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TUNGSTEN
In rat hepatocytes, molybdate and tungstate inactivate glycogen synthase by a mechanism independent of Ca2+ and activate glycogen phosphorylase by a Ca(2+)-dependent mechanism. On the other hand, both molybdate and tungstate increase fructose 2,6-bisphosphate levels and counteract the decrease in this metabolite induced by glucagon. These effectors do not directly modify 6-phosphofructo-2-kinase activity, even though they partially counteract the inactivation of this enzyme induced by glucagon. These effects are related to an increase on the glycolytic flux, as indicated by the increase in L-lactate and CO2 production and the decrease in glucose 6-phosphate levels in the presence of glucose. All these effects are similar to those previously reported for vanadate, although molybdate and tungstate are less effective than vanadate. These results could indicate that molybdate, tungstate and vanadate act on glucose metabolism in isolated hepatocytes by a similar mechanism of action.
Anionic activation of rod outer segment phosphodiesterase by vanadate, molybdate and tungstate is demonstrated. Comparisons are made to adenylate cyclase, which is known to be activated by vanadate and molybdate but not by tungstate. In view of the differences in anionic activation between these two important enzymatic regulators of intracellular cyclic nucleotide metabolism, it is possible that tungstate can be used as a selective probe for the effects of phosphodiesterase activity in photoreceptors and other cells. The known electrophysiological stimulation of Limulus photoreceptors by these anions is also interpreted in light of our results. If anionic production of quantum bumps in Limulus photoreceptors is mediated by changes in cyclic nucleotides, then the electrophysiological response of Limulus photoreceptors to tungstate may indicate a role for phosphodiesterase rather than adenylate cyclase in mediating light-induced cyclic nucleotide alterations in this cell.
Recent studies indicate that oxyanions, such as vanadate (V) or vanadyl (IV), cause insulin-like effects on rats by stimulating the insulin receptor tyrosine kinase. Tungstate (VI) and molybdate (VI) show the same effects on rat adipocytes and hepatocytes. Results of uncontrolled trials on volunteers accumulated in Japan also suggest that tungstate effectively regulates diabetes mellitus without detectable side effects. Since these oxyanions naturally exist in organisms, oxyanion therapy, the oral administration of vanadate, vanadyl, molybdate, or tungstate, can be considered to be orthomolecular medicine. Therefore, these oxyanions may provide a viable alternative to chemotherapy. Many diseases in addition to diabetes mellitus might also be treated since the implication of these results is that tyrosine kinases are involved in a variety of diseases.
Whole-body autoradiography and impulse counting experiments were used to study the distribution and retention of radioactivity in the pregnant mouse after administration of [185W]tungstate. A rapid uptake was found in a number of tissues--skeleton, red pulp of the spleen, adrenal, liver, thyroid, pituitary, and ovary--and in the intestine and kidneys, through which it was rapidly excreted. 185W was also readily transported from mother to fetus, although more in late than in early gestation. The largest metal retention was found in the maternal skeleton, kidneys, and spleen and in the visceral yolk sac epithelium and the skeleton of the fetus. Furthermore, in vitro cytotoxicity experiments showed inhibition by tungstate of cartilage production in limb bud mesenchymal cultures at concentrations similar to those found in vivo. [185W]trithio- and tetrathiotungstates (0.5 mg W) were injected intravenously into sheep. The compounds circulated in plasma bound reversibly to plasma proteins, particularly to albumin. After the first few minutes, levels declined exponentially with a T 1/2 of 12-14 hr. The initial movement of [185W]trithiotungstate from the plasma compartment was delayed transiently by the immediate injection of copper (2-6 mg); the longer-term metabolism was unaffected. The final fate of the compounds appeared to be hydrolysis and excretion in urine as [185W]tungstate. 