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.
Highlights
Thiamin is a pharmacological agent boosting central metabolism through the action of the coenzyme thiamin diphosphate (ThDP)
To advance the understanding of molecular mechanisms of thiamin action in brain, we aimed at the identification of the synaptosomal proteins binding and/or transforming thiamin or its derivatives
The protocol of partial purification of a subset of such proteins included affinity chromatography on sorbents derivatized with thiamin or its thiazolium heterocycle covalently bound to a spacer
Summary
Thiamin (vitamin B1) is a pharmacological agent boosting central metabolism through the action of the coenzyme thiamin diphosphate (ThDP). Natural thiamin derivatives may be pharmacologically significant due to the well-known coenzyme role of ThDP in central metabolism Another important aspect is that pharmacological compounds often possess heterocycles which are structurally similar to those present in thiamin and derivatives, and may act by targeting thiamin-dependent pathways[23]. Drugs which reduce hyperphosphorylated tau-protein in AD mouse models[24] possess structural similarity to thiamin and may mimic or interfere with the pathways of the thiamin non-coenzyme action in synaptic transmission The existence of such pathways, in addition to the known metabolic role of ThDP, could explain the absence of a robust correlation between positive effects of thiamin in patients with neurodegenerative diseases and activities of ThDP-dependent enzymes and ThDP levels in the brain of these patients[13,25]. In view of the thiamin action in neurodegenerative diseases, the identification in the thiazolium proteome of β -amyloid precursor proteins is of particular interest
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