and 73%, respectively) by the simultaneous uptake of either folate or thiamine; biotin, however, had only a minimal effect on either folate or thiamine transport. The nicotinate transport system was unaffected by co-transport with folate, thiamine, or biotin. These results are consistent with the hypothesis that the folate, thiamine, and biotin transport systems of L. casei each function via a specific binding protein, and that they require, in addition, a common component present in limiting amounts per cell. The latter may be a protein required for the coupling of energy to these transport processes.

Biological Transport, Active↗
PubMed1976

Subcellular localization of gamma-glutamyl carboxypeptidase and of folates.

The subcellular distributions of glutamyl carboxypeptidase, folate specific activities, and radioactive metabolites of injected [3H] folic acid were studied in rat liver. The specific activity of glutamyl carboxypeptidase in the lysosomal fraction was near or greater than four times that in the other subcellular fractions. The specific activity of folates was highest in the soluble fraction (102 ng folate/mg protein) and lowest in the microsomal fraction (22 ng folate/mg protein). Nuclear, mitochondrial, and lysosomal folates were 95% folate polyglutamates, and microsomal and soluble folates were 85--90% folate polyglutamates. Injected [3H] folic acid was initially concentrated in the microsomal fraction, as measured by 3h cpm per ng folate. Initially, injected [3H] folic acid was found converted to folate penta- and hexaglutamates in all fractions to a similar extent except in the microsomes where the percentage conversion was much less, as measured by the percentage of total 3H cpm determined to be [3H] folate penta- and hexaglutamates. At 24 h, the conversion of [3H] folates to penta- and hexaglutamates in each fraction was less than that found for the endogenous folates. Injected [3H] folic acid after 2h was found to consist of 94% reduced folates in the soluble fraction, 56% in the mitochondrial, 55% in the nuclear, 20% in the lysosomal, and 15% in the microsomal fraction.

Acid Phosphatase↗
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↗
PubMed1979

Kinetics of the normal folate enterohepatic cycle.

Detailed studies were undertaken to better define the role of the liver and the folate enterohepatic cycle in folate homeostasis. Three isotopes of folate were employed in a rat model to study several parameters: (a) intestinal transport; (b) variation in hepatic uptake after different routes of administration; (c) hepatic reduction, methylation, and polyglutamate formation; (d) biliary excretion; (e) transport of folate to tissue and its return to liver for re-entry into the enterohepatic cycle. Folate absorption was not affected by the type of folate administered, but subsequent liver accumulation was greater when PteGlu(1) was given rather than CH(3)H(4)PteGlu(1). After liver uptake, CH(3)H(4)PteGlu(1) is rapidly and quantitatively excreted into bile, whereas nonmethylated folates are either methylated and transported into bile or incorporated into a hepatic polyglutamate pool. Bile folate is then reabsorbed for distribution to both tissue and liver, completing the enterohepatic cycle. The importance of this cycle was demonstrated by long-term bile drainage and by transport studies with two isotopes of CH(3)H(4)PteGlu(1). With bile drainage, serum folate levels fell to 30-40% of normal within 6 h, a much more dramatic drop than that seen with folate-free diets alone. Studies with labeled CH(3)H(4)PteGlu(1) demonstrated that about one-third was taken up by tissue, demethylated, and returned to liver for remethylation and recirculation through the bile and gut. This establishes the enterohepatic cycle as a major factor in folate homeostasis and, for the first time, demonstrates a transport pathway between tissue and liver for nonmethylated folate.

Animals↗
PubMed1979

Enzymatic reduction and methylation of folate following pH-dependent, carrier-mediated transport in rat jejunum.

Intestinal transport of [3H] folate was studied using everted sacs of rat jejunum. The proximal small intestine transports folate against a concentration gradient by a system which is saturable, pH-dependent, energy-dependent, sodium-dependent, sensitive to temperature, and appears to be a common transport system for folate compounds. Chromatographic analysis of folate compounds in the serosal compartment after a 60 min incubation with folate in the mucosal medium in sodium phosohate buffer indicated that metabolism of folate to 5-methyltetrahydrofolate was extensive at pH 6.0 and negligible at pH 7.5. The percent conversion of folate to 5-methyltetrahydrofolate at pH 6.0 was reduced by increasing the concentration of folate in the mucosal medium, thus indicating saturation of the reduction and methylation process. These findings indicate that folate transport in rat jejunum occurs by an energy-dependent, carried-mediated system and that both folate transport and intestinal conversion of folate to 5-methyltetrahydrofolate are pH-dependent.

Animals↗
PubMed1975

Purification of folate binding factor in normal umbilical cord serum.

Human umbilical cord serum was found to contain both free folate and folate complexed to a high-molecular weight factor. The complexed folate was bound to a very high affinity binder and was present in concentrations equivalent to as much as 60 ng of 5-methyltetrahydrofolic acid per ml of serum. Acidification of the serum caused disassociation of the folate-binder complex. Released folates were separated from binder by Sephadex gel filtration, zonal centrifugation through sucrose gradients, or adsorption onto activated charcoal. The separated binding factor, either saturated or unsaturated with folate, had a molecular weight of about 40,000 on Sephadex G-200 chromatography. Binding of [3H]pteroylglutamic acid was rapid and, as in the original endogenous folate-binder complex, was essentially irreversible at neutral pH. The affinity and specificity of the binder were examined by competition experiments using [3H]pteroylglutamic acid and nonradioactive folate derivatives. Oxidized folates were bound in preference to reduced derivatives, but only three to four times more unlabeled 5-methyltetrahydrofolic acid than pteroylglutamic acid was required to produce an equal level of competition. The strong affinity for 5-methyltetrahydrofolic acid, the main serum folate, suggests that the binder could be part of the mechanism by which the fetus concentrates maternally supplied folate for its growth and development.

Binding Sites↗