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PubMed1979

Thiamine intestinal transport and phosphorylation : a study in vitro of potential inhibitors of small intestinal thiamine-pyrophosphokinase using a crude enzymatic preparation.

Using as enzymatic source the cytoplasmatic fraction of enterocytes isolated from the rat small intestine, thiamine-pyrophosphokinase activity was studied with a radiometric method using [thiazole-2-(14)C] thiamine. The Km value for thiamine was 2.14 X 10(-6) M and V 0.87 nmol of thiamine pyrophosphate mg-1 protein h-1. Eleven thiamine structural analogs and derivatives were assayed for their inhibitory action on the small intestine thiamine-pyrophosphokinase activity. Their Ki values were : pyrithiamine, 2.25 X 10(-6) M; thiamine monophosphate, 4 X 10(-6) M; 2'-ethylthiamine, 8 X 10(-6) M; 2'-butylthiamine, 6 X 10(-6) M; chloroethylthiamine and dimethalium, 1.5 X 10(-5) M; amprolium, 1.8 X 10(-4) M; L-582571, 1.65 X 10(-4) M; oxythiamine, 4.2 X 10(-3) M. Of the miscellaneous compounds tested (toxopyrimidine, Na-pyrophosphate, choline, L-phenylalanine, ethyl-urethane and 5-fluorouracil), none had any inhibitory action on intestinal thiamine-pyrophosphokinase activity, even if used at concentrations hundred times higher than that of labelled thiamine.

Animals↗

PubMed1984

Thiamin absorption by small intestine.

In different animal species, including man, thiamin is absorbed in vivo from the small intestine by means of two mechanism: at low intraluminal concentrations (less than 1.5 microM), absorption shows a saturation kinetics; at higher concentrations, passive transport (diffusion) takes place. The absorption is maximal in the duodenum, its rate decreasing caudally along the small intestine. In vitro at low concentrations, the transcellular transport system of thiamin shows the following general features: it takes place against a chemical concentration gradient, is easily saturable (Km = 0.16-0.63 microM; Vmax = 5.2 mumol X g-1 X h-1), is blocked by cellular metabolic inhibitors, anoxia, low temperature and thiamin structural analogues. It is Na+-dependent and operates mainly from mucosa to serosa. In contrast, distinctive features of the thiamin transfer are the following: entry in the enterocyte in the free form (sodium-independent); pyrophosphorylation by means of a cytoplasm thiamin-pyrophosphokinase; the dephosphorylation of thiamin-pyrophosphate by means of particulate intracellular phosphatases; the cellular exit mainly in the free form, through the action of the controluminal Na-K activated ATPase. A working scheme for thiamin intestinal transport is proposed and discussed.

Animals↗

PubMed1980

Recurrent febrile lymphadenopathy treated with large doses of vitamin B1: report of two cases.

The 2 children whose cases are reported here both had recurrent episodes of fever and cervical lymphadenopathy. The conventional approach had been unsuccessful in identifying the cause or therapy. In neither case was there an infectious agent demonstrated, and biopsy of a pathologically enlarged lymph gland revealed only reactive hyperplasia in each case. Abnormal metabolism was revealed in the first patient by detecting a substance in urine which is reported to be diagnostic for a form of subacute necrotizing encephalomyelopathy. In the second case, red cell transketolase indicated thiamine pyrophosphate deficiency. Both children had elevated concentrations of folate and B12 in serum. Neither of the 2 patients had further episodes when given a clinical trial with large doses of thiamine hydrochloride. Recurrent episodes of febrile lymphadenopathy are extemely frequent in children and spontaneous resolution occurs, while in others there is either proven or assumed infection. Although final proof of therapeutic efficacy is lacking, the rapid improvement and maintenance of health in both children was striking after conventional therapy had failed.

Child, Preschool↗

PubMed2006

Flipping off the riboswitch: RNA structures that control gene expression.

Riboswitches are metabolite-sensing RNA structures that have been discovered in regulatory regions of messenger RNA (mRNA). They have the remarkable ability to shut off the transcription or translation of their own mRNAs in response to binding a specific metabolite. In other words, riboswitches regulate their own genes using RNA instead of protein. Three new crystal structures reveal how S-adenosylmethionine and thiamine pyrophosphate riboswitches accomplish this task.

Animals↗

PubMed1981

Wernicke-Korsakoff syndrome in monozygotic twins: a biochemical peculiarity.

