Critical Review Biological Functions of Thiamine

Page 1 of 9 Critical review Biological functions of thiamine derivatives: focus on non-coenzyme roles Metabolism L Bettendorff*, P Wins Abstract functions of thiamine derivatives, Introduction mainly focusing on non-coenzyme remains unknown3, and it was Thiamine (vitamin B1) is mainly roles. suggestedsensitive thatto thiaminethis selective deficiency vulner- known for its diphosphorylated Conclusion ability could be due to a coenzyme- derivatives, an essential coenzyme in A hundred years ago, the discovery of independent role of thiamine or one energy metabolism. However, non- thiamine opened the way to the of its derivatives4. coenzyme roles have been suggested vitamin era of biochemistry, leading Indeed, in addition to ThDP and for this vitamin for many years. Such to the discovery of the importance of free thiamine, several other phos- roles have remained hypothetical, but pyruvate oxidation in energy metabo- phorylated and adenylated deriva- recent data from various sources lism. This vitamin still has not tives are observed (Figure 2): thia- have shed a new light on this hypoth- revealed all of its secrets at a time mine monophosphate (ThMP), esis. First, other phosphorylated thia- when metabolomics is emerging as a thiamine triphosphate (ThTP), aden- mine derivatives, most prominently osine thiamine triphosphate (AThTP) thiamine triphosphate and adenosine knowledge of cellular reactions. and adenosine thiamine diphosphate thiamine triphosphate, can reach new powerful tool to refine our (AThDP)5,6. The existence of such Escherichia coli, Introduction forms in many living cells would respectively, during amino acid star- Like other B vitamins, thiamine suggest that they also have some vationsignificant and levelsenergy in stress. Although (vitamin B1, Figure 1a) is an indis- biological role(s). It is indeed worth much less is known about these pensable molecule for all known wondering why the diphosphoryl- compounds in animals, mammalian organisms. This is mainly because, in ated form of thiamine is the mammalian cells, its diphosphoryl- coenzyme, when the monophospho- thiamine triphosphatase controlling ated form, thiamine diphosphate rylated form would do just as well, as cytosoliccells contain thiamine a highly specifictriphosphate soluble is the case for pyridoxal phosphate concentrations. Second, there is now metabolic enzymes (Figure 1b)1, the for instance. It is indeed true that the growing evidence in favour of the most(ThDP), important is the coenzyme being mitochondrial for five key diphosphate contributes to the existence of thiamine-binding pyruvate and oxoglutarate dehydro- binding energy of apoenzymes, but genase complexes as well as the the catalytic properties of thiamine nervous system, possibly in the regu- cytosolic transketolase. Therefore, it solely rely on the thiazolium ring’s lationproteins of withneurotransmitter specific roles release.in the is generally believed that thiamine ability to lose a proton and form a Thiamine and some of its synthetic - reactive ylide (Figure 1c). Ylide precursors with higher bioavaila- tive metabolism, which eventually causesdeficiency cell leads death. to decreasedIn animals, oxida the presence of phosphate groups on the models of Alzheimer’s disease and brain heavily relies on oxidative hydroxyethylformation is notarm, influenced and there by is theno bility have beneficial effects in several metabolism for the synthesis of ATP, obvious advantage to use ThDP suffering from Alzheimer’s or Parkin- making this organ particularly sensi- (rather than ThMP or ThTP) as son’smay diseases.be beneficial These effectsfor mightpatients be coenzyme. related to non-coenzyme roles of - - thiamine, possibly involving thia- ciencytive to leads thiamine to beriberi, deficiency. a polyneu In- cial effects of benfotiamine (a thiamine-binding proteins. The aim of ritichumans, condition, nutritional rapidly thiamine reversed afterdefi mineA recent precursor) study emphasisesin a transgenic benefi this review was to discuss biological thiamine administration. In alco- mouse model of Alzheimer’s disease, holics, and also in children, thiamine although only levels of unphospho- - rylated thiamine were increased in the tive diencephalic brain lesions2 brain of the animals. Levels of thiamine- * Corresponding author Email: [email protected] generallydeficiency referredcan lead toto astypical Wernicke– selec phosphorylated derivatives, including 7 GIGA-Neurosciences, University of Liège, Liège, Korsakoff syndrome. The reason ThDP, were unaffected . Moreover, it Belgium why some brain regions are more was recently suggested that the Licensee OA Publishing Bettendorff L,London Wins P 2013. Creative Commons Attribution License (CC-BY) Competing interests: none declared. Conflict