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.

Widespread episodic thiamine deficiency in Northern Hemisphere wildlife

“…We also found that thiamine deficiency in aquatic wildlife was much more widespread than previously reported, both geographically and among taxa—a finding that may be related to recently observed thiamine depletion in the aquatic environment7. Thiamine deficiency is ultimately lethal, but it also has a number of preceding sublethal health effects, such as memory and learning disorders, immunosuppression, damage to the blood-brain barrier, neurological disorders, reduced food intake, and altered carbohydrate, protein, and lipid metabolism891011. Thiamine deficiency was systematically investigated in seven feral species belonging to three animal classes: bivalves, ray-finned fishes, and birds.…”

Multiple Forms of Glutamate Dehydrogenase in Animals: Structural Determinants and Physiological Implications

“…GDH has recently been found to be among the most abundant enzymes in the fractions from bovine brain obtained by affinity chromatography using the thiazolium fragment of thiamine, (3-decyloxycarbonylmethyl-4-methyl-5-(2-hydroxyethyl)thiazolium, further referred to as decylthiazolium) (Figure 4), as a ligand [116]. Kinetic study of the regulatory effects of thiamine and its derivatives on GDH activity showed that thiamine diphosphate (ThDP), but not thiamine, inhibits glutamate dehydrogenase at non-saturating NADH concentrations [116].…”

“…Kinetic study of the regulatory effects of thiamine and its derivatives on GDH activity showed that thiamine diphosphate (ThDP), but not thiamine, inhibits glutamate dehydrogenase at non-saturating NADH concentrations [116]. Since the inhibitory effect decreases at NADH saturation, partial overlapping of the ThDP- and catalytic NADH-binding sites in GDH may be assumed.…”

“…Although the inhibitory effect of ThDP is observed at relatively high ThDP concentrations (0.1–1 mM), the non-coenzyme thiamine derivatives, thiamine triphosphate (ThTP) and adenylated thiamine triphosphate (AThTP), act as GDH activators at micromolar concentrations [116]. We suggest that the non-coenzyme derivatives of thiamine are allosteric activators of GDH, whereas ThDP binding does not result in a conformation required for the activation effect, causing inhibition instead.…”

Vitamin B1 in critically ill patients: needs and challenges

“…Its involvement in these metabolic pathways and its intracellular abundance has made TPP a popular analyte for assessing thiamine status. However, there are also proposed non-cofactor roles of thiamine compounds within the immune system, gene regulation, oxidative stress response, cholinergic activity, chloride channels and neurotransmission [8,[56][57][58][59][60][61].…”