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See detailChapter 17: Thiamin (E-book)
Bettendorff, Lucien ULg

in Erdman, Jr, John W.; MacDonald, Ian A.; Zeisel, Steven H. (Eds.) Present Knowledge in Nutrition (E-book) (2012)

Thiamin (vitamin B1) was the first vitamin characterized and its discovery was at the origin of the concept of vitamin. Thiamin deficiency mainly affects the nervous system and causes two classical ... [more ▼]

Thiamin (vitamin B1) was the first vitamin characterized and its discovery was at the origin of the concept of vitamin. Thiamin deficiency mainly affects the nervous system and causes two classical diseases, beriberi (a polyneuritic syndrome) and Wernicke-Korsakoff syndrome (anterograde amnesia resulting from brain lesions in alcoholics). Thiamin transport through the membranes of intestinal and other cells requires specific carriers. As the process is rather slow, various lipid-soluble thiamin precursors with better bioavailability have been developed. In the cytosol, thiamin is pyrophosphorylated to thiamin diphosphate (ThDP), an indispenable cofactor in cell energy metabolism. Therefore, thiamin deficiency causes decreased cofactor function, leading to neuronal death. In addition, non-cofactor roles of the triphosphorylated derivatives thiamin triphosphate (ThTP) and adenosine thiamin triphosphate (AThTP) may play a role in metabolic regulation and may contribute to the pathology of thiamin deficiency-induced brain lesions. Current research interests are focused on the metabolism and role of thiamin derivatives (especially in catalysis by ThDP-dependent enzymes) and the biochemical and pathophysiological mechanisms by which thiamin deficiency induces specific brain lesions and may be implicated in other disorders such as Alzheimer’s disease and diabetes. [less ▲]

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See detailThe effect of thiamin tetrahydrofurfuryl disulfide on behavior of juvenile DBA/2J mice
Hills, Judith I.; Golub, Mari S.; Bettendorff, Lucien ULg et al

in Neurotoxicology & Teratology (2012), 34

Due to genetic defects or illness some individuals require higher amounts of thiamin than are typically provided by the diet. Lipid-soluble thiamin precursors can achieve high blood levels of thiamin and ... [more ▼]

Due to genetic defects or illness some individuals require higher amounts of thiamin than are typically provided by the diet. Lipid-soluble thiamin precursors can achieve high blood levels of thiamin and result in increased concentrations in the central nervous system. High intakes of thiamin have been reported as beneficial in children with autism and attention deficit/hyperactivity disorder. The current study examined the effect of thiamin tetrahydrofurfuryl disulfide (TTFD), a lipophilic precursor, on behavior in the juvenile male DBA/2J mouse. Mice given by oral gavage deionized water or deionized water providing 100mg or 340mg TTFD/kg body weight daily for 17days, starting at postnatal day 18, were tested for effects on operant learning, social interaction, general activity level, and prepulse inhibition of acoustic startle, as well as effects on growth and select organ weights. Results indicate lower activity and altered social interaction at both treatment levels and decreased acoustic startle at the 100mg/kg level. Compared to controls, percent weight gain was lower in the TTFD-treatment groups, but percent body length increase was not affected by TTFD treatment. TTFD treatment did not influence percent organ weights as percentage of body weights. TTFD treatment resulted in increased whole brain thiamin concentrations. These results support the concept that lipophilic thiamin precursors provided during early development can affect a number of behavioral parameters. In clinical trials with children with behavior disorders, attention should be given to preventing possible adverse gastrointestinal irritant effects associated with TTFD therapy. [less ▲]

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See detailUne invitée surprise
Binet, Audrey; Delvaux, David ULg; Bettendorff, Lucien ULg

Learning material (2011)

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See detailThiamin derivatives in the brain of a mouse model of Alzheimer's disease and in cultured Neuroblastoma cells treated with benfotiamine
Vignisse, Julie ULg; Liégeois, Jean-François ULg; Wins, Pierre et al

Poster (2011, July)

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder for which any disease-modifying treatment is available. It is estimated that approximately 36 million people suffer from this disease ... [more ▼]

