title: Molecular mechanisms of the non-coenzyme action of thiamin in brain: biochemical, structural and pathway analysis.
abstract: Thiamin (vitamin B1) is a pharmacological agent boosting central metabolism through the action of the coenzyme thiamin diphosphate (ThDP). However, positive effects, including improved cognition, of high thiamin doses in neurodegeneration may be observed without increased ThDP or ThDP-dependent enzymes in brain. Here, we determine protein partners and metabolic pathways where thiamin acts beyond its coenzyme role. Malate dehydrogenase, glutamate dehydrogenase and pyridoxal kinase were identified as abundant proteins binding to thiamin- or thiazolium-modified sorbents. Kinetic studies, supported by structural analysis, revealed allosteric regulation of these proteins by thiamin and/or its derivatives. Thiamin triphosphate and adenylated thiamin triphosphate activate glutamate dehydrogenase. Thiamin and ThDP regulate malate dehydrogenase isoforms and pyridoxal kinase. Thiamin regulation of enzymes related to malate-aspartate shuttle may impact on malate/citrate exchange, responsible for exporting acetyl residues from mitochondria. Indeed, bioinformatic analyses found an association between thiamin- and thiazolium-binding proteins and the term acetylation. Our interdisciplinary study shows that thiamin is not only a coenzyme for acetyl-CoA production, but also an allosteric regulator of acetyl-CoA metabolism including regulatory acetylation of proteins and acetylcholine biosynthesis. Moreover, thiamin action in neurodegeneration may also involve neurodegeneration-related 14-3-3, DJ-1 and β-amyloid precursor proteins identified among the thiamin- and/or thiazolium-binding proteins.
authors.affiliation: Faculty of Bioengineering and Bioinformatics of Lomonosov Moscow State University, Leninskije Gory 1, 119992 Moscow, Russian Federation.
authors.forename: Garik
authors.initials: G
authors.lastname: Mkrtchyan
authors.affiliation: Faculty of Bioengineering and Bioinformatics of Lomonosov Moscow State University, Leninskije Gory 1, 119992 Moscow, Russian Federation.
authors.forename: Vasily
authors.initials: V
authors.lastname: Aleshin
authors.affiliation: Department of Vitamin and Coenzyme Biochemistry, Palladin Institute of Biochemistry, NAS of Ukraine, 9 Leontovicha Street, 01601 Kyiv, Ukraine.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Parkhomenko
authors.affiliation: Institute of Experimental Internal Medicine, Otto-von-Guericke University Magdeburg, Germany.
authors.forename: Thilo
authors.initials: T
authors.lastname: Kaehne
authors.affiliation: Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza Università di Roma, via degli Apuli 9, 00185 Roma, Italy.
authors.forename: Martino Luigi
authors.initials: ML
authors.lastname: Di Salvo
authors.affiliation: Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza Università di Roma, via degli Apuli 9, 00185 Roma, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Parroni
authors.affiliation: Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza Università di Roma, via degli Apuli 9, 00185 Roma, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Contestabile
authors.affiliation: Institute of Bioorganic Chemistry and Petrochemistry National Academy of Sciences of Ukraine, Kyiv, Ukraine.
authors.forename: Andrey
authors.initials: A
authors.lastname: Vovk
authors.affiliation: GIGA Neurosciences, University of Liege, Quartier Hôpital, Avenue Hippocrate 15, 4000 Liege, Belgium.
authors.forename: Lucien
authors.initials: L
authors.lastname: Bettendorff
authors.affiliation: 1] Faculty of Bioengineering and Bioinformatics of Lomonosov Moscow State University, Leninskije Gory 1, 119992 Moscow, Russian Federation [2] Belozersky Institute of Physicochemical Biology of Lomonosov Moscow State University, Leninskije Gory 1, 119992 Moscow, Russian Federation.
authors.forename: Victoria
authors.initials: V
authors.lastname: Bunik
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D008297:Male; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D013831:Thiamine / Q000737:chemistry* / Q000378:metabolism*; D013835:Thiamine Pyrophosphate / Q000737:chemistry / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D009419:Nerve Tissue Proteins; D013835:Thiamine Pyrophosphate; D013831:Thiamine