185W from [185W]trithiotungstate appeared more rapidly than from [185W]tetrathiotungstate, but in both the rate was unaffected by copper injections. Since the appearance in urine did not correspond to the disappearance from plasma, it was suggested that the hydrolysis occurred in extravascular tissues and that the liver might be the site. A control experiment showed that [185W]tungstate in plasma was very rapidly cleared (and appeared in urine). At higher W levels (25-50 mg W per sheep per day), systematic copper metabolism was perturbed since plasma copper levels rose. The experiments demonstrated that in sheep the behavior and the effects of thiotungstates and thiomolybdates are sufficiently similar for 185W to be used as a more convenient alternative to 99Mo for longer-term studies on the interaction of the compounds with copper metabolism in animals. tunstates--thiotungstates affect copper metabolism.doc
The intraperitoneal administration of tetrathiotungstate to rats (6-17.4 mg W/Kg BW) caused profound changes in copper metabolism in both normal rats and in rats pretreated with copper. Plasma copper associated with albumin increased, liver copper, particularly cytosol copper, was depleted, and biliary excretion was increased. There was also a movement of copper to higher molecular weight proteins in both liver cytosol and bile. In contrast to penicillamine, tetrathiotungstate did not increase liver cytosolic apometallothionein levels and reduced the rise provoked by copper. Metallothionein-bound copper was removed. Ceruloplasmin oxidase activity was inhibited and there was evidence for increased movement of copper into subcellular organelles, probably lysosomes. It is concluded that tetrathiotungstate has a genuine "decoppering" effect and could be considered as an alternative to thiomolybdates in the treatment of copper storage diseases.
The effects of dietary supplementation with ammonium tetrathiotungstate and dithiotungstate on copper metabolism in young rats have been investigated. The addition of WS4(2-) (4-32 mg W/kg diet) decreased growth rates and induced clinical and biochemical signs of Cu deficiency. These were overcome by increasing the dietary content of Cu. The intestinal absorption of 64Cu was impaired and the tissue distribution of absorbed Cu modified by the administration of WS4(2-). No clinical or biochemical defects indicative of Cu deficiency developed in rats receiving WO2S2(2-) in their diet at concentrations up to 32 mg W/kg. In contrast, this oxythioanion enhanced the content of Cu in plasma liver and kidney, especially when dietary Cu was increased. Most of the additional Cu retained by plasma and kidney was associated with albumin and metallothionein, respectively. The effects of these W sources are compared with those caused by their thio- and oxythiomolybdate analogs and are discussed in relation to the mechanisms whereby Mo induces Cy deficiency in ruminants.
BACKGROUND: Copper-containing amine oxidases catalyze the oxidative deamination of primary amines to aldehydes, in a reaction that requires free radicals. These enzymes are important in many biological processes, including cell differentiation and growth, would healing, detoxification and signalling. The catalytic reaction requires a redox cofactor, topa quinone (TPQ), which is derived by post-translational modification of an invariant tyrosine residue. Both the biogenesis of the TPQ cofactor and the reaction catalyzed by the enzyme require the presence of a copper atom at the active site. The crystal structure of a prokaryotic copper amine oxidase from E. coli (ECAO) has recently been reported. RESULTS: The first structure of a eukaryotic (pea seedling) amine oxidase (PSAO) has been solved and refined at 2.2 A resolution. The crystallographic phases were derived from a single phosphotungstic acid derivative. The positions of the tungsten atoms in the W12 clusters were obtained by molecular replacement using E. coli amine oxidase as a search model. tunstate in copper amine oxidase.doc
