Critical Review Biological Functions of Thiamine

Belgium GIGA-Neurosciences, University of Liège, Liège, Email: * this review was to discuss biological mine-binding proteins. The aim of thiamine, possibly involving thia related to non-coenzyme roles of patients for son’s diseases. These effects mightbe beneficial suffering from Alzheimer’s or Parkin be may models ofAlzheimer’s disease and bility have beneficial effects in several precursors with higher bioavaila Thiamine andsomeofitssynthetic of neurotransmitterlation release. the in nervous system, possibly intheregu roles specific with proteins existence ofthiamine-binding growing evidence in favour of the concentrations.Second, there isnow cytosolic thiamine triphosphate thiamine triphosphatasecontrolling soluble specific highly a contain cells compounds mammalian in animals, much lessisknownthese about vationand energy stress. Although respectively, duringaminoacidstar in levels significant thiamine triphosphate, canreach thiamine triphosphate andadenosine mine derivatives, mostprominently otherphosphorylatedesis. First, thia have shed a newlight onthishypoth recent datafrom various sources roles have remained hypothetical,but forfor thisvitamin many years. Such coenzyme roles have beensuggested energy However, metabolism. non- derivatives, an essentialcoenzyme in knownfor its diphosphorylated Thiamine (vitamin B1)is mainly Introduction Abstract OA Biochemistry 2013 May 01;1(1):10. Forcitation purposes: Corresponding author Metabolism [email protected] Licensee OA Publishing London2013.Creative Commons Attribution License(CC-BY) Biological functionsofthiaminederivatives:focuson L Bettendorff*, PWins L Bettendorff*,

Escherichia coli BettendorffP Wins L, ------, metabolism for thesynthesis ofATP, brain heavily relies onoxidative causes celldeath.Inanimals,the tive metabolism,which eventually oxida decreased to leads deficiency is generally believed thatthiamine cytosolic transketolase. Therefore, it genase complexes aswell as the pyruvate andoxoglutarate dehydro most importantbeingmitochondrial metabolic enzymes(Figure 1b) fivekeyfor coenzyme the is (ThDP), ated form, thiaminediphosphate mammalian cells,itsdiphosphoryl organisms. Thisismainly because,in pensable moleculefor allknown (vitamin B1,Figure 1a) isanindis Like otherBvitamins,thiamine Introduction our refine to knowledge ofcellularreactions. tool powerful new whenis emerging metabolomics as a revealedof itssecrets all time a at lism. Thishas vitamin stillnot pyruvate oxidation inenergymetabo to the discovery of the importanceof eravitamin of biochemistry, leading thiamine openedtheway to the A hundred yearsthe discovery ago, of Conclusion roles. mainly focusing onnon-coenzyme functions of thiamine derivatives, whybrainsome regions are more Korsakoff syndrome. Thereason generally referred to asWernicke– tivebraindiencephalic lesions selec typical to lead can deficiency holics, andalsoinchildren, thiamine thiamine administration. Inalco ritic condition,rapidly reversed after In ciency leadsto beriberi, apolyneu deficiency. defi thiamine thiamine nutritional humans, to tive making thisorgan particularly sensi non-coenzyme roles . Biological functions of thiamine derivatives:thiamine of roles.functions non-coenzyme Biological on focus. 1 , the ------2

and adenosinethiaminediphosphate osine thiaminetriphosphate (AThTP) thiamine triphosphate (ThTP),aden monophosphatemine (ThMP), tivesare observed (Figure thia 2): phorylated andadenylated deriva free thiamine,several other phos of itsderivatives independent role ofthiamineorone ability couldbedueto acoenzyme- suggested thatthisselective vulner deficiency thiamine remains unknown to sensitive was recently suggestedthe that ThDP, were unaffected phosphorylated derivatives, including brain oftheanimals.Levels ofthiamine- thiamine were increased inthe rylated although only levels of unphospho mouse model of Alzheimer’s disease, mine precursor) in atransgenic effectscial ofbenfotiamine (athia coenzyme. (rather thanThMPorThTP)as obvious advantage to useThDP hydroxyethyl arm, andthere isno the presenceof phosphate groups onthe by influenced not is formation reactive ylide (Figure 1c).Ylide ability to loseaproton andform a solely rely onthethiazolium ring’s the catalytic propertiesthiamineof binding energy ofapoenzymes,but diphosphate contributes to the for instance.Itisindeedtruethatthe forcase the is pyridoxal phosphate rylated form would dojustaswell, as coenzyme, when themonophospho ated form ofthiamineisthe wondering why thediphosphoryl biological role(s). Itis indeedworth suggest thatthey alsohave some formsmanyin living wouldcells (AThDP) Indeed, inadditionto ThDPand A recent study emphasises benefi emphasises study recent A 5,6 . Theexistence ofsuch Critical review 4 . 3 , anditwas 7 . Moreover, it