A pair of monozygotic twins, one suffering from the Wernicke-Korsakoff syndrome, verified at autopsy, and the other healthy, was studied biochemically. The erythrocyte transketolase of each twin showed abnormalities, though these differed in the two individuals. In the healthy twin, the basal transketolase was low, but responded normally to thiamine pyrophosphate (TPP) added in vitro. In the twin with the Wernicke-Korsakoff syndrome the basal level of the enzyme and its response in vitro were normal, but a period of treatment with thiamine tetrahydrofurfuryldisulphide, led to loss of the in vitro response. It is suggested that, initially, an inborn error of metabolism may have been common to both twins.

Alcohol Amnestic Disorder↗

PubMed1995

Biotin synthase from Escherichia coli, an investigation of the low molecular weight and protein components required for activity in vitro.

We have developed a radiochemical method for the measurement of biotin synthase activity in vitro. A cell-free extract from an Escherichia coli strain containing a cloned bioB (biotin synthase) gene was incubated with [14C]dethiobiotin, which was converted to [14C] biotin. The assay was used to identify the low molecular weight compounds and two of the proteins that, in addition to the bioB gene product, are required for biotin synthase activity in vitro. The low molecular weight compounds are cysteine; S-adenosylmethionine; thiamine pyrophosphate; Fe2+; a pyridine nucleotide (the most effective being NADPH); and one of the amino acids asparagine, aspartate, glutamine, or serine. The proteins ae flavodoxin and ferredoxin (flavodoxin)-NADP+ reductase (EC 1.18.1.2). A third thiamine pyrophosphate-dependent protein is also required for activity. When the cell-free extract was incubated with nonlabeled dethiobiotin and either [35S]cysteine or [35S]cystine, 35S was incorporated into biotin, and we present further evidence that cysteine, and not S-adenosylmethionine or methionine, is the sulfur donor for the biotin synthase reaction.

Amino Acid Sequence↗

PubMed1993

Reappraisal of regional thiamine content in the central nervous system of the normal and thiamine-deficient mice.

The regional distribution of thiamine and its phosphate esters was measured in the central nervous system (CNS) of normal and thiamine-deficient mice. Twelve small areas were punched out from frozen sections and they were individually analyzed by high performance liquid chromatography (HPLC). Regional difference was noted in both the content and ratio of thiamine and its phosphate esters in the normal CNS. In pyrithiamine-induced thiamine deficiency, thiamine pyrophosphate (TPP) content in all the areas was reduced to less than 13% of the control values on day 10, when the neurological signs developed. Although there were considerable regional variations in the reduction rate of thiamine and its phosphate esters, no correlation was established between the severity of tissue damage and the magnitude of thiamine reduction in individual areas. These results indicate that a derangement in TPP-dependent processes, either alone or in combination with other factors, plays a more critical role in the neuronal damage under thiamine deficiency than depletion of thiamine compounds per se.

Animals↗

PubMed1997

The response to treatment of subclinical thiamine deficiency in the elderly.

The significance of subclinical thiamine deficiency in the elderly was determined by assessing response to thiamine supplementation in a randomized double-blind, placebo-controlled trial. Thirty-five of 222 people aged > or = 65 y had two concentrations of erythrocyte thiamine pyrophosphate (TPP) < 140 nmol/L 3 mo apart and 41 other people had the first, but not the second, TPP concentration below this value. Both groups were randomly assigned in a double-blind trial to oral thiamine (10 mg/d) or a placebo. All subjects randomly assigned to receive thiamine showed increases in TPP concentrations compared with control subjects. Only the subjects with persistently low TPP concentrations showed subjective benefits from treatment with improvements in quality of life (measured on a visual analogue scale; P = 0.02) and decreases in systolic blood pressure (P = 0.05) and weight (P < 0.01) when compared with subjects given placebo. There was a trend toward benefits in sleep and energy (P = 0.07). We conclude that a low TPP concentration on two occasions is a better predictor of response to treatment than an isolated measurement. Quality of life was enhanced by providing thiamine supplements. Blood pressure and weight were lower after thiamine supplementation.

Administration, Oral↗

PubMed1998

Thiamin and riboflavin status of medical inpatients.

