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Sci Rep. 2015 Jul 27;5:12583. doi: 10.1038/srep12583.

Molecular mechanisms of the non-coenzyme action of thiamin in brain: biochemical, structural and pathway analysis.

Author information

1
Faculty of Bioengineering and Bioinformatics of Lomonosov Moscow State University, Leninskije Gory 1, 119992 Moscow, Russian Federation.
2
Department of Vitamin and Coenzyme Biochemistry, Palladin Institute of Biochemistry, NAS of Ukraine, 9 Leontovicha Street, 01601 Kyiv, Ukraine.
3
Institute of Experimental Internal Medicine, Otto-von-Guericke University Magdeburg, Germany.
4
Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza Università di Roma, via degli Apuli 9, 00185 Roma, Italy.
5
Institute of Bioorganic Chemistry and Petrochemistry National Academy of Sciences of Ukraine, Kyiv, Ukraine.
6
GIGA Neurosciences, University of Liege, Quartier Hôpital, Avenue Hippocrate 15, 4000 Liege, Belgium.
7
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.

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.

PMID:
26212886
PMCID:
PMC4515825
DOI:
10.1038/srep12583
[Indexed for MEDLINE]
Free PMC Article

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