Page 1 of9 ------

Competing interests: none declared. Conflict of interests: none declared. All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript. All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure. 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 by vitro 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 + Interestingly Pi � 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 levels latter are reactions, 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, a transporter closely molecule involved in the adaptation strongly dependent on metabolic related to thiamine transporters, and to amino acid starvation12. While it conditions. While on one hand there was long thought that ThTP is such as blood plasma, cerebrospinal synthesised by an ATP:ThDP phos- enzyme involved in ThTP synthesis, it is present in extracellular fluids photransferase, the existence of onis presently the other no hand, evidence mammalian for a specific cells such a mechanism has never been Thefluid case(CSF) of and ThTP breast milk. unambiguously demonstrated. It triphosphatase (ThTPase)17–19. This ThTP is a particularly intriguing appears now that two ATP-synthe- 25contain kDa acytoplasmic highly specific protein thiamine is a molecule. It is found in nearly all sising mechanisms may be diverted - organisms and is the only known towards the synthesis of ThTP: one tously expressed in adult mamma- triphosphorylated compound that using adenylate kinase isoform 1 lianhighly tissues. efficient However, ThTPase it seems ubiqui to be is not a nucleotide. With two phos- most abundant in highly differenti- phoanhydride bonds, it is an energy- AMP)13 and another via FoF1-ATP ated cells while it is hardly detect- rich compound, and as such it has synthase(AK1) (ThDP by a chemiosmotic + ADP � ThTP mecha +- able in cultured cells, suggesting that

