Metabolism of Thiamine Triphosphate in Rat Brain: Correlation with Chloride Permeability

Bettendorff, Lucien; Peeters, Maryline; Wins, Pierre; Schoffeniels, E.

doi:10.1111/j.1471-4159.1993.tb03168.x

Cited by 59 publications

(35 citation statements)

References 34 publications

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“…Incorporation of Labeled P i into ThTP-The mitochondrial fraction was incubated in the presence of [ 32 P]PO 4 3Ϫ and pyruvate, and then thiamine derivatives were separated by HPLC, the ThTP peak was collected, and the specific radioactivity was determined as described previously (29). Based on the final specific radioactivity of 32 P i (9.99 GBq/mmol), the specific radioactivity of ThTP was 11.1 Ϯ 3.3 GBq/mmol (n ϭ 4).…”

Section: Thtp Synthesis Is Tightly Coupled To Electron Flow Through Tmentioning

confidence: 99%

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Thiamine Triphosphate Synthesis in Rat Brain Occurs in Mitochondria and Is Coupled to the Respiratory Chain

Gangolf

Wins

Thiry

et al. 2010

Journal of Biological Chemistry

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In animals, thiamine deficiency leads to specific brain lesions, generally attributed to decreased levels of thiamine diphosphate, an essential cofactor in brain energy metabolism. However, another far less abundant derivative, thiamine triphosphate (ThTP), may also have a neuronal function. Here, we show that in the rat brain, ThTP is essentially present and synthesized in mitochondria. In mitochondrial preparations from brain (but not liver), ThTP can be produced from thiamine diphosphate and P i . This endergonic process is coupled to the oxidation of succinate or NADH through the respiratory chain but cannot be energized by ATP hydrolysis. ThTP synthesis is strongly inhibited by respiratory chain inhibitors, such as myxothiazol and inhibitors of the H ؉ channel of Thiamine (vitamin B1) is essential for brain function, and its deficiency causes specific brain lesions (1, 2). It is thought that this selective vulnerability results from decreased levels of thiamine diphosphate (ThDP), 3 an indispensable cofactor for several key enzymes in cell energy metabolism (especially pyruvate and oxoglutarate dehydrogenases and transketolase).

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Section: Thtp Synthesis Is Tightly Coupled To Electron Flow Through Tmentioning

confidence: 99%

“…Except for AK, we have been unable to measure any ThTPsynthesizing activity involving a soluble enzyme, but we have previously shown that when rat brain homogenates were incubated with ThDP, a significant amount of ThTP was detected in the particulate fraction containing cell debris, synaptosomes, and mitochondria (29,30).…”

mentioning

confidence: 99%

Thiamine Triphosphate Synthesis in Rat Brain Occurs in Mitochondria and Is Coupled to the Respiratory Chain

Gangolf

Wins

Thiry

et al. 2010

Journal of Biological Chemistry

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“…In addition, ThTP is believed to act as one of the messengers in cell signaling in response to cellular stress (7). Despite the relatively high turnover rate of ThTP in neural cells (8), its level is strictly maintained at a low concentration in vivo, presumably through the activity of ThTPase.…”

mentioning

confidence: 99%

Structural Basis for the Catalytic Mechanism of Mammalian 25-kDa Thiamine Triphosphatase

