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At least 631 records · Page 35Linked to original sources
PubMed1986

Modification of hepatic folate metabolism in rats fed excess retinol.

Feeding rats a diet containing 1000 IU of retinol/g diet enhances the folate-dependent oxidation to CO2 of formate and histidine. The activity of hepatic methylenetetrahydrofolate reductase, which plays a critical role in the regulation of liver folate metabolism, is suppressed in these animals, resulting in decreased 5-methyltetrahydrofolate synthesis. This ensures a greater concentration of hepatic tetrahydrofolate, the coenzyme on which formate and histidine oxidation depend, but also compromises the level of S-adenosylmethionine in the liver.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1991

The toxicity of methanol.

Methanol toxicity in humans and monkeys is characterized by a latent period of many hours followed by a metabolic acidosis and ocular toxicity. This is not observed in most lower animals. The metabolic acidosis and blindness is apparently due to formic acid accumulation in humans and monkeys, a feature not seen in lower animals. The accumulation of formate is due to a deficiency in formate metabolism which is, in turn, related, in part, to low hepatic tetrahydrofolate (H4 folate). An excellent correlation between hepatic H4 folate and formate oxidation rates has been shown within and across species. Thus, humans and monkeys possess low hepatic H4 folate levels, low rates of formate oxidation and accumulation of formate after methanol. Formate, itself, produces blindness in monkeys in the absence of metabolic acidosis. In addition to low hepatic H4 folate concentrations, monkeys and humans also have low hepatic 10-formyl H4 folate dehydrogenase levels, the enzyme which is the ultimate catalyst for conversion of formate to carbon dioxide. This review presents the basis for the role of folic acid-dependent reactions in the regulation of methanol toxicity.

Animals↗
PubMed1992

Formate metabolism in micropigs.

The toxicity of methanol is directly related to the accumulation of formate which, in turn, is related to the adequacy of the folate-dependent metabolism of formate to carbon dioxide. Thus, humans who possess low hepatic folates and low 10-CHO H4folate dehydrogenase activity metabolize formate poorly and are sensitive to methanol. Conversely, most laboratory species do not exhibit methanol toxicity because they metabolize formate at high rates. Studies reported here show that the Yucatan micropig has the lowest hepatic folates of any animal species studied. Formate oxidation rates in micropigs were 23% of rates reported for rats. The half-life of formate disappearances from the blood was 74 min, a value twice that reported for rats. In addition, 10-CHO H4folate dehydrogenase activity and amount in micropig liver is markedly reduced. Micropigs may prove useful in studies of methanol poisoning due to their low capacity for formate oxidation and their reasonable size and ease in handling.

Animals↗
PubMed1982

ZTP (5-amino 4-imidazole carboxamide riboside 5'-triphosphate): a proposed alarmone for 10-formyl-tetrahydrofolate deficiency.

Starvation of Salmonella typhimurium for folate in six different ways triggers the intracellular accumulation of a novel ribotide, 5-amino 4-imidazole carboxamide riboside 5'-triphosphate (ZTP). Numerous other starvations not involving folate do not cause ZTP to accumulate. We propose that ZTP is an alarmone for C-1-folate deficiency and present evidence that it is formed from ZMP, an intermediate in purine biosynthesis. ZMP accumulates rapidly in cells when 10-formyl-tetrahydrofolate, a substrate for ZMP transformylase, is depleted. We review previous evidence that Z-ribotides may be involved in physiological processes in many types of cells, including sporulation of Bacillus subtilis. We also discuss the implications of ZTP synthesis for chemotherapy and other pharmacological uses of antifolates and analogs of Z-ribosides.

Aminoimidazole Carboxamide↗
PubMed1991

De novo purine nucleotide biosynthesis: cloning, sequencing and expression of a chicken PurH cDNA encoding 5-aminoimidazole-4-carboxamide-ribonucleotide transformylase-IMP cyclohydrolase.

The purH cDNA, encoding 5-aminoimidazole-4-carboxamide-ribonucleotide (AICAR) transformylase-inosine monophosphate cyclohydrolase (ATIC), was cloned by functional complementation of an Escherichia coli purH mutant using a chicken liver cDNA expression library. This represents the first report of the cloning of any eukaryotic ATIC-encoding cDNA (PurH). The avian ATIC mRNA is 2.3 kb long and encodes a protein with an Mr of 64,422. The deduced amino acid sequence is 36% identical to the bacterial purH-encoded enzymes from Bacillus subtilis and E. coli. The avian cDNA was expressed as a glutathione S-transferase (GST) fusion protein that was purified in a single step by affinity chromatography. A novel vector was employed which permits rapid and highly efficient cleavage of the GST fusion protein yielding 10 mg of purified PurH product per liter of bacterial culture. Km values were determined with the purified fusion protein utilizing AICAR and (6-R)N10-formyl-tetrahydrofolate as substrates. These values compare favorably with the isolated avian enzyme, supporting the idea that kinetic, as well as other physical properties of the recombinant fusion protein are similar to the native avian enzyme. Large quantities of purified enzyme and the ability to generate site-directed mutations should make mechanistic studies possible. The recombinant enzyme also affords a simple and reliable approach to identifying new antifolates.