Critical review

the expression of this enzyme is to act as a coenzyme. Likewise, we while synaptic vesicles are not, linked to the degree of cellular shall not consider enzymes using suggesting that they are localised in differentiation20,21. thiamine derivatives as substrates the axoplasm28. Another study It was suggested that ThTPase is a (i.e. enzymes involved in the metabo- suggested that thiamine is an integral repair enzyme whose role is to remove lism of phosphoryl derivatives, see component of synaptosomal potentially toxic ThTP produced as a Figure 2) nor thiamine transporters. membranes29. A role of thiamine in by-product of the above-mentioned mammalian neuromuscular trans- reactions22. However, in those organ- bind the unphosphorylated form of mission has also been suggested in isms where 25 kDa ThTPase is absent theSeveral vitamin proteins have been that specificallydescribed. other studies30. Taken together, all Some are thiamine-storage proteins, those data suggest that thiamine may - and they were characterised mainly in - mulates,(chicken) and or in catalytically skeletal muscles inefficient and plant tissues. In mammals, a few thia- pendent role in synapses. The exist- electric(fish, pig), organs, cytosolic its ThTP levels indeed can accueven mine-binding proteins have been encehave of aThDP-binding specific, coenzyme-inde proteins other exceed those of ThDP but without described, but their possible roles than apoenzymes using ThDP as apparent toxic effect21. It is possible remain unclear. Such a protein has coenzyme has long been debated. that ThTP has mainly a mitochondrial 25. Cooper and associates claimed that role, that is, intramitochondrial ThTP It is a soluble 32 kDa protein binding protein-bound ThDP, isolated from a synthesised by FoF1-ATP synthase is unphosphorylatedbeen purified from thiamine.rat erythrocytes It is not soluble liver fraction, was the the physiologically relevant pool, clear whether it also binds phosphate substrate for ThTP synthesis31, but it while cytosolic ThTP synthesised by was later shown that the only ThDP- adenylate kinase would be only a group of Yulia Parkhomenko in Kiev binding protein in liver cytosol was by-product of this enzyme activity. In extensivelyesters or whether studied itthiamine-binding is specific. The transketolase32. In rat brain, Yoshioka this respect, cytosolic ThTP concen- - et al. described the immunohisto- - matography (thiamine covalently chemical localisation of a 68 kDa dance of AK1 in the absence of 25 kDa boundproteins to froma Sepharose brain. By 4B affinitymatrix), chro they ThDP-binding protein33. In this case ThTPase.trations might just reflect the abun isolated a thiamine-binding protein too, the protein probably corre- from a synaptosomal acetone sponds to transketolase as the molec- Adenylated thiamine derivatives powder26. This 103–107 kDa protein ular mass is about the same. AThTP (or thiaminylated ATP, also binds ThMP and ThTP and to a lesser extent ThDP. The same group Thiamine in neurotransmitter E. coli, where it accumulates in later showed that the thiaminerelease responseFigure 2) to was carbon first discoveredstarvation or in binding activity is mainly associated uncoupling5,23. While other B vita- with synaptic vesicles and synapto- relation to nerve excitability has been mins have long been known to form somal membranes26. It was also postulatedA specific neuroactive as early as role the of 1940s,thiamine and in coenzymes by combination with claimed that this thiamine-binding these data have been previously proteins had ThTPase activity27, but reviewed9. While there is presently no acid in NAD+, pantothenic acid in CoA this has not yet been proven using a convincing evidence that thiamine has adenylate (riboflavin in FAD, nicotinic - physiologically relevant effects on that such a condensation product was ration. If this synaptosomal thiamine- axonal conductance, it has been reported demonstratedfor instance), thisfor wasthiamine. the first AThTP time bindingpurified protein homogenous is indeed protein a membrane- prepa consistently that thiamine (and/or exists in small amounts not only in associated membrane protein, it could some of its phosphate esters) facilitates animals and plants (mainly in roots) act as a presynaptic ‘thiamine neurotransmission in various prepara- but also in many cultured mamma- receptor’. There is some evidence that tions, probably by potentiation of the lian cells21. AThTP was shown to be thiamine can act as a neuromodulator release of the neurotransmitters acetyl- an inhibitor of poly(ADP-ribose) at some synapses, regulating neuro- choline28,34,35, dopamine36 and noradren- polymerase-1 in vitro24. Moreover, transmitter release (see next section). aline35. Here, we are exclusively small amounts of AThDP were also It is also worth pointing out that the interested in direct (rapid) effects on discovered in various organisms6. antinociceptive effect of thiamine neurotransmission, as in chronic experi- - ments (for instance, after administra- Thiamine-binding proteins phatase, which could act as or be part tion of thiamine for several weeks in - ofseems a thiamine to require receptor prostatic8. acid phos - cally bind thiamine or one of its phos- Synaptosomes prepared from nate between putative coenzyme-in phorylatedWe refer here derivatives, to proteins but that the specifi bound Torpedo electric organ are enriched dependentanimals), it isand very coenzyme-dependent difficult to discrimi thiamine compound is not supposed in thiamine and its phosphate esters, effects: for instance, increased pyruvate

