title: Thiamine triphosphate: a ubiquitous molecule in search of a physiological role.
abstract: Thiamine triphosphate (ThTP) was discovered over 60 years ago and it was long thought to be a specifically neuroactive compound. Its presence in most cell types, from bacteria to mammals, would suggest a more general role but this remains undefined. In contrast to thiamine diphosphate (ThDP), ThTP is not a coenzyme. In E. coli cells, ThTP is transiently produced in response to amino acid starvation, while in mammalian cells, it is constitutively produced at a low rate. Though it was long thought that ThTP was synthesized by a ThDP:ATP phosphotransferase, more recent studies indicate that it can be synthesized by two different enzymes: (1) adenylate kinase 1 in the cytosol and (2) FoF1-ATP synthase in brain mitochondria. Both mechanisms are conserved from bacteria to mammals. Thus ThTP synthesis does not seem to require a specific enzyme. In contrast, its hydrolysis is catalyzed, at least in mammalian tissues, by a very specific cytosolic thiamine triphosphatase (ThTPase), controlling the steady-state cellular concentration of ThTP. In some tissues where adenylate kinase activity is high and ThTPase is absent, ThTP accumulates, reaching ≥ 70% of total thiamine, with no obvious physiological consequences. In some animal tissues, ThTP was able to phosphorylate proteins, and activate a high-conductance anion channel in vitro. These observations raise the possibility that ThTP is part of a still uncharacterized cellular signaling pathway. On the other hand, its synthesis by a chemiosmotic mechanism in mitochondria and respiring bacteria might suggest a role in cellular energetics.
authors.affiliation: GIGA-Neurosciences, University of Liège, Avenue de l'Hôpital, 1, 4000, Liège, Belgium, L.Bettendorff@ulg.ac.be.
authors.forename: Lucien
authors.initials: L
authors.lastname: Bettendorff
authors.forename: Bernard
authors.initials: B
authors.lastname: Lakaye
authors.forename: Gregory
authors.initials: G
authors.lastname: Kohn
authors.forename: Pierre
authors.initials: P
authors.lastname: Wins
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005544:Forecasting; D006801:Humans; D007888:Leigh Disease / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D008959:Models, Neurological; D009928:Organ Specificity; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D006180:Proton-Translocating ATPases / Q000378:metabolism; D015398:Signal Transduction; D013045:Species Specificity; D013837:Thiamin-Triphosphatase / Q000378:metabolism; D013838:Thiamine Triphosphate / Q000096:biosynthesis / Q000502:physiology*
chemical_list: D000596:Amino Acids; D013838:Thiamine Triphosphate; D000255:Adenosine Triphosphate; D000263:Adenylate Kinase; C110939:adenylate kinase 1; D013837:Thiamin-Triphosphatase; D006180:Proton-Translocating ATPases