of interests: none declared. interests: none declared. Conflict of interests: Competing the final manuscript. as well read and approved design, and preparation of the manuscript, the conception, to All authors contributed rules of disclosure. ethical Ethics (AME) for Medical the Association All authors abide by For citation purposes: . Biological functions of thiamine derivatives: focus on non-coenzyme roles. OA Biochemistry 2013 May 01;1(1):10. Page 2 of 9 Critical review Figure 1: Thiamine diphosphate as a coenzyme. (a) Structural formula of thiamine with both heterocycles numbered according to the usual conventions. (b) Enzyme-catalysed proton loss at the C2 of the thiazolium ring and ylide formation is at the molecular basis of the catalytic properties of thiamine. (c) ThDP-dependent enzymes in a mammalian cell and subcellular localization. TK, transketolase; PDHC, pyruvate dehydrogenase complex; OGDHC, oxoglutarate dehydrogenase Reference 1). complex; BCODC, branched chain 2-oxo acid dehydrogenase complex; HACL1, 2-hydroxyacyl-CoA lyase 1. (Modified from antinociceptive effects of thiamine in Discussion accordance with the institution humans and animals could be medi- The authors have referenced some guidelines. ated by the non-phosphorylated form of their own studies in this review. of the vitamin8, raising the possibility These referenced studies have been Thiamine derivatives that free thiamine has pharmacolog- conducted in accordance with the other than ThDP ical effects independent of ThDP. Declaration of Helsinki (1964), and Thiamine is transported into Nearly 20 years ago, we have the protocols of these studies have - reviewed data concerning a possible been approved by the relevant ethics porters and immediately phospho- non-coenzyme role of thiamine or its committees related to the institu- rylatedmammalian to ThDP cells by bycytosolic specific thiamine trans derivatives, particularly in relation to tion in which they were performed. pyrophosphokinase (Figure 2). ThDP nerve function9. Here, we want to All human subjects, in these refer- can then be phosphorylated to ThTP critically examine the new data that enced studies, gave informed or transformed to adenylated deriva- have been obtained since then. consent to participate in these tives. However, the most obvious fate studies. Animal care was also in for cytosolic-free ThDP is hydrolysis Licensee OA Publishing Bettendorff L,London Wins P 2013. Creative Commons Attribution License (CC-BY) Competing interests: none declared. Conflict of interests: none declared. interests: none declared. Conflict of interests: Competing the final manuscript. as well read and approved design, and preparation of the manuscript, the conception, to All authors contributed rules of disclosure. ethical Ethics (AME) for Medical the Association All authors abide by For citation purposes: . Biological functions of thiamine derivatives: focus on non-coenzyme roles. OA Biochemistry 2013 May 01;1(1):10. Page 3 of 9 Critical review Figure 2: Thiamine derivatives observed in living organisms. (Adapted from References 1 and 63). ThDP is synthesised from thiamine and ATP by thiamine pyrophosphokinase (1). Hydrolysis of ThDP by thiamine pyrophosphatases (2) yields ThMP, which in turn can be hydrolysed to thiamine by thiamine monophosphatases (3). ThDP can be phosphorylated to ThTP by two mechanisms: mitochondrial FoF1-ATP synthase (4) and cytosolic adenylate kinase (5). ThTP can be hydrolysed adenylyl transferase (7). AThTP can be hydrolysed to ThDP and AMP by a putative AThTP hydrolase (8). AThDP has been shownto ThDP to by exist a very in prokaryotes specific cytosolic and eukaryotes, 25 kDa thiamine but its triphosphatasemechanism of synthesis (6). ThDP has can not also yet be been converted demonstrated to AThTP in byvitro a ThDP. to ThMP, which is recycled to thia- been shown to be able to phospho- 14–16 in rylate proteins11, although it is not intact E. coli cells and isolated brain clear whether such phosphoryla- mitochondria.nism (ThDP + InterestinglyPi � ThTP) both andmine. there No specific is no known enzymes role havefor ThMP. been tion is of physiological significance. mechanisms are conserved from Intracellularidentified for ThMP the levelslatter arereactions, gener- While ThTP seems to be constitu- bacteria to mammals. However, while ally much lower than ThDP levels. tively synthesised in animal cells, in the synthesis by adenylate kinase However, ThMP seems to be excreted, Escherichia coli, it accumulates only seems to be constitutive and is prob- probably by a process involving the in the absence of amino acids and ably merely a side reaction, the reduced folate carrier (RFC1 or therefore could be a signalling synthesis by FoF1-ATP synthase is SLC19A1)10,

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