Critical review

dehydrogenase activity could lead to epigenetic phenomenon that cannot This effect could be antagonised by increased acetyl-CoA production that in be explained by decrease in ThDP- pyrithiamine. turn could increase acetylcholine dependent enzyme activities; indeed, Potential non-coenzyme roles of synthesis. ThDP levels should have been thiamine and its derivatives are In addition to thiamine, several restored by thiamine treatment. It summarised in Figure 4. thiamine antimetabolites, the most can indeed not be explained by a widely used being pyrithiamine and decrease in ThDP-dependent enzyme Thiamine in stress, diabetes and oxythiamine (Figure 3), have been activities, as brain thiamine and ThDP neurodegenerative diseases tested. These structural analogues of levels have presumably been thiamine are called antimetabolites, restored. It is thought that phospho- probiotic effects of thiamine (and/or as when administered to animals rylation of synapsin I leads to a pharmaceuticalIn many instances, preparations beneficial of thia and- - detachment of synapsin from the mine precursors with higher bioa- ciency, pyrithiamine acting primarily synaptic vesicles allowing their vailability) have been demonstrated. In centrallythey produce and signs oxythiamine of thiamine acting defi fusion with the presynaptic these cases, we are most likely dealing peripherally as it presumably does membrane and neurotransmitter with pharmacological effects as thera- not cross the blood–brain barrier. release. An interesting hypothesis peutic (superphysiological) doses were Both compounds competitively would be that thiamine, directly or used. Indeed, under laboratory condi- inhibit thiamine transport37 and indirectly, acts on synapsin I, thereby tions, either animals or cultured cells ThDP synthesis by thiamine pyroph- promoting neurotransmitter release. are generally in a thiamine-rich osphokinase38,39 (although pyrithiamine is more effective). The fact that they are antimetabolites does not preclude the possibility that they may also act as thiamine agonists when thiamine acts as a non-coenzyme modulator. Indeed, oxythiamine stimulates potassium- evoked acetylcholine release in the presence of Ca2+ in isolated brain slices40. These results suggest a coenzyme- independent effect of thiamine on neurotransmitter release, affecting at least three different neurotransmitters (acetylcholine28,34,35, dopamine36 and noradrenaline35) in different - tric organ to mammalian brain. This suggestspreparations a rather ranging conserved from fish mecha elec- leads to synaptic vesicle dysfunction withnism. Conversely,decreased thiaminerelease deficiencyof dopa- mine41, glutamate42 or acetylcholine43. Moreover, episodes of pyrithiamine- phosphosynapsininduced thiamine I deficiency44. Although, in the animalsrat lead towere a significant treated forreduction 3 weeks in with thiamine after appearance of Figure 3: Thiamine provitamins and antimetabolites. Fursultiamine (thiamine O reductionthiamine deficiencyof phosphosynapsin symptoms (losswas S-benzoylthiamine O-monophosphate) is a notof righting reversed. reflex Thus, and seizures),reduction theof thioester.tetrahydrofurfuryl The most disulfide) common and thiamine sulbutiamine antimetabolites ( -isobutyrylthiamine are oxythiamine disulfide) and phosphosynapsin appears to be an pyrithiamine.are disulfides, while benfotiamine (

Critical review

Figure 4: Potential non-coenzyme roles of thiamine and its phosphorylated derivatives. For explanations, see text.

environment: animal chows as well against glutamate toxicity50 and been demonstrated to reach the brain as cell culture media are enriched in promotes the survival of hippocampal parenchyma. They are all converted to vitamins. neurons in high cell density culture51. thiamine either during the passage According to some reports, thiamine - from intestine to blood or in the liver. increases disease resistance in porters to enter cells52. As the rate of As the blood–brain barrier strongly plants45,46. Moreover, intracellular thia- transportThiamine by requires these transporters specific trans is limits thiamine uptake by the brain mine and thiamine phosphate pools relatively slow, membrane transport (thiamine entry could be limited by a are regulated by various stress is a rate-limiting step in thiamine self-exchange), no important increase conditions in Zea mays and Arabidopsis homeostasis. For that reason, in brain thiamine levels are observed thaliana seedlings; it was suggested synthetic thiamine precursors were even with these derivatives7,53–55. It that thiamine is a signalling molecule developed. These molecules are either would therefore be interesting to important for the adaptation to various relatively hydrophobic (sulbutiamine, synthesise derivatives that have a stress conditions47,48. Interestingly, fursultiamine) or are converted to a such a signalling role is assigned to hydrophobic precursor (benfoti- unphosphorylated thiamine in plants, amine) allowing them to cross blood–brainhalf-life sufficiently barrier. long to reach while it should be assigned to ThTP membranes relatively freely (Figure significantNonetheless, blood thiamine levels toand/or cross thia the- and AThTP in E. coli5,6,12 (see above). 3). The general effect of these deriva- mine precursors have been shown to Note that in Arabidopsis leaves, ThTP tives is to rapidly increase circulating accumulates during withering49. thiamine to levels higher than those an animal model of Alzheimer’s Protective effects of thiamine have also diseasehave beneficial7,56,57. One effects study in diabeteshas shown and been described in mammalian cells: thiamine. It must be emphasised than improved cognitive functions and a thiamine protects retinal neurons noneobtained of these by an precursors equivalent have dose ever of striking decrease in charge of