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder for which any disease-modifying treatment is available. It is estimated that approximately 36 million people suffer from this disease and it comes with a high prize for the society. Recently, it has been shown that chronic administration of benfotiamine, a precursor of thiamin, in a mouse model of AD (APP/PS1 mice) significantly reduced key features of this disease namely memory impairment, β-amyloid accumulation and tau hyperphosphorylation. These beneficial effects are thought to be mediated by the PI3K/Akt/GSK3 signalling pathway (Pan et al., 2010). GSK3 is a kinase involved in the tau protein hyperphosphorylation in Alzheimer’s disease. It is however not clear how and which thiamine derivatives could interact with this kinase. Thiamine diphosphate is a well-known co-factor, in particular for mitochondrial pyruvate and oxo-glutarate dehydrogenases. However, other derivatives such as thiamine triphosphate and the newly discovered adenosine thiamine triphosphate are investigated in our laboratory. Therefore, we shall first try do determine whether benfotiamine (or one of its degradation products) or one of the above-mentioned thiamine derivatives are directly or indirectly involved in the regulation of the PI3K/Akt/GSK3 pathway in cultured neuroblastoma cells. For this purpose, neuroblastoma 2a cells will be grown in a thiamine-deficient medium containing benfotiamine, and thiamine derivatives (thiamine mono-, di- and triphosphate) will be measured by HPLC whereas Akt and GSK3 expression and phosphorylation levels will be assessed by immunoblotting. These experiments will give us new insights into the mechanism of action of thiamine derivatives, and according to the results obtained, we could then design new synthetic derivatives that would be more efficient than benfotiamine (very high doses were required in the animal experiments) in slowing down the neurodegenerative processes in Alzheimer’s disease. [less ▲]

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See detailA specific inorganic triphosphatase from Nitrosomonas europaea: structure and catalytic mechanism
Delvaux, David ULg; Murty, Mamidana R.V.S; Gabelica, Valérie ULg et al

in Journal of Biological Chemistry (2011), 286

The CYTH superfamily of proteins is named after its two founding members, the CyaB adenylyl cyclase from Aeromonas hydrophila and the human 25-kDa thiamine triphosphatase. Because these proteins often ... [more ▼]

The CYTH superfamily of proteins is named after its two founding members, the CyaB adenylyl cyclase from Aeromonas hydrophila and the human 25-kDa thiamine triphosphatase. Because these proteins often form a closed β-barrel, they are also referred to as “Triphosphate Tunnel Metalloenzymes” (TTM). Functionally, they are characterized by their ability to bind triphosphorylated substrates and divalent metal ions. These proteins exist in most organisms and catalyze different reactions, depending on their origin. Here we investigate structural and catalytic properties of the recombinant TTM protein from Nitrosomonas europaea (NeuTTM), a 19-kDa protein. Crystallographic data show that it crystallizes as a dimer and that, in contrast to other TTM proteins, it has an open β-barrel structure. We demonstrate that NeuTTM is a highly specific inorganic triphosphatase, hydrolyzing tripolyphosphate (PPPi) with high catalytic efficiency in the presence of Mg2+. These data are supported by native mass spectrometry analysis showing that the enzyme binds PPPi (and Mg-PPPi) with high affinity (Kd < 1.5 μM), while it has a low affinity for ATP or thiamine triphosphate. In contrast to Aeromonas and Yersinia CyaB proteins, NeuTTM has no adenylyl cyclase activity, but it shares several properties with other enzymes of the CYTH superfamily, e.g. heat-stability, alkaline pH optimum and inhibition by Ca2+ and Zn2+ ions. We suggest a catalytic mechanism involving a catalytic dyad formed by K52 and Y28. The present data provide the first characterization of a new type of phosphohydrolase (unrelated to pyrophosphatases or exopolyphosphatases), able to hydrolyze inorganic triphosphate with high specificity. [less ▲]

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See detailThiamine Status in Humans and Content of Phosphorylated Thiamine Derivatives in Biopsies and Cultured Cells
Gangolf, Marjorie ULg; Czerniecki, Jan; Radermecker, Marc ULg et al

in PLoS ONE (2010), 5(10), 13616

Background Thiamine (vitamin B1) is an essential molecule for all life forms because thiamine diphosphate (ThDP) is an indispensable cofactor for oxidative energy metabolism. The less abundant thiamine ... [more ▼]