Recent evidence in vivo indicates that spontaneously hypertensive rats (SHR) exhibit an increase in oxyradical production in and around microvascular endothelium. This study is aimed to examine whether xanthine oxidase plays a role in overproduction of oxidants and thereby may contribute to hypertensive states as a consequence of the increasing microvascular tone. The xanthine oxidase activity in SHR was inhibited by dietary supplement of tungsten (0.7 g/kg) that depletes molybdenum as a cofactor for the enzyme activity as well as by administration of (-)BOF4272 [(-)-8-(3-methoxy-4-phenylsulfinylphenyl)pyrazolo(1,5-alpha)-1,3, 5-triazine-4-monohydrate], a synthetic inhibitor of the enzyme. The characteristic elevation of mean arterial pressure in SHR was normalized by the tungsten diet, whereas Wistar Koto (WKY) rats displayed no significant alteration in the pressure. Multifunctional intravital videomicroscopy in mesentery microvessels with hydroethidine, an oxidant-sensitive fluoroprobe, showed that SHR endothelium exhibited overproduction of oxyradicals that coincided with the elevated arteriolar tone as compared with WKY rats. The tungsten diet significantly repressed these changes toward the levels observed in WKY rats. The activity of oxyradical-producing form of xanthine oxidase in the mesenteric tissue of SHR was approximately 3-fold greater than that of WKY rats, and pretreatment with the tungsten diet eliminated detectable levels of the enzyme activity. The inhibitory effects of the tungsten diet on the increasing blood pressure and arteriolar tone in SHR were also reproducible by administration of (-)BOF4272. These results suggest that xanthine oxidase accounts for a putative source of oxyradical generation that is associated with an increasing arteriolar tone in this form of hypertension.
Hyperhomocysteinemia results from an impaired methionine metabolism. Sulfite oxidase, which is an important enzyme in methionine metabolism, contains molybdenum. In contrast, tungsten has a molybdenum-antagonistic effect. Thus, we hypothesized that dietary tungsten may decrease plasma homocysteine levels and influence methionine metabolism. Male New Zealand White rabbits (n=15) were fed a low-cholesterol basal diet and then placed on three different diets: 0.1% cholesterol (Chol), Chol plus 1% methionine (Met), and Chol plus Met plus 0.1% tungsten (W). The animals received these diets for 20 weeks. Biochemical tests of blood and urine were performed. Plasma homocysteine levels were significantly lower in the Chol+Met+W group than in the Chol+Met group. Plasma levels of total cholesterol, triglyceride, lipid peroxide, and urinary 24-h taurine concentrations were higher in the Chol + Met + W group than in the Chol + Met group. In comparison, concentrations of 2, 3-diphosphoglycerate (2, 3-DPG), reduced glutathione (GSH) in erythrocytes, and urinary 24-h SO4(2) were lower in the Chol+Met+W group than in the Chol+Met group. From these results, tungsten could be expected to exhibit an antiatherogenic effect. Conversely, it may have effects on atherogenic factors. Thus, tungsten may play a number of roles in the methionine metabolism.
Virgin female rats of SD strain were given ad libitum a nutritionally adequate semipurified diet containing 0.026 ppm molybdenum and deionized water (groups 1-3) or the same diet with 150 ppm tungsten and the drinking water (group 4). Group 1 was used as control. After 15 days, all the animals in groups 2-4 received an intravenous injection of N-nitroso-N-methylurea (NMU) 5 mg/100 g body weight. One week after administration of carcinogen, 10 ppm Mo was added to the drinking water in group 3. After 125 days, the mammary cancer incidence in group 4 (79.2%) was significantly higher than that in group 2 (50.0%) or group 3 (45.5%) (P less than 0.05). After 198 days, the average number of mammary cancer in each animal and mammary cancer incidence in group 3 (1.5 and 50.0%) were obviously lower than those in group 2 (2.0 and 90.5%) or group 4 (2.6 and 95.7%). The first palpable mammary tumor was found in the W-supplemented group only 56 days after the injection of NMU, whereas in the W-unsupplemented and Mo-supplemented groups, the first mammary tumor was observed 71 and 85 days after NMU treatment. Of these 181 mammary tumors, 177 (97.8%) were adenocarcinoma or papillary carcinoma, only 4 (2.2%) fibroadenocarcinoma. The results of this study show, for the first time, the inhibitory effect of Mo on the mammary carcinogenesis and promoting effect of Tungsten, an antagonist of molybdenum, on the tumor growth. Title: Tungsten in biological systems. Author: Kletzin A; Adams MW