Critical review

Acknowledgements of Alzheimer’s disease58. This study, LB is Research Director and PW the antinociceptive effects of thiamine Prostatic acid phosphatase is required for β-amyloid plaques in a mouse model honorary Research Associate at the and benfotiamine. PLoS One. 2012;7(10): A relationship between thiamine e48562. Bettendorff L. Thiamine in excitable andhowever, Parkinson’s needs confirmation. disease has recently FNRS’. This work was supported by been suggested59,60. It had previously ‘Fonds de la Recherche Scientifique- grant number 2.4508.10 (LB) from Metab9. Brain Dis. 1994 Sep;9(3):183–209. been shown that free thiamine levels the ‘Fonds de la Recherche Fonda- tissues:Zhao reflections R, Gao F, onGoldman a non-cofactor ID. Reduced role. are decreased in the CSF of patients mentale Collective’ (FRFC). folate carrier transports thiamine with Parkinson’s disease compared monophosphate:10. an alternative route for with control patients61. Moreover, a thiamine delivery into mammalian cells. Am very recent preliminary clinical study Abbreviations list J Physiol Cell Physiol. 2002 AThTP, adenosine thiamine triphos- - Jun;282(6):C1512–7. mine treatment (100–200 mg daily Nghiêm HO, Bettendorff L, Changeux thiamine diphosphate; ThMP, thia- dosesreported of theparenteral beneficial thiamine) effects of onthia a minephate; monophosphate;CSF, cerebrospinal ThTP,fluid; ThDP,thia- 11. limited number of patients62. This 43K rapsyn by endogenous kinase(s) mine triphosphate; ThTPase, withJP. Specific thiamine phosphorylation triphosphate as of the Torpedo phos- thiamine triphosphatase. phate donor. FASEB J. 2000 Mar; again needs confirmation. 14(3):543–54. Conclusion Lakaye B, Wirtzfeld B, Wins P, Grisar Thiamine, by the number of its References T, Bettendorff L. Thiamine triphosphate, a derivatives, is certainly one of the Bettendorff L, Wins P. Biochemistry of 12. most diverse B vitamins. By virtue of thiamine and thiamine phosphate Escherichia coli during amino acid starva- the role of ThDP as coenzyme of compounds.1. In: Lane M, DLennarz WJ, tion.new signalJ Biol requiredChem. 2004 for optimal Apr 23;279(17): growth of several key enzymes, it is involved in editors. Encyclopedia of biological chem- 17142–7. nearly all aspects of cell metabolism: istry. Vol. 1. Oxford, UK: Elsevier; 2013. Shikata H, Koyama S, Egi Y, Yamada K, energy production, ribose and p.202–9. Kawasaki T. Cytosolic adenylate kinase Victor M, Adams RD, Collins GH. The 13. nucleic acid synthesis, lipid biosyn- catalyzes the synthesis of thiamin triphos- Wernicke–Korsakoff syndrome. A clinical thesis and neurotransmitter phate from thiamin diphosphate. Biochem and2. pathological study of 245 patients, 82 Int. 1989 May;18(5):933–41. synthesis to name only the most with post-mortem examinations. Contemp Gigliobianco T, Lakaye B, Makar- important. Therefore, thiamine is Neurol Ser. 1971;7:1–206. chikov AF, Wins P, Bettendorff L. Adenylate particularly important for the Hazell AS, Faim S, Wertheimer G, Silva kinase-independent14. thiamine triphos- nervous system, which is highly phate accumulation under severe energy 3. - stress in Escherichia coli. BMC Microbiol. However, the existence of potential torialVR, Marques targeting CS. Theissue. impact Neurochem of oxidative Int. 2008 Jan;8:16. non-coenzymesensitive to thiamineroles remains deficiency. a 2013stress Apr;62(5):796–802. in thiamine deficiency: a multifac Gangolf M, Wins P, Thiry M, El Moualij puzzling issue. First, the existence of Cooper JR, Pincus JH. The role of thia- B, Bettendorff L. Thiamine triphosphate triphosphorylated derivatives, mine in nervous tissue. Neurochem Res. synthesis15. in rat brain occurs in mitochon- 19794. Apr;4(2):223–39. unable to replace the coenzyme dria and is coupled to the respiratory chain. Bettendorff L, Wirtzfeld B, Makar- ThDP, is highly suggestive of such J Biol Chem. 2010 Jan;285(1):583–94. chikov AF, Mazzucchelli G, Frédérich M, Gigliobianco T, Gangolf M, Lakaye B, roles. ThTP and AThTP may be Gigliobianco5. T, et al. Discovery of a natural Pirson B, von Ballmoos C, Wins P, et al. An involved in some signalling processes thiamine adenine nucleotide. Nat Chem alternative16. role of FoF1-ATP synthase in Biol. 2007 Apr;3(4):211–2. Escherichia coli: synthesis of thiamine stress. Second, thiamine itself, Frédérich M, Delvaux D, Gigliobianco T, triphosphate. Sci Rep. 2013;3:1071. under specific conditions of cellular Gangolf M, Dive G, Mazzucchelli G, et al. Makarchikov AF, Chernikevich IP. binding proteins, may regulate Thiaminylated6. adenine nucleotides. - processespossibly through such as specificneurotransmitter thiamine- Chemical synthesis, structural characteri- mine17. triphosphatase from bovine brain. release and in plants protect against zation and natural occurrence FEBS J. BiochimPurification Biophys and characterizationActa. 1992 Oct;1117(3): of thia disease and stress. Although there is 2009 Jun;276(12):3256–68. 326–32. Pan X, Gong N, Zhao J, Yu Z, Gu F, Chen J, still no direct evidence for a physio- Lakaye B, Makarchikov AF, Antunes - AF, Zorzi W, Coumans B, De Pauw E, et al. logically important non-coenzyme amine7. on cognitive impairment and beta- 18. role of thiamine, in view of the amyloidet al. Powerful deposition beneficial in amyloid effects ofprecursor benfoti thiamine triphosphatase widely expressed potential therapeutic interest of protein/presenilin-1 transgenic mice. inMolecular mammalian characterization tissues. J Biol of Chem. a specific 2002 thiamine in Alzheimer’s and Parkin- Brain. 2010 May;133(Pt 5):1342–51. Apr;277(16):13771–7. son’s diseases, this may become a Hurt JK, Coleman JL, Fitzpatrick BJ, Delvaux D, Kerff F, Murty MR, Lakaye key issue in the future. Taylor-Blake B, Bridges AS, Vihko P, et al. B, Czerniecki J, Kohn G, et al. Structural 8. 19.