Acyltransferases↗
PubMed1990

Folates: epileptogenic effects and enhancing effects on [3H]TBOB binding to the GABAA-receptor complex.

The biochemical mechanism responsible for the convulsive effects of folates was investigated. The epileptogenic effects of folates were determined in vivo by quantification of the seizures following intracortical application in rats. The rank order of epileptogenic effects is: folic acid greater than or equal to 5-HCO-H4 folate greater than H2 folate greater than 5-CH3-H4 folate. This sequence of epileptogenicity in vivo is compared to the rank order of the effects of folates on radioligand binding to the GABAA-receptor complex in vitro. The inhibitory potencies of folates on [3H]muscimol and [3H]diazepam bindings did not correlate with their epileptogenic effects. However, folates reverse the inhibiting effect of GABA on the binding of the cage convulsant [3H]TBOB [( 3H]t-butylbicycloorthobenzoate). The rank order of this in vitro effect (folic acid greater than 5-HCO-H4 folate greater than H2 folate = 5-CH3-H4 folate) resembles the rank order of epileptogenicity determined in vivo. A relationship between the in vivo and in vitro effects is therefore suggested.

Animals↗
PubMed1982

Purification and partial characterization of rat liver folate binding protein: cytosol I.

The high molecular weight folate binding protein of rat liver cytosol has been purified to apparent homogeneity. Purification was achieved by using a combination of gel filtration, O-(diethylaminoethyl)cellulose chromatography, and affinity chromatography. This folate binding protein was initially identified during purification by an in vivo labeling procedure involving intraperitoneal injection of [3H]folic acid prior to sacrifice and subsequently by its ability to bind naturally reduced [3H]folate polyglutamates in vitro. A molecular weight of 210 000 was estimated by gel chromatography. This is distinct from the trifunctional formyl-methenyl-methylene synthetase of rat liver which has a molecular weight of 225 000. Sodium dodecyl sulfate electrophoresis revealed a single band with a molecular weight of about 100 000 which suggests the native protein is composed of two identical subunits. The partially purified protein contains bound tetrahydropteroylpentaglutamate.

Animals↗
PubMed1979

Preparation and purification of L-(+/-)-5-formyl-5,6,7,8-tetrahydrofolic acid.

Reinvestigation of the conversion of folic acid to leucovorin [L-(+/-)-5-CHO-THF] led to improved methods for the synthesis of this drug, which is suitable for clinical use. Also, methods were developed for the chromatographic and nonchromatographic purification of less pure samples of L-(+/-)-5-CHO-THF.

Chromatography, Liquid↗
PubMed1975

Folate metabolism in the rat liver during regeneration after partial hepatectomy.

1. Folate metabolism was studied during the early phases of liver regeneration after partial hepatectomy in rats accustomed to eating during the first 8h of a daily 12h dark period. 2. The content of 5-CH(3)-H(4)folate was drastically decreased during the first hours of regeneration. 3. The total HCO-H(4)folate coenzymes showed a constant decrease during the first 3 days of regeneration, and a continuous interconversion between 5-HCO-H(4)folate and 10-HCO-H(4)folate. 4. 10-HCO-H(4)folate synthetase, serine hydroxymethyl-transferase and 5,10-CH(2)-H(4)folate dehydrogenase activities were relatively low during the first hours after the operation, and increased only several hours later. 5. The increase in enzyme activities showed a stepwise pattern, apparently due to an interaction between the regeneration process and the controlled feeding schedules.

Animals↗
PubMed1977

The effects of hyperphenylalaninaemia on the concentrations of aminoacyl-transfer ribonucleic acid in vivo. A mechanism for the inhibition of neural protein synthesis by phenylalanine.