Tungsten (atomic number 74) and the chemically analogous and very similar metal molybdenum (atomic number 42) are minor yet equally abundant elements on this planet. The essential role of molybdenum in biology has been known for decades and molybdoenzymes are ubiquitous. Yet, it is only recently that a biological role for tungsten has been established in prokaryotes, although not as yet in eukaryotes. The best characterized organisms with regard to their metabolism of tungsten are certain species of hyperthermophilic archaea (Pyrococcus furiosus and Thermococcus litoralis), methanogens (Methanobacterium thermoautotrophicum and Mb. wolfei), Gram-positive bacteria (Clostridium thermoaceticum, C. formicoaceticum and Eubacterium acidaminophilum), Gram-negative anaerobes (Desulfovibrio gigas and Pelobacter acetylenicus) and Gram-negative aerobes (Methylobacterium sp. RXM). Of these, only the hyperthermophilic archaea appear to be obligately tungsten-dependent. Four different types of tungstoenzyme have been purified: formate dehydrogenase, formyl methanufuran dehydrogenase, acetylene hydratase, and a class of phylogenetically related oxidoreductases that catalyze the reversible oxidation of aldehydes. These are carboxylic reductase, and three ferredoxin-dependent oxidoreductases which oxidize various aldehydes, formaldehyde and glyceraldehyde 3-phosphate. All tungstoenzymes catalyze redox tungsten in these enzymes is bound by a pterin moiety similar to that found in molybdoenzymes. The first crystal structure of a tungsten- or pterin-containing enzyme, that of aldehyde ferredoxin oxidoreductase from P. furiosus, has revealed a catalytic site with one W atom coordinated to two pterin molecules which are themselves bridged by a magnesium ion. The geochemical, ecological, biochemical and phylogenetic basis for W- vs. Mo-dependent organisms is discussed.Oral administration of tungstate for 15 days normalized glycemia in streptozotocin-induced diabetic rats. Simultaneously, the alterations in hepatic glucose metabolism due to diabetes were almost completely counteracted by this treatment. Thus, 6-phosphofructo-2-kinase, L-pyruvate kinase, and glycogen phosphorylase alpha activities reached levels similar to those observed in healthy animals. Hepatic levels of fructose 2,6-bisphosphate and glycogen also recovered. However, the recovery of glucokinase activity and hepatic levels of glucose 6-phosphate was only partial. The total activity of glycogen synthase increased, although the activation state was not recovered. Moreover, mRNA levels of hepatic glucokinase, glycogen phosphorylase, and phosphoenolpyruvate carboxykinase were also normalized. Tungstate administration in healthy animals also affected all these parameters, although to a much lesser extent. All these effects were similar to those previously reported for vanadate, suggesting a common mechanism of action in vivo. tunsten corrects diabetes.doc
The recent growth in the chemistry of the oxo-molybdenum enzymes has demonstrated the need for developing systematic methods for naming and abbreviating the novel pterin cofactors that bind to the metal ion via the sulfur atoms of an ene-1,2-dithiolate moiety. Historically, the term "molybdopterin" was coined to designate a special pterin that binds molybdenum and the molybdenum-bound form was termed the "molybdenum cofactor". However, recent studies have demonstrated that this novel pterin also binds tungsten. Furthermore, considerable variation has been found in the pterin entity itself. Taken together, these facts show that molybdenum- and tungsten-containing enzymes possess a family of cofactors rather than a single "molybdenum cofactor". This article proposes a unified methodology for describing these cofactors and their metal-free pterin units in light of recent results from protein crystallography. The various numbering schemes that have been used for this heterocycle are considered, as well as the IUPAC rules which are currently being used for related tricyclic compounds. A unified methodology for uniquely designating and abbreviating each cofactor is proposed. The available chemical and spectroscopic information on the pyranopterin entities that are present in the molybdenum and tungsten enzymes, the precursors to these centers, and synthetic pyranopterins are in part the basis of the systematic names and simplifying abbreviations.