Critical review

Nishino K, Itokawa Y, Nishino N, Piros Lê O, Héroux M, Butterworth RF. mechanism in mammalian 25-kDa thia- K, Cooper JR. Enzyme system involved in - minedeterminants triphosphatase. of specificity Biochim and catalyticBiophys the31. synthesis of thiamin triphosphate. I. ciency42. results in decreased Ca(2+)- Acta. 2013 Oct;1830(10):4513–23. dependentPyrithiamine-induced release of glutamate thiamine from defi rat Czerniecki J, Chanas G, Verlaet M, protein-bound thiamin diphosphate: ATP hippocampal slices. Metab Brain Dis. Bettendorff L, Makarchikov AF, Leprince phosphorylPurification transferase. and characterization J Biol Chem. 1983 of 1991 Sep;6(3):125–32. P,20. et al. Neuronal localization of the Oct;258(19):11871–8. Jankowska-Kulawy A, Bielarczyk H, Voskoboev AI, Chernikevich IP. Pawelczyk T, Wroblewska M, Szutowicz A. in rodent brain. Neuroscience. 2004; Biosynthesis of thiamine triphosphate Acetyl-CoA43. and acetylcholine metabolism 125(4):833–40.25-kDa specific thiamine triphosphatase 32. - in nerve terminal compartment of thia- Gangolf M, Czerniecki J, Radermecker phate-binding protein of rat liver hyalo- M, Detry O, Nisolle M, Jouan C, et al. Thia- plasm.and identification Biokhimiya. of 1985 thiamine Sep;50(9): diphos 2010 Oct;115(2):333–42. mine21. status in humans and content of 1421–7. mineResende deficient LS, rat Ribeiro brain. AM, J Neurochem. Werner D, phosphorylated thiamine derivatives in Yoshioka H, Nishino K, Miyake T, biopsies and cultured cells. PLoS One. Ohshio G, Kimura T, Hamashima Y. Immu- degrades44. the link between spatial 2010 Oct;5(10):e13616. nohistochemical33. localization of a new behaviorHall JM, Savage and hippocampal LM. Thiamine synapsin deficiency I and Linster CL, Van Schaftingen E, Hanson thiamine diphosphate-binding protein in phosphorylated synapsin I protein levels. AD. Metabolite damage and its repair or the rat nervous system. Neurosci Lett. Behav Brain Res. 2012 Apr;232:421–5. pre-emption.22. Nat Chem Biol. 2013 1987 Jun;77(1):10–4. Goyer A. Thiamine in plants: aspects Feb;9(2):72–80. Dyatlov VA. Effect of thiamine on the of its metabolism and functions. Phyto- Gigliobianco T, Lakaye B, Wins P, El processes responsible for acetylcholine chemistry.45. 2010 Oct;71(14–15):1615–24. Moualij B, Zorzi W, Bettendorff L. Adeno- secretion34. in the frog neuromuscular Wang G, Ding X, Yuan M, Qiu D, Li X, sine23. thiamine triphosphate accumulates synapses. Neurophysiology. 1994;26: Xu C, et al. Dual function of rice OsDR8 in Escherichia coli cells in response to 291–8. gene46. in disease resistance and thiamine Romanenko AV, Gnatenko VM, accumulation. Plant Mol Biol. 2006 Feb; BMC Microbiol. 2010 May;10:148. Vladimirova IA. Effect of thiamine on 60(3):437–49. specificTanaka conditions T, Yamamoto of metabolic D, Sato T, Tanaka stress. neuromuscular35. transmission in smooth Rapala-Kozik M, Kowalska E, S, Usui K, Manabe M, et al. Adenosine thia- muscles. Neurophysiology. 