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      Thiamine triphosphate: a ubiquitous molecule in search of a physiological role.

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          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.

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          Author and article information

          Journal
          Metab Brain Dis
          Metabolic brain disease
          Springer Nature America, Inc
          1573-7365
          0885-7490
          Dec 2014
          : 29
          : 4
          Affiliations
          [1 ] GIGA-Neurosciences, University of Liège, Avenue de l'Hôpital, 1, 4000, Liège, Belgium, L.Bettendorff@ulg.ac.be.
          Article
          10.1007/s11011-014-9509-4
          24590690
          12903307-6ebc-4d34-b15d-40adbd023510
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