Background Thiamine (vitamin B1) is an essential molecule for all life forms because thiamine diphosphate (ThDP) is an indispensable cofactor for oxidative energy metabolism. The less abundant thiamine monophosphate (ThMP), thiamine triphosphate (ThTP) and adenosine thiamine triphosphate (AThTP), present in many organisms, may have still unidentified physiological functions. Diseases linked to thiamine deficiency (polyneuritis, Wernicke-Korsakoff syndrome) remain frequent among alcohol abusers and other risk populations. This is the first comprehensive study on the distribution of thiamine derivatives in human biopsies, body fluids and cell lines. Methodology and Principal Findings Thiamine derivatives were determined by HPLC. In human tissues, the total thiamine content is lower than in other animal species. ThDP is the major thiamine compound and tissue levels decrease at high age. In semen, ThDP content correlates with the concentration of spermatozoa but not with their motility. The proportion of ThTP is higher in humans than in rodents, probably because of a lower 25-kDa ThTPase activity. The expression and activity of this enzyme seems to correlate with the degree of cell differentiation. ThTP was present in nearly all brain and muscle samples and in ~60% of other tissue samples, in particular fetal tissue and cultured cells. A low ([ThTP]+[ThMP])/([Thiamine]+[ThMP]) ratio was found in cardiovascular tissues of patients with cardiac insufficiency. AThTP was detected only sporadically in adult tissues but was found more consistently in fetal tissues and cell lines. Conclusions and Significance The high sensitivity of humans to thiamine deficiency is probably linked to low circulating thiamine concentrations and low ThDP tissue contents. ThTP levels are relatively high in many human tissues, as a result of low expression of the 25-kDa ThTPase. Another novel finding is the presence of ThTP and AThTP in poorly differentiated fast-growing cells, suggesting a hitherto unsuspected link between these compounds and cell division or differentiation. [less ▲]

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See detailThiamine triphosphate synthesis in rat brain occurs in mitochondria and is coupled to the respiratory chain
Gangolf, Marjorie ULg; Wins, Pierre; Thiry, Marc ULg et al

in Journal of Biological Chemistry (2010), 285

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See detailThiaminylated adenine nucleotides — chemical synthesis, structural characterization and natural occurrence
Frederich, Michel ULg; Delvaux, David ULg; Gigliobianco, Tiziana ULg et al

in FEBS Journal (2009), 276(12), 32563268

Thiamine and its three phosphorylated derivatives (mono-, di- and triphosphate) occur naturally in most cells. Recently, we reported the presence of a fourth thiamine derivative, adenosine thiamine ... [more ▼]

Thiamine and its three phosphorylated derivatives (mono-, di- and triphosphate) occur naturally in most cells. Recently, we reported the presence of a fourth thiamine derivative, adenosine thiamine triphosphate (AThTP), produced in E. coli in response to carbon starvation. Here, we show that the chemical synthesis of AThTP leads to another new compound, adenosine thiamine diphosphate (thiaminylated ADP, AThDP), as a side product. The structure of both compounds was confirmed by mass spectrometry and 1H-, 13C- and 31P-NMR and some of their chemical properties were determined. Our results show an upfield shifting of the C-2 proton of the thiazolium ring in adenosine thiamine derivatives compared to the conventional thiamine phosphate derivatives. This modification of the electronic environment of the C-2 proton might be explained by a through-space interaction with the adenosine moiety, suggesting an U-shaped folding of adenosine thiamine derivatives. Such a structure where the C-2 proton is embedded in a closed conformation can be located using molecular modeling as an energy minimum. In E. coli, AThTP may account for 15% of total thiamine under energy stress. It is less abundant in eukaryotic organisms, but is consistently found in mammalian tissues and in some cell lines. Using a HPLC method, we show for the first time that AThDP may also occur in small amounts in E. coli and in vertebrate liver. The discovery of two natural thiamine adenine compounds further highlights the complexity and diversity of thiamine biochemistry, which is not restricted to the cofactor role of thiamine diphosphate. [less ▲]