1994;26(6): Ostrowska K. Modulation of thiamine mine24. triphosphate (AThTP) inhibits 370–6. metabolism47. in Zea mays seedlings under poly(ADP-ribose) polymerase-1 (PARP-1) Yamashita H, Zhang YX, Nakamura S. conditions of abiotic stress. J Exp Bot. activity. J Nutr Sci Vitaminol (Tokyo). The effects of thiamin and its phosphate 2008;59(15):4133–43. 2011;57(2):192–6. esters36. on dopamine release in the rat stri- Tunc-Ozdemir M, Miller G, Song L, Voskoboyev AI, Averin VA. Thiamine- atum. Neurosci Lett. 1993 Aug;158(2): Kim J, Sodek A, Koussevitzky S, et al. binding protein from rat erythrocytes. 229–31. Thiamin48. confers enhanced tolerance to Acta25. Vitaminol Enzymol. 1983;5(4): Bettendorff L, Wins P. Mechanism of oxidative stress in Arabidopsis. Plant 251–4. thiamine transport in neuroblastoma Physiol. 2009 Sep;151(1):421–32. Parkhomenko YM, Protasova ZS, 37. Makarchikov AF, Lakaye B, Gulyai IE, Yanchiy OR, Khosla K, Donchenko GV. by sodium channel activators and depend- Czerniecki J, Coumans B, Wins P, et al. Localization26. of thiamine-binding protein encecells. of Inhibition thiamine of uptake a high affinityon membrane carrier Thiamine49. triphosphate and thiamine in synaptosomes from the rat brain. potential and intracellular ATP. J Biol triphosphatase activities: from bacteria Neurophysiology. 2001;33(3):135–9. Chem. 1994 May 20;269(20):14379–85. to mammals. Cell. Mol. Life Sci. 2003 Parkhomenko IUM, Strokina AA, Liu JY, Timm DE, Hurley TD. Pyrithia- Jul;60(7):1477–88. Pilipchuk Slu, Stepanenko SP, Chekhovs- mine as a substrate for thiamine pyroph- Kaneda K, Kikuchi M, Kashii S, Honda kaia27. LI, Donchenko GV. Existence of two osphokinase.38. J Biol Chem. 2006 Mar; Y, Maeda T, Kaneko S, et al. Effects of B different active sites on thiamine binding 281(10):6601–7. vitamins50. on glutamate-induced neurotox- protein in plasma membranes of synapto- Voskoboyev AI, Ostrovsky YM. icity in retinal cultures. Eur J Pharmacol. somes. Ukr Biokhim Zh. 2010 Jan– Thiamin pyrophosphokinase: structure, 1997 Mar;322(2–3):259–64. Feb;82(1):34–41. properties,39. and role in thiamin metabo- Geng MY, Saito H, Katsuki H. The Eder L, Hirt L, Dunant Y. Possible lism. Ann N Y Acad Sci. 1982;378:161–76. effects of thiamine and oxythiamine on involvement of thiamine in acetylcholine Hirsch JA, Parrott J. New considera- the51. survival of cultured brain neurons. release.28. Nature. 1976;264(5582):186–8. tions on the neuromodulatory role of Jpn J Pharmacol. 1995 Jul;68(3):349–52. Matsuda T, Cooper JR. Thiamine as an thiamine.40. Pharmacology. 2012;89(1–2): Subramanian VS, Subramanya SB, integral component of brain synapto- 111–6. Said HM. Relative contribution of THTR-1 somal29. membranes. Proc Natl Acad Sci U S Mousseau DD, Rao VL, Butterworth and52. THTR-2 in thiamin uptake by pancre- A. 1981 Sep;78(9):5886–9. RF. Vesicular dysfunction during experi- atic acinar cells: studies utilizing Slc19a2 Waldenlind L. Possible role of thia- 41. and Slc19a3 knockout mouse models. Am mine in neuromuscular transmission. Acta alterations in dopamine metabolism. Eur J J Physiol Gastrointest Liver Physiol. 2012 Physiol30. Scand. 1979 Jan;105(1):1–10. Pharmacol.mental thiamine 1996 deficiencyDec;317(2–3):263–7. is indicated by Mar;302(5):G572–8.

