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

摘要

Thiamin (vitamin B1) is a pharmacological agent boosting central metabolism through the action of\udthe coenzyme thiamin diphosphate (ThDP). However, positive effects, including improved cognition,\udof high thiamin doses in neurodegeneration may be observed without increased ThDP or ThDPdependent\udenzymes in brain. Here, we determine protein partners and metabolic pathways where\udthiamin acts beyond its coenzyme role. Malate dehydrogenase, glutamate dehydrogenase and\udpyridoxal kinase were identified as abundant proteins binding to thiamin- or thiazolium-modified\udsorbents. Kinetic studies, supported by structural analysis, revealed allosteric regulation of these\udproteins by thiamin and/or its derivatives. Thiamin triphosphate and adenylated thiamin triphosphate\udactivate glutamate dehydrogenase. Thiamin and ThDP regulate malate dehydrogenase isoforms and\udpyridoxal kinase. Thiamin regulation of enzymes related to malate-aspartate shuttle may impact\udon malate/citrate exchange, responsible for exporting acetyl residues from mitochondria. Indeed,\udbioinformatic analyses found an association between thiamin- and thiazolium-binding proteins\udand the term acetylation. Our interdisciplinary study shows that thiamin is not only a coenzyme\udfor acetyl-CoA production, but also an allosteric regulator of acetyl-CoA metabolism including\udregulatory acetylation of proteins and acetylcholine biosynthesis. Moreover, thiamin action in\udneurodegeneration may also involve neurodegeneration-related 14-3-3, DJ-1 and β-amyloid precursor\udproteins identified among the thiamin- and/or thiazolium-binding proteins.