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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 ?-amyloid precursor proteins identified among the thiamin- and/or thiazolium-binding proteins.

SUBMITTER: Mkrtchyan G

PROVIDER: S-EPMC4515825 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Mkrtchyan Garik G Aleshin Vasily V Parkhomenko Yulia Y Kaehne Thilo T Di Salvo Martino Luigi ML Parroni Alessia A Contestabile Roberto R Vovk Andrey A Bettendorff Lucien L Bunik Victoria V

Scientific reports 20150727

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 ...[more]

PMID: 26212886

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Dataset Information

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

Publications

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

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