Yellow lupine seeds were found to contain two proteins and a low molecular weight fraction possessing the ability to bind Mo, W and radionuclides from the Chernobyl nuclear power in vivo and the 185W isotope in vitro. These proteins differ in their electrophoretic mobility. The electrophoretically less mobile protein undergoes proteolytic degradation; the proteolytic product retains the ability to accumulate microelements. (Perhaps this means that peas would be a good source of tungsten and molybdenum?JJ)
Two large, electron dense heavy-metal complexes were found to bind to crystals of heavy riboflavin synthase. The crystallographic analysis by difference Fourier methods shows that the tungsten cluster compound [(W3O2(O2CCH3)6]2+, which has trigonal symmetry, binds to a site on the 3-fold axis of the protein. The heteropolytungstate compound [NaP5W30O110]14-, which has pentagonal symmetry, binds to a site on the 5-fold axis of the protein. J Inorg Biochem 1994 Feb 15;53(3):191-203Thiotungstate-copper interactions. I. Studies on the metabolism of [185W] tetrathiotungstate and the systemic interactions of labeled pharmacological doses with copper in rats.McQuaid A, Lamand M, Mason JBiochemistry Department, Trinity College, Dublin University, Ireland. [185W] tetrathiotungstate was employed to study the metabolism of thiocompounds in rats after i.v. injection. At tracer levels (12.5 micrograms W) the most important plasma binding protein eluted in the position of ceruloplasmin but the association did not prevent uptake of thiotungstate by the liver. At higher dose levels (1.5 mg W) there was considerable hydrolysis immediately after injection with rapid excretion of label in urine. The [185W] tetrathiotungstate remaining in plasma was associated with albumin and the amount retained was increased by pretreatment of the rats with copper. The increased binding to albumin did not prevent hepatic uptake and over the short-term pretreatment with copper increased the movement of the isotope into subcellular organelles, probably lysosomes. The excretion in bile was increased and the label was associated with high molecular weight proteins. In liver cytosol the 185W was bound by specific, as yet uncharacterized, proteins. At the higher dose levels there was some movement to higher molecular weight proteins and this was greatly increased by the pretreatment with copper. The studies show that the metabolism of 185W tetrathiotungstate is sufficiently similar to 99Mo or 35S tetrathiomolybdate for work on the systemic interactions of thiocompounds and copper in man and animals.
WESTPORT, CT (Reuters Health) Feb 13 - Administration of sodium tungstate markedly reduces glycemia in a rat model of type 2 diabetes, Spanish researchers report in the January issue of Diabetes. Dr. Joan J. Guinovart from Universitat de Barcelona and colleagues have previously shown that tungstate lowers blood glucose levels in rats made insulin deficient to simulate type 1 diabetes. In the current study, the researchers administered tungstate orally to 7.5-week-old Zucker diabetic fatty rats, which are "considered the closest available rat model to human type 2 diabetes associated with obesity." The animals had begun to show hyperglycemia, and the treatment temporarily reversed this for about 10 days. Glucose levels then rose again but stabilized at about 200 mg/dL at day 24. In contrast, the glucose level of untreated rats rose to a maximum value of 450 mg/dL. Tungstate treatment caused serum triglyceride levels to fall by 42%, and normalized hepatic concentrations of glucose-6-phosphate. The researchers also found that the treatment led to 55% higher glycogen levels in the liver compared with untreated diabetic or healthy rats. Treatment did not cause a significant change in phosphotyrosine-modified proteins in cultured hepatocytes from diabetic animals. "These data suggest that tungstate administration to Zucker diabetic fatty rats causes a considerable reduction of glycemia, mainly through a partial restoration of hepatic glucose metabolism and a decrease in lipotoxicity," Dr. Guinovart and colleagues conclude. Diabetes 2001;50:131-138.
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