Vitamin B6 is essential for serine de novo biosynthesis

Abstract

Pyridoxal 5′-phosphate (PLP), the metabolically active form of vitamin B6, plays an essential role in brain metabolism as a cofactor in numerous enzyme reactions. PLP deficiency in brain, either genetic or acquired, results in severe drug-resistant seizures that respond to vitamin B6 supplementation. The pathogenesis of vitamin B6 deficiency is largely unknown. To shed more light on the metabolic consequences of vitamin B6 deficiency in brain, we performed untargeted metabolomics in vitamin B6-deprived Neuro-2a cells. Significant alterations were observed in a range of metabolites. The most surprising observation was a decrease of serine and glycine, two amino acids that are known to be elevated in the plasma of vitamin B6 deficient patients. To investigate the cause of the low concentrations of serine and glycine, a metabolic flux analysis on serine biosynthesis was performed. The metabolic flux results showed that the de novo synthesis of serine was significantly reduced in vitamin B6-deprived cells. In addition, formation of glycine and 5-methyltetrahydrofolate was decreased. Thus, vitamin B6 is essential for serine de novo biosynthesis in neuronal cells, and serine de novo synthesis is critical to maintain intracellular serine and glycine. These findings suggest that serine and glycine concentrations in brain may be deficient in patients with vitamin B6 responsive epilepsy. The low intracellular 5-mTHF concentrations observed in vitro may explain the favourable but so far unexplained response of some patients with pyridoxine-dependent epilepsy to folinic acid supplementation.

Three-Dimensional Graphene Enhances Neural Stem Cell Proliferation Through Metabolic Regulation

“…Arginine succinate synthetase is a ligase that is involved in amino acid metabolism, signaling pathways, and cell growth processes in cardiovascular diseases (Valeev et al, 2016). Several reactions in vitamin B 6 metabolic pathway were catalyzed by Pyridoxamine 5'-phosphate oxidase and pyridoxine kinase which contribute to neurotransmitter and amino acid metabolism (Pandey et al, 2014;Huang et al, 2016;Ramos et al, 2017;Kim et al, 2018). In this study, the above enzyme scores in the 3DG-2DG comparison were higher than in the 2DG-TCPS comparison which also indicate the 3DG can enhance the proliferation of NSCs.…”

Disorders affecting vitamin B6 metabolism

“…Studies on vitamin B 6 ‐deprived Neuro‐2a cells showed reduced synthesis of glycine, serine, and 5‐methyl‐tetrahydrofolate. The authors suggested that the low intracellular 5‐methyl‐THF concentrations observed in vitro may explain the favorable but so far unexplained response of some patients with ALDH7A1 deficiency epilepsy to folinic acid supplementation …”

“…The authors suggested that the low intracellular 5-methyl-THF concentrations observed in vitro may explain the favorable but so far unexplained response of some patients with ALDH7A1 deficiency epilepsy to folinic acid supplementation. 50 There are some dangers in extrapolating from animal models and cultured neuronal cells to human subjects with inborn errors affecting vitamin B 6 metabolism. Some conclusions on the causes of epilepsy due to PLP deficiency can perhaps be drawn from human inborn errors affecting specific PLP-dependent enzymes 51 (Table S1).…”

Direct Infusion Based Metabolomics Identifies Metabolic Disease in Patients’ Dried Blood Spots and Plasma

“…Thus, DI-HRMS is in potential a powerful technique for the development of a high-throughput [23,24] broad test requiring limited patient material. DI-HRMS has been used in a quantitative and non-quantitative fashion for biomarker identification [25,26,27,28,29,30]. Moreover, Denes et al started to explore its use for metabolic diagnostics by studying phenylketonuria, medium-chain acyl-coenzyme A dehydrogenase deficiency and homocystinuria [12].…”