- A Convenient Synthesis of 1'-Alkyl- and 1'-Benzylthiaminium Salts
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A convenient and efficient method for the quaternization at N-1' of thiamin and 2-(1-hydroxyethyl)-thiamin with various alkyl halides and benzyl bromide is presented.Quaternization of 2-(1-ethoxycarbonyl-1-hydroxyethyl)-thiamin was unsuccessful, resulting in the release of ethyl pyruvate and the formation of quaternized thiamin.The N-1'-derivatized thiaminium salts were found to possess drastically different physical properties as compared to their parent heterocycles.
- Karimian, Khashayar,Mohanazadeh, Farajollah
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- Product inhibition of mammalian thiamine pyrophosphokinase is an important mechanism for maintaining thiamine diphosphate homeostasis
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Background: Thiamine diphosphate (ThDP), an indispensable cofactor for oxidative energy metabolism, is synthesized through the reaction thiamine + ATP ? ThDP + AMP, catalyzed by thiamine pyrophosphokinase 1 (TPK1), a cytosolic dimeric enzyme. It was claimed that the equilibrium of the reaction is in favor of the formation of thiamine and ATP, at odds with thermodynamic calculations. Here we show that this discrepancy is due to feedback inhibition by the product ThDP. Methods: We used a purified recombinant mouse TPK1 to study reaction kinetics in the forward (physiological) and for the first time also in the reverse direction. Results: Keq values reported previously are strongly underestimated, due to the fact the reaction in the forward direction rapidly slows down and reaches a pseudo-equilibrium as ThDP accumulates. We found that ThDP is a potent non-competitive inhibitor (Ki ≈ 0.4 μM) of the forward reaction. In the reverse direction, a true equilibrium is reached with a Keq of about 2 × 10?5, strongly in favor of ThDP formation. In the reverse direction, we found a very low Km for ThDP (0.05 μM), in agreement with a tight binding of ThDP to the enzyme. General significance: Inhibition of TPK1 by ThDP explains why intracellular ThDP levels remain low after administration of even very high doses of thiamine. Understanding the consequences of this feedback inhibition is essential for developing reliable methods for measuring TPK activity in tissue extracts and for optimizing the therapeutic use of thiamine and its prodrugs with higher bioavailability under pathological conditions.
- Alhama-Riba, Judit,Bettendorff, Lucien,Brans, Alain,Pavlova, Oleksandra,Sambon, Margaux,Wins, Pierre
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- NOVEL THIAMINE-ORGANIC ACID SALT
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The present disclosure relates to novel thiamine-organic acid salt, and the method of making the novel thiamine-organic acid salt.
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- BASE-CATALYZED OXIDATION OF 2-(α-HYDROXYBENZYL)THIAMINE BY MOLECULAR OXYGEN
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Oxidation of 2-(α-hydroxybenzyl)thiamine by molecular oxygen in the presence of an acetate buffer in methanol includes formation of an intermediate enamine and its subsequent oxidation with concurrent protonation.Using the dependence of the reciprocal rate constant for acetate-catalyzed oxidation on /-> the values of k1 and k-1/k2 have been calculated.Comparison of oxidation kinetics of 2-(α -hydroxybenzyl)thiamine, 2-(α-hydroxybenzyl)-3- benzyl-4-methyl-5-(2-hydroxyethyl)thiazolium chloride, and 2(α-hydroxybenzyl)-3-benzyl- 4-methylthiazolium chloride indicates that the reaction of the intermediate enamine with O2 is governed by the 3- and 5-substituents.It is assumed that the 5-hydroxyethyl group causes steric hindrance, and the amino group in position 4 of the pyrimidine fragment favors deprotonation of the Cα-hydroxy group.
- Vovk, A. I.,Murav'eva, I. V.
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p. 119 - 122
(2007/10/03)
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- OXIDATIVE DECOMPOSITION OF 2-(α-HYDROXYBENZYL)THIAMINE UNDER THE ACTION OF A BASE AND SUBSTITUTED QUINONES
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The reaction of 2-(α-hydroxybenzyl)thiamine and its thiazolium structural analogs with substituted quinones in the presence of acetate buffer in deaerated methanolic solutions at 27 deg C and ionic strength of 0.15 is characterized by first-order kinetics with respect to the thiazolium salt and the acetate and by zero-order kinetics with resoect to quinone.The rate constant of the reaction catalyzed by the basic component of the buffer decreases in the following series of oxidants: 2-methyl-5-isopropyl-p-benzoquinone, trimethyl-p-benzoquinone, tetramethyl-p-benzoquinone.It was supposed that fast reversible formation of a complex between the deprotonated 2-(α-hydroxybenzyl)thiazole and the oxidant precedes electron transfer to the quinone.In the one-electron transfer stage, which determines the overall reaction rate, the 5-hydroxyethyl substituent exerts an adverse effect for steric reasons.
- Vovk, A. I.,Murav'eva, I. V.
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p. 937 - 940
(2007/10/02)
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- Thiamin Biosynthesis in Saccharomyces cerevisiae: Origin of the Pyrimidine Unit
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Radioactivity from 14C>formate, from D-14C>-, D-14C>-, and D-3H,6-14C>glucose, from D-14C>fructose and from 14C>- and 14C>glycerol is incorporated nonrandomly into the pyrimidine moiety of thiamin in Saccharomyces cerevisiae.The observed incorporation pattern, established by a new chemical degradation, leads to the inference that there are two biosynthetic pathways to the pyrimidine moiety of thiamin in yeast.In the major pathway, formate is the precursor of C-4 of the pyrimidine nucleus, while hexose metabolites serve as the source of the remaining five carbon atoms of the pyrimidine unit.In the minor pathway, it is C-2 and not C-4 of the pyrimidine nucleus which is derived from formate, while C-4,-5 orginates from carbohydrate.The source of C-2', C-5', and C-6 of the pyrimidine unit in this minor pathway remains unknown.Activity from 14C>citrulline and 14C>urea is not incorporated into thiamin.
- Grue-Sorensen, Gunnar,White, Robert L.,Spenser, Ian D.
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p. 146 - 158
(2007/10/02)
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- Fluorodehydroxylation of serine
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Organic compounds containing one or more alcoholic hydroxyl groups are transformed into fluorine compounds by reacting them with sulfur tetrafluoride in liquid hydrogen fluoride solution, at temperatures between around -80° C. and +20° C. The method can be descriptively termed "fluorodehydroxylation", because it represents the reaction:
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