An acute administration of phenylalanine to neonatal animals has been reported to result in large decreases in the intracellular concentrations of several essential amino acids in neural tissue, as well as an inhibition of neural protein synthesis. The present report evaluates the effects of the loss of amino acids on the concentrations of aminoacyl-tRNA in vivo, with the view that an alteration in the concentrations of specific aminoacyl-tRNA molecules could be the rate-limiting step in brain protein metabolism during hyperphenylalaninaemia. tRNA was isolated from saline- and phenylalanine-injected mice 30-45 min after injection, by using a procedure designed to maintain the concentrations of aminoacyl-tRNA present in vivo. Periodate oxidation of the non-acylated tRNA and aminoacylation with radioactively labelled amino acids was used to determine the proportion of tRNA that was present in vivo as aminoacyl-tRNA. Although decreases in the intracellular concentrations of alanine, lysine and leucine were observed after phenylalanine administration, the concentrations of alanyl-tRNA, lysyl-tRNA and leucyl-tRNA actually increased by 15%. Although tryptophan has been suggested to be rate-limiting during hyperphenylalaninaemia, the proportion of tryptophan tRNA that was acylated was maximal in both normal and hyperphenylalaninaemic animals. This unexpected increase in aminoacyl-tRNA concentration is discussed as perhaps a secondary effect resulting from the phenylalanine-induced inhibition of protein synthesis. In contrast, the proportion of methionine tRNA that was acylated in vivo after phenylalanine administration was demonstrated to be decreased by approx. 17%. When the isoaccepting species of methionine tRNA were separated by reverse-phase column chromatography, three species were separated, one of which was demonstrated to be the initiator species, tRNAfMet, by the selective aminoacylation and formylation with Escherichia coli enzymes. After the administration of phenylalanine, the acylation of each of the three methionine tRNA species was decreased, with the initiator species being lowered by 10%. This effect on aminoacylation of tRNAfMet may be the primary step by which phenylalanine affects neural protein synthesis, and this is consistent with previous reports that re-initiation may be inhibited during hyperphenylalaninaemia.

Acylation↗
PubMed1998

A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells.

A common mutation (C677T) in the gene encoding for methylenetetrahydrofolate reductase (MTHFR) (5-methyltetrahydrofolate:(acceptor) oxidoreductase, EC 1.7.99.5), a key regulatory enzyme in one-carbon metabolism, results in a thermolabile variant of the MTHFR enzyme with reduced activity in vitro. In the present study we used a chromatographic method for folate analysis to test the hypothesis that this mutation would be associated with altered distribution of red blood cell (RBC) folates. An alteration was found as manifested by the presence of formylated tetrahydrofolate polyglutamates in addition to methylated derivatives in the RBCs from homozygous mutant individuals. 5-Methyltetrahydrofolate polyglutamates were the only folate form found in RBCs from individuals with the wild-type genotype. Existence of formylated folates in RBCs only from individuals with the thermolabile MTHFR is consistent with the hypothesis that there is in vivo impairment in the activity of the thermolabile variant of MTHFR and that this impairment results in an altered distribution of RBC folates.

Adult↗
PubMed1982

Studies on the response of Lactobacillus casei to different folate monoglutamates.

1. The response of Lactobacillus casei was measured for a number of the monoglutamyl forms of folate derivatives. 2. At the concentrations of folate commonly used in the assay of folate vitamin in foods the response of L. casei to folic acid, (pteroylglutamic acid) and 5-formyl-tetrahydrofolic acid was similar, but 5-methyl-tetrahydrofolic acid gave as little as half the response of folic acid. 3. The response was modified by altering pH but not by concentration of ascorbate. 4. These results have implications for the assays of foods for folate where mixtures of folate derivatives are present. 5. A modified procedure is suggested in which the monoglutamates give similar responses.

Ascorbic Acid↗
PubMed1982

Interaction of aminoacyl-tRNA with bacterial elongation factor Tu: GTP complex: effects of the amino group of amino acid esterified to tRNA, the amino acid side chain, and tRNA structure.

The present investigation was undertaken to see to what extent the alpha-amino group of the amino acid, the side chain of the amino acid of aminoacyl-tRNA, and the tRNA structure are involved in determining the affinity of aminoacyl-tRNA for bacterial elongation factor Tu-GTP complex. Various aminoacyl-tRNAs, mis-aminoacylated tRNAs, and formylated aminoacyl-tRNAs were prepared, and the dissociation constants of the ternary complexes of aminoacyl-tRNA with ET-Tu: GTP were determined by the RNase-resistance assay. The results indicated that the free amino-acid group of the amino acids in aminoacyl-tRNA is strongly required for binding with EF-Tu : GTP. In this concentration, the biological significance of formylation for Met-tRNAMetf species is discussed.

Amino Acids↗