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See detailThiamin diphosphate in biological chemistry: new aspects of thiamin metabolism, especially triphosphate derivatives acting other than as cofactors
Bettendorff, Lucien ULg; Wins, Pierre

in FEBS Journal (2009), 276(11), 2917-2925

Prokaryotes, yeasts and plants synthesize thiamine (vitamin B1) via complex pathways. Animal cells capture the vitamin through specific high-affinity transporters essential for internal thiamine ... [more ▼]

Prokaryotes, yeasts and plants synthesize thiamine (vitamin B1) via complex pathways. Animal cells capture the vitamin through specific high-affinity transporters essential for internal thiamine homeostasis. Inside the cells, thiamine is phosphorylated to higher phosphate derivatives. Thiamine diphosphate (ThDP) is the best-known thiamine compound for its role as an enzymatic cofactor. However, besides ThDP, at least three other thiamine phosphates occur naturally in most cells: thiamine monophosphate (ThMP), thiamine triphosphate (ThTP) and the recently discovered adenosine thiamine triphosphate (AThTP). It was suggested that ThTP has a specific neurophysiological role, but recent data are in favor of a much more basic metabolic function. During amino acid starvation, Escherichia coli accumulate ThTP possibly acting as a signal involved in the adaptation of the bacteria to changing nutritional conditions. In animal cells, ThTP can phosphorylate some proteins, but the physiological significance of this mechanism remains unknown. AThTP, recently discovered in E. coli, accumulates during carbon starvation and might act as an alarmone. Among the proteins involved in thiamine metabolism, thiamine transporters, thiamine pyrophosphokinase and a soluble 25-kDa thiamine triphosphatase have been characterized at the molecular level, in contrast to thiamine mono- and diphosphatases whose specificities remain to be proven. A soluble enzyme catalyzing the synthesis of AThTP from ThDP and ADP or ATP has been partially characterized in E. coli, but the mechanism of ThTP synthesis remains elusive. The data reviewed here illustrate the complexity of thiamine biochemistry, which is not restricted to the cofactor role of ThDP. [less ▲]

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See detailStructural basis for the catalytic mechanism of mammalian 25 kDa thiamine triphosphatase
Song, J.; Bettendorff, Lucien ULg; Tonelli, Marco et al

in Journal of Biological Chemistry (2008), 283

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See detailAdenylate Kinase-Independent Thiamine Triphosphate Accumulation under Severe Energy Stress in Escherichia Coli
Gigliobianco, Tiziana ULg; Lakaye, Bernard ULg; Makarchikov, Alexander F et al

in BMC Microbiology (2008), 8

BACKGROUND: Thiamine triphosphate (ThTP) exists in most organisms and might play a role in cellular stress responses. In E. coli, ThTP is accumulated in response to amino acid starvation but the mechanism ... [more ▼]

BACKGROUND: Thiamine triphosphate (ThTP) exists in most organisms and might play a role in cellular stress responses. In E. coli, ThTP is accumulated in response to amino acid starvation but the mechanism of its synthesis is still a matter of controversy. It has been suggested that ThTP is synthesized by an ATP-dependent specific thiamine diphosphate kinase. However, it is also known that vertebrate adenylate kinase 1 catalyzes ThTP synthesis at a very low rate and it has been postulated that this enzyme is responsible for ThTP synthesis in vivo. RESULTS: Here we show that bacterial, as vertebrate adenylate kinases are able to catalyze ThTP synthesis, but at a rate more than 106-fold lower than ATP synthesis. This activity is too low to explain the high rate of ThTP accumulation observed in E. coli during amino acid starvation. Moreover, bacteria from the heat-sensitive CV2 strain accumulate high amounts of ThTP (>50% of total thiamine) at 37 degrees C despite complete inactivation of adenylate kinase and a subsequent drop in cellular ATP. CONCLUSION: These results clearly demonstrate that adenylate kinase is not responsible for ThTP synthesis in vivo. Furthermore, they show that E. coli accumulate large amounts of ThTP under severe energy stress when ATP levels are very low, an observation not in favor of an ATP-dependent mechanisms for ThTP synthesis. [less ▲]

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