Song

Bettendorff

Tonelli

et al. 2008

Journal of Biological Chemistry

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Mammalian soluble thiamine triphosphatase (ThTPase) is a 25-kDa cytosolic enzyme that specifically catalyzes the conversion of thiamine triphosphate (ThTP) to thiamine diphosphate and has an absolute requirement for divalent cations. We have investigated the kinetic properties of recombinant mouse thiamine triphosphatase (mThTPase) and determined its solution structure by NMR spectroscopy. Residues responsible for binding Mg 2؉ and ThTP were determined from NMR titration experiments. The binding of Mg 2؉ induced only a minor local conformational change, whereas ThTP binding was found to cause a more global conformational change. We derived a structural model for the mThTPase⅐ThTP⅐Mg 2؉ ternary complex and concluded from this that whereas free mThTPase has an open cleft fold, the enzyme in the ternary complex adopts a tunnel fold. Our results provide a functional rationale for a number of conserved residues and suggest an essential role for Mg 2؉ in catalysis. We propose a mechanism underlying the high substrate specificity of mThTPase and discuss the possible role of water molecules in enzymatic catalysis.Two classes of enzymes are known to convert thiamine triphosphate (ThTP) 3 to thiamine diphosphate in animal tissues: a membrane-associated enzyme that is yet to be characterized and a soluble thiamine triphosphatase (ThTPase). ThTPase was first identified in rat brain (1) and has been found in most mammalian tissues studied to date (2). Biochemical studies of the purified, homogeneous ThTPase further revealed that the enzyme is a 24 -25-kDa monomer with virtually absolute specificity for ThTP (3, 4). The enzyme has an alkaline pH optimum, and its catalytic activity depends critically on a divalent metal cofactor, such as Mg 2ϩ . ThTPase is thought to regulate the intracellular concentration of ThTP, which is found in most animal cells but at a much lower level than other forms of thiamine (5). Several lines of biochemical evidence have shown that ThTP can phosphorylate proteins in the electric organ of Torpedo marmorata and in rodent brain (6). In addition, ThTP is believed to act as one of the messengers in cell signaling in response to cellular stress (7). Despite the relatively high turnover rate of ThTP in neural cells (8), its level is strictly maintained at a low concentration in vivo, presumably through the activity of ThTPase.The sequence of ThTPase does not closely resemble that of any other protein identified in the mammalian genomes. However, recent bioinformatic analysis has suggested that mammalian 25-kDa ThTPase and adenylate cyclase CyaB from Aeromonas hydrophila define an ancient superfamily of domains, called the CYTH domains, which play a role at the interface of polyphosphate and nucleotide metabolism (9). The structures of several CYTH domains have been determined, including class IV adenylyl cyclase from Yersinia pestis (YpAC4, Protein Data Bank (PDB) 2FJT) (10) and proteins with unknown functions from Pyrococcus furiosus (PDB accession numbers 1YEM and 2DC4), Vibrio parahemeolyticus (P...

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“…Thiamin triphosphate (TTP) acts in nerves (and possibly also muscle) to activate a chloride ion channel. Bettendorf et al (1993bBettendorf et al ( , 1994 showed that the formation of TTP in brain-membrane-vesicle preparations was correlated with chloride uptake. In neuroblastoma cells in culture the addition of TTP results in activation of the chloride ion channel, which is not reversed by washing out, suggesting that it acts by phosphorylation of the chloride-channel protein (Bettendorf et al 1993a).…”

Section: Thiaminmentioning

confidence: 99%

Optimum nutrition: thiamin, biotin and pantothenate

Bender

1999

Proc. Nutr. Soc.

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The metabolism of glucose is deranged in thiamin deficiency, but once any deficiency has been corrected there is no further effect of increased thiamin intake on the ability to metabolize glucose through either pyruvate dehydrogenase (EC 1.2.4.1) and the citric acid cycle, or the pentose phosphate pathway, in which transketolase (EC 2.2.1.1) is the thiamin-dependent step. It has been suggested that the Wernicke-Korsakoff syndrome is associated with a genetic variant of transketolase which requires a higher than normal concentration of thiamin diphosphate for activity. This finding would suggest that there may be a group of the population who have a higher than average requirement for thiamin, but the evidence is not convincing. There are no estimates of biotin requirements, but either coenzyme saturation of erythrocyte pyruvate carboxylase, or the excretion of 3-hydroxy-isovalerate (perhaps after a test dose of leucine) could be used to assess requirements in depletion–repletion studies. Biotin deficiency leads to impaired glucose tolerance, but it is unlikely that glucose tolerance could be used to assess optimum biotin status, since other more common factors affect glucose tolerance to a greater extent. Plasma triacylglycerol and non-esterified fatty acids are moderately elevated in pantothenic acid deficiency. However, this is unlikely to be useful in assessing pantothenate status, since again, other more common factors affect plasma lipids. To date there are no biochemical indices of adequate pantothenate nutrition, and no estimates of requirements.

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Metabolism of Thiamine Triphosphate in Rat Brain: Correlation with Chloride Permeability

Cited by 59 publications

References 34 publications

Thiamine Triphosphate Synthesis in Rat Brain Occurs in Mitochondria and Is Coupled to the Respiratory Chain

Thiamine Triphosphate Synthesis in Rat Brain Occurs in Mitochondria and Is Coupled to the Respiratory Chain

Structural Basis for the Catalytic Mechanism of Mammalian 25-kDa Thiamine Triphosphatase

Optimum nutrition: thiamin, biotin and pantothenate

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