Critical review

Bettendorff L, Weekers L, Wins P, Rabbani N, Thornalley PJ. Emerging treatment for Parkinson’s disease. BMJ Schoffeniels E. Injection of sulbutiamine role of thiamine therapy for prevention Case Rep. 2013 Aug;2013. induces53. an increase in thiamine triphos- and56. treatment of early-stage diabetic Jiménez-Jimenez FJ, Molina JA, Hernanz phate in rat tissues. Biochem Pharmacol. nephropathy. Diabetes Obes Metab. 2011 A, Fernandez-Vivancos E, de Bustos F, 1990 Dec;40(11):2557–60. Jul;13(7):577–83. 61. Volvert ML, Seyen S, Piette M, Evrard Gibson GE, Hirsch JA, Cirio RT, Jordan of thiamine in patients with Parkinson’s B, Gangolf M, Plumier JC, et al. Benfoti- BD, Fonzetti P, Elder J. Abnormal thia- disease.Barcenilla Neurosci B, et al. CerebrospinalLett. 1999 Aug;271(1): fluid levels amine,54. a synthetic S-acyl thiamine deriva- mine-dependent57. processes in Alzhei- 33–6. tive, has different mechanisms of action mer’s Disease. Lessons from diabetes. Mol Cell Neurosci. 2013 Jul;55:17–25. role of thiamine in Parkinson’s disease: Asakura T, Kodera S, Kanda J, Ikeda M. preliminary62. Luong KV, report. Nguyen J LTH.Neurol The Res. beneficial 2012; derivatives.and a different BMC pharmacological Pharmacol. 2008 profile Jun; Thiamine-responsive pulmonary hyper- 2(5):211–4. 8(1):10.than lipid-soluble thiamine disulfide tension.58. BMJ Case Rep. 2013 Jan. Bettendorff L, Wins P. Thiamin Hills JI, Golub MS, Bettendorff L, Keen Lu’o’ng KV, Nguyên LT. Thiamine and diphosphate in biological chemistry: new CL. The effect of thiamin tetrahydrofur- Parkinson’s disease. J Neurol Sci. 2012 aspects63. of thiamin metabolism, especially 55. Mar;316(1–2):1–8.59. triphosphate derivatives acting other than DBA/2J mice. Neurotoxicol Teratol. 2012 Costantini A, Pala MI, Compagnoni L, as cofactors. FEBS J. 2009 Jun;276(11): Mar;34(2):242–52.furyl disulfide on behavior of juvenile Colangeli M. High-dose thiamine as initial 2917–25. 60.