Thiamin status was assessed by erythrocyte transketolase activity (ETKA) and thiamin pyrophosphate effect (TPPE) and riboflavin status by erythrocyte glutathione reductase activity (EGRA) and activity coefficient (AC) in 165 medical inpatients in Ramathibodi Hospital. Based on TPPE > 15 per cent, 9 per cent of the medical inpatients had thiamin depletion. Most of them were patients with renal, cardiovascular, hematological and infectious diseases. Based on AC > or = 1.2, 17 per cent of these inpatients had riboflavin depletion. Most of them were patients with pulmonary, cardiovascular and hematological diseases. Only one patient with pulmonary disease had both thiamin and riboflavin depletion. The proportion of thiamin depletion (2/37) in subjects with thiamin supplementation (mean 32.4, median 6, mode 2 md/d) tended to be less than those without (9/98). But, subjects with riboflavin supplementation (mean 3.3, median 4, mode 1 md/d) had the proportion of riboflavin depletion (0/31) significantly (Z-test, p < 0.005) lower than without supplementation (23/104). The data suggested that although the usual dose of vitamin supplementation in medical inpatients is beneficial thiamin depletion can still be present in catabolic patients.

Adult↗

PubMed1982

Thiamine transport in Saccharomyces cerevisiae protoplasts.

Thiamine was found to be accumulated in protoplasts of Saccharomyces cerevisiae in the same manner as in intact cells, suggesting that a soluble thiamine-binding protein in periplasm may not be an essential component of the thiamine transport system of S. cerevisiae. It was also found that thiamine pyrophosphate cannot be taken up by yeast protoplasts.

Acid Phosphatase↗

PubMed1999

The effects of maternal thiamine nutrition on thiamine status of the offspring in broiler chickens.

The response of broiler chickens to a wide range of dietary supplementation of thiamine to broiler breeder diet was studied in order to understand the effects of maternal thiamine nutrition on the status of thiamine indices in the offspring. Thiamine, and thiamine pyrophosphate (TPP) content, and alpha-ketoglutarate dehydrogenase (KGDH) activity were measured in hearts from 20 day old chicken embryos and from chickens at 1, 7, 14, and 21 days of age and in blood at 21 days of age. Total thiamine content in the heart of day old chicks was higher in comparison to 20 day old embryos. Maternal supplementation of thiamine increased heart thiamine in the offspring (p < 0.001), and increased the activity of KGDH in the hearts of day old chicks (p < 0.001), but not in the embryo. The TPP content in the heart increased in response to both maternal and offspring thiamine supplementation (p < 0.001), however the effect of broiler thiamine supplementation was largely independent from the maternal effect. The effect of maternal thiamine nutrition on the offspring's heart KGDH activity was apparent, but the responses to broiler supplementation were dependent largely on the maternal effect. Blood TPP content was not affected by maternal thiamine supplementation (p = 0.39), but thiamine supplementation in the offspring diets increased blood TPP (p < 0.001). Both maternal and offspring thiamine supplementation increased blood free base thiamine content (both p < 0.001). It is concluded from this study that maternal thiamine nutrition affects thiamine status indices and thiamine metabolism of the offspring.

Aging↗

PubMed1978

A radiochemical method for the determination of transketolase activity in erythrocyte hemolysates.

A radiochemical method for the determination of transketolase activity is reported. It is based on incubation of erythrocyte hemolysates with radioactive ribose 5-phosphate followed by isolation of sedoheptulose 7-phosphate on anion-exchange columns. The experimental conditions are discussed and the presence of phosphatase activity in the incubation mixture is demonstrated. The proposed method is compared with a current colorimetric method. Reference values are given for the transketolase activity and the thiamine pyrophosphate effect.

Adult↗

PubMed1981

[Characterization of the kinase activity of bovine adrenal pyruvate dehydrogenase complex].

In the presence of [gamma-32P]ATP the bovine adrenal pyruvate dehydrogenase complex accepts the label simultaneously and becomes inactivated. This suggests the existence of kinase in the composition of the complex as is typical of the complexes from other animal sources. The Pi is incorporated into the subunit with molecular weight of 42 000. The kinase activity of the adrenal pyruvate dehydrogenase complex is high: within the first 20 sec of incubation with ATP the inactivation is as high as 60%. The pH optimum for kinase is around 7.3. The apparent Km value for ATP with 50 mM KCl is 7 microM; that in the absence of KCl is 10 microM. ADP is a competitive inhibitor of kinase with respect to ATP (Ki = 100 microM), when K+ are present in the medium. Thiamine pyrophosphate and pyruvate decrease the rate of pyruvate dehydrogenase complex inactivation.

