Product inhibition of mammalian thiamine pyrophosphokinase is an important mechanism for maintaining thiamine diphosphate homeostasis

Sambon, Margaux; Pavlova, Oleksandra; Alhama-Riba, Judit; Wins, Pierre; Brans, Alain; Bettendorff, Lucien

doi:10.1016/j.bbagen.2021.130071

Cited by 7 publications

(9 citation statements)

References 53 publications

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“…Interestingly, despite reductions in thiamine levels due to THTR2 ablation or the administration of trimethoprim, TDP levels were not affected. Previous studies suggest that changes in plasma and brain thiamine do not result in linear changes in brain TDP [ 54 , 55 ] as TDP levels are regulated in response to thiamine availability and energy demand [ 4 , 56 ].…”

Section: Discussionmentioning

confidence: 99%

“…Thiamine and TMP are influenced by recent exposure and are the main forms in plasma available for tissue uptake [ 1 , 2 ], whereas intracellular TDP is a cofactor for several metabolic enzymes involved in sugar, amino acid, and fat metabolism [ 3 ]. TDP levels are regulated [ 4 ] and often used as a clinical status biomarker for deficiency either directly or via functional assays in red blood cells (RBC) [ 1 ]. In addition to energy metabolism, this vitamin has downstream effects in cellular oxidation, nucleotide production, and neurotransmitter functions [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

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The Impacts of Slc19a3 Deletion and Intestinal SLC19A3 Insertion on Thiamine Distribution and Brain Metabolism in the Mouse

et al. 2023

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The Thiamine Transporter 2 (THTR2) encoded by SLC19A3 plays an ill-defined role in the maintenance of tissue thiamine, thiamine monophosphate, and thiamine diphosphate (TDP) levels. To evaluate the impact of THTR2 on tissue thiamine status and metabolism, we expressed the human SLC19A3 transgene in the intestine of total body Slc19a3 knockout (KO) mice. Male and female wildtype (WT) and transgenic (TG) mice were fed either 17 mg/kg (1×) or 85 mg/kg (5×) thiamine hydrochloride diet, while KOs were only fed the 5× diet. Thiamine vitamers in plasma, red blood cells, duodenum, brain, liver, kidney, heart, and adipose tissue were measured. Untargeted metabolomics were performed on the brain tissues of groups with equivalent plasma thiamine. KO mice had ~two- and ~three-fold lower plasma and brain thiamine levels than WT on the 5× diet. Circulating vitamers were sensitive to diet and equivalent in TG and WT mice. However, TG had 60% lower thiamine but normal brain TDP levels regardless of diet, with subtle differences in the heart and liver. The loss of THTR2 reduced levels of nucleic acid and amino acid derivatives in the brain. Therefore, mutation or inhibition of THTR2 may alter the brain metabolome and reduce the thiamine reservoir for TDP biosynthesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Impacts of Slc19a3 Deletion and Intestinal SLC19A3 Insertion on Thiamine Distribution and Brain Metabolism in the Mouse

et al. 2023

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“…Textbooks have stated that TPK1 uses ATP to phosphorylate thiamine and produce TPP ( 34 , 35 ). However, TPK1 might also use pyrimidine nucleotides directly instead of ATP to promote thiamine phosphorylation and TPP synthesis.…”

Section: Requirement Of Uridine Triphosphate For Tpk1 Activity and Py...mentioning

confidence: 99%

Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis

Sahu,

Villa,

Reczek

et al. 2024

Science

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Cellular purines, particularly adenosine 5′-triphosphate (ATP), fuel many metabolic reactions, but less is known about the direct effects of pyrimidines on cellular metabolism. We found that pyrimidines, but not purines, maintain pyruvate oxidation and the tricarboxylic citric acid (TCA) cycle by regulating pyruvate dehydrogenase (PDH) activity. PDH activity requires sufficient substrates and cofactors, including thiamine pyrophosphate (TPP). Depletion of cellular pyrimidines decreased TPP synthesis, a reaction carried out by TPP kinase 1 (TPK1), which reportedly uses ATP to phosphorylate thiamine (vitamin B1). We found that uridine 5′-triphosphate (UTP) acts as the preferred substrate for TPK1, enabling cellular TPP synthesis, PDH activity, TCA-cycle activity, lipogenesis, and adipocyte differentiation. Thus, UTP is required for vitamin B1 utilization to maintain pyruvate oxidation and lipogenesis.

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“…In the case of TDP, there are several checkpoints that allow the management of its metabolism. Cellular biosynthesis can be controlled by regulating thiamine entry through transporters (akin to gatekeepers) and by the activity of TPK (Sambon et al., 2022). Equally, the degradation or turnover of TDP may trigger any of the salvage pathways as a function of the availability of their corresponding substrate, which can happen under stress conditions.…”

Section: The Vitamin B1 Familymentioning

confidence: 99%

B vitamin supply in plants and humans: the importance of vitamer homeostasis

et al. 2022

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B vitamins are a group of water-soluble micronutrients that are required in all life forms. With the lack of biosynthetic pathways, humans depend on dietary uptake of these compounds, either directly or indirectly, from plant sources. B vitamins are frequently given little consideration beyond their role as enzyme accessory factors and are assumed not to limit metabolism. However, it should be recognized that each individual B vitamin is a family of compounds (vitamers), the regulation of which has dedicated pathways. Moreover, it is becoming increasingly evident that individual family members have physiological relevance and should not be sidelined. Here, we elaborate on the known forms of vitamins B 1 , B 6 and B 9 , their distinct functions and importance to metabolism, in both human and plant health, and highlight the relevance of vitamer homeostasis. Research on B vitamin metabolism over the past several years indicates that not only the total level of vitamins but also the oft-neglected homeostasis of the various vitamers of each B vitamin is essential to human and plant health. We briefly discuss the potential of plant biology studies in supporting human health regarding these B vitamins as essential micronutrients. Based on the findings of the past few years we conclude that research should focus on the significance of vitamer homeostasisat the organ, tissue and subcellular levelswhich could improve the health of not only humans but also plants, benefiting from cross-disciplinary approaches and novel technologies.

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Product inhibition of mammalian thiamine pyrophosphokinase is an important mechanism for maintaining thiamine diphosphate homeostasis

Cited by 7 publications

References 53 publications

The Impacts of Slc19a3 Deletion and Intestinal SLC19A3 Insertion on Thiamine Distribution and Brain Metabolism in the Mouse

The Impacts of Slc19a3 Deletion and Intestinal SLC19A3 Insertion on Thiamine Distribution and Brain Metabolism in the Mouse

Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis

B vitamin supply in plants and humans: the importance of vitamer homeostasis

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