Adrenal Glands↗

PubMed1999

Biosynthesis of the pyrimidine moiety of thiamine independent of the PurF enzyme (Phosphoribosylpyrophosphate amidotransferase) in Salmonella typhimurium: incorporation of stable isotope-labeled glycine and formate.

Genetic analyses have suggested that the pyrimidine moiety of thiamine can be synthesized independently of the first enzyme of de novo purine synthesis, phosphoribosylpyrophosphate amidotransferase (PurF), in Salmonella typhimurium. To obtain biochemical evidence for and to further define this proposed synthesis, stable isotope labeling experiments were performed with two compounds, [2-13C]glycine and [13C]formate. These compounds are normally incorporated into thiamine pyrophosphate (TPP) via steps in the purine pathway subsequent to PurF. Gas chromatography-mass spectrometry analyses indicated that both of these compounds were incorporated into the pyrimidine moiety of TPP in a purF mutant. This result clearly demonstrated that the pyrimidine moiety of thiamine was being synthesized in the absence of the PurF enzyme and strongly suggested that this synthesis utilized subsequent enzymes of the purine pathway. These results were consistent with an alternative route to TPP that bypassed only the first enzyme in the purine pathway. Experiments quantitating cellular thiamine monophosphate (TMP) and TPP levels suggested that the alternative route to TPP did not function at the same capacity as the characterized pathway and determined that levels of TMP and TPP in the wild-type strain were significantly altered by the presence of purines in the medium.

Amidophosphoribosyltransferase↗

PubMed1989

Acrylamide and thiamine.

Acrylamide administration to rats caused clear alteration of blood thiamine content, which appeared to reflect suppressed intake and/or utilization of the vitamin in the body. Decreased utilization of thiamine does not seem to be induced by decreased binding of thiamine pyrophosphate (TPP) and apotransketolase, because acrylamide did not affect the Km of TPP for transketolase activity.

Acrylamides↗

PubMed1975

Erythrocyte transketolase activity in adult Ghanaian subjects.

The erythrocyte transketolase activity, and the effect of thiamin pyrophosphate stimulation (TPP effect) on this enzyme, was determined in 263 adult Ghanaian subjects who included normal males and females, male labourers known to consume a diet high in carbohydrate, diabetics and pregnant women. Using the guideline that a TPP effect of greater than 25% indicates thiamin deficiency, it was found that a significant proportion of apparently healthy subjects (36%-47%) may be regarded as thiamin deficient. The results are discussed in the light of similar studies carried out by other workers.

Diabetes Mellitus↗

PubMed2006

A Korean female patient with thiamine-responsive pyruvate dehydrogenase complex deficiency due to a novel point mutation (Y161C)in the PDHA1 gene.

Pyruvate dehydrogenase complex (PDHC) deficiency is mostly due to mutations in the X-linked E1alpha subunit gene (PDHA1). Some of the patients with PDHC deficiency showed clinical improvements with thiamine treatment. We report the results of biochemical and molecular analysis in a female patient with lactic acidemia. The PDHC activity was assayed at different concentrations of thiamine pyrophosphate (TPP). The PDHC activity showed null activity at low TPP concentration (1 x 10(-3) mM), but significantly increased at a high TPP concentration (1 mM). Sequencing analysis of PDHA1 gene of the patient revealed a substitution of cysteine for tyrosine at position 161 (Y161C). Thiamine treatment resulted in reduction of the patient's serum lactate concentration and dramatic clinical improvement. Biochemical, molecular, and clinical data suggest that this patient has a thiamine-responsive PDHC deficiency due to a novel mutation, Y161C. Therefore, to detect the thiamine responsiveness it is necessary to measure activities of PDHC not only at high but also at low concentration of TPP.

Cells, Cultured↗

PubMed2000

Reduced flux through the purine biosynthetic pathway results in an increased requirement for coenzyme A in thiamine synthesis in Salmonella enterica serovar typhimurium.

Work presented here establishes a connection between cellular coenzyme A (CoA) levels and thiamine biosynthesis in Salmonella enterica serovar Typhimurium. Prior work showed that panE mutants (panE encodes ketopantoate reductase) had a conditional requirement for thiamine or pantothenate. Data presented herein show that the nutritional requirement of panE mutants for either thiamine or pantothenate is manifest only when flux through the purine biosynthetic pathway is reduced. Further, the data show that under the above conditions it is the lack of thiamine pyrophosphate, and not decreased CoA levels, that directly prevents growth.

Adenine↗