A5043922644- Metabolism and Genetic Disorders
- Folate and B Vitamins Research
- Amino Acid Enzymes and Metabolism
- Mitochondrial Function and Pathology
- Enzyme Structure and Function
- Epilepsy research and treatment
- Neuroscience and Neuropharmacology Research
- Zebrafish Biomedical Research Applications
- Alkaline Phosphatase Research Studies
- Neonatal Health and Biochemistry
- Prostate Cancer Treatment and Research
- Biochemical and Molecular Research
- Analytical Chemistry and Chromatography
- Vitamin D Research Studies
- Renal and related cancers
- Vitamin C and Antioxidants Research
- Pesticide Residue Analysis and Safety
- Pancreatic function and diabetes
- Autophagy in Disease and Therapy
- Radiation Therapy and Dosimetry
- Epigenetics and DNA Methylation
- Cancer Research and Treatment
- Hemoglobinopathies and Related Disorders
- Acute Lymphoblastic Leukemia research
- Heterotopic Ossification and Related Conditions
University Medical Center Utrecht
2011-2025
Utrecht University
2012-2020
Amsterdam UMC Location University of Amsterdam
2017
University Medical Center
2012
University Hospital and Clinics
2012
Netherlands Metabolomics Centre
2011-2012
Vrije Universiteit Amsterdam
2002
Food & Nutrition
1974
Pyridoxine-dependent epilepsy (PDE) is a rare disease characterized by mutations in the lysine degradation gene
The malate-aspartate shuttle (MAS) is a redox that transports reducing equivalents across the inner mitochondrial membrane while recycling cytosolic NADH to NAD+. We genetically disrupted each MAS component generate panel of MAS-deficient HEK293 cell lines in which we performed [U-13C]-glucose tracing. cells have reduced serine biosynthesis, strongly correlates with lactate M+3/pyruvate M+3 ratio (reflective NAD+/NADH ratio), consistent NAD+ dependency phosphoglycerate dehydrogenase...
Biallelic pathogenic variants in PLPBP (formerly called PROSC) have recently been shown to cause a novel form of vitamin B6-dependent epilepsy, the pathophysiological basis which is poorly understood. When left untreated, disease can progress status epilepticus and death infancy. Here we present 12 previously undescribed patients six PLPBP. Suspected clinical diagnoses prior identification included mitochondrial encephalopathy (two patients), folinic acid-responsive epilepsy (one patient)...
Dravet syndrome is caused by dominant loss-of-function mutations in SCN1A which cause reduced activity of Nav1.1 leading to lack neuronal inhibition. On the other hand, gain-of-function SCN8A can lead a severe epileptic encephalopathy subtype over activating NaV1.6 channels. These observations suggest that and Nav1.6 represent two opposing sides balance between inhibition activation. Here, we hypothesize may be treated either enhancing or reducing activity. To test this hypothesis generated...
Background Vitamin B6 is present in various forms (vitamers) the diet that need to be metabolized pyridoxal phosphate (PLP), active cofactor form of vitamin B6. In literature, liver has been reported major site for this conversion, whereas exact role intestine remains elucidated. Objective To gain insight into human metabolism. Materials and Methods Expression enzymes kinase (PK), pyridox(am)ine oxidase (PNPO) PLP-phosphatase was determined Caco-2 cells lysates intestine. uptake, conversion...
Pyridoxal 5′-phosphate (PLP) is the active form of vitamin B6. Mammals cannot synthesize B6, so they rely on dietary uptake different B6 forms, and via salvage pathway interconvert them into PLP. Humans possess three enzymes in this pathway: pyridoxal kinase, pyridox(am)ine phosphate oxidase phosphatase. Besides these, a fourth enzyme has been described plants yeast but not humans: reductase. We analysed vitamers remnant CSF samples PLP-treated patients four mammalian cell lines (HepG2,...
Recently, biallelic variants in PLPBP coding for pyridoxal 5'-phosphate homeostasis protein (PLPHP) were identified as a novel cause of early-onset vitamin B6-dependent epilepsy. The molecular function and precise role PLPHP B6 metabolism are not well understood. To address these questions, we used PLPHP-deficient patient skin fibroblasts HEK293 cells YBL036C (PLPHP ortholog)-deficient yeast. We showed that independent extracellular vitamer type (pyridoxine, pyridoxamine, or pyridoxal),...
Over the past years, essential role of vitamin B6 in brain development and functioning has been recognized genetic metabolic disorders resulting functional deficiency have identified. However, data on vitamers children are scarce.B6 vitamer concentrations simultaneously sampled plasma cerebrospinal fluid (CSF) 70 with intellectual disability were determined by ultra performance liquid chromatography-tandem mass spectrometry. For ethical reasons, CSF samples could not be obtained from healthy...
To stimulate cell growth, the protein kinase complex mTORC1 requires intracellular amino acids for activation. Amino-acid sufficiency is relayed to by Rag GTPases on lysosomes, where growth factor signaling enhances activity via GTPase Rheb. In absence of acids, GATOR1 inactivates Rags, resulting in lysosomal detachment and inactivation mTORC1. We demonstrate that human cells, release from lysosomes depends its activity. accordance with a negative feedback mechanism, activated mTOR mutants...
Hypophosphatasia (HPP) is a rare inborn error of metabolism caused by pathogenic var-iants in ALPL, coding for tissue non-specific alkaline phosphatase. HPP patients suffer from impaired bone mineralization and severe cases vitamin B6-responsive sei-zures. To study we generated alpl-/- zebrafish line using CRISPR/Cas9 gene-editing technology. At 5 days post fertilization (dpf) no alpl mRNA 89% lower total phosphatase activity was detected compared to alpl+/+ embryos. The survival strongly...
Hypophosphatasia (HPP) is a rare inborn error of metabolism caused by pathogenic variants in ALPL, coding for tissue non-specific alkaline phosphatase. HPP patients suffer from impaired bone mineralization, and severe cases vitamin B6-responsive seizures. To study HPP, we generated alpl-/- zebrafish using CRISPR/Cas9 gene-editing technology. At 5 days post fertilization (dpf), no alpl mRNA 89% lower total phosphatase activity was detected compared to alpl+/+ embryos. The survival strongly...
Current intensive chemotherapy regimens have improved overall survival in pediatric acute lymphoblastic leukemia (ALL) but fail to cure some high-risk patient subgroups. We observed that lysine methyltransferase 2A (KMT2A)-rearranged leukemia, an aggressive subset with a dismal prognosis, is particularly vulnerable perturbations of the methionine cycle. demonstrate this dependency driven by increased need for S-adenosylmethionine (SAM) maintain hypermethylated state KMT2A-r leukemias....
Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disease caused by mutations in the ALDH7A1 gene leading to blockade of lysine catabolism pathway. PDE characterized recurrent seizures that are resistant conventional anticonvulsant treatment but well-controlled pyridoxine (PN). Most patients also suffer from neurodevelopmental deficits despite adequate seizure control with PN. To investigate potential pathophysiological mechanisms associated deficiency, we generated...
Pyridox(am)ine 5'-phosphate oxidase (PNPO) catalyzes oxidation of pyridoxine (PNP) and pyridoxamine (PMP) to pyridoxal (PLP), the active form vitamin B6. PNPO deficiency results in neonatal/infantile seizures neurodevelopmental delay. To gain insight into this disorder we generated Pnpo deficient (pnpo-/-) zebrafish (CRISPR/Cas9 gene editing). Locomotion analysis showed that pnpo-/- develop resulting only 38% surviving beyond 20 days post fertilization (dpf). The age seizure onset varied...
BACKGROUND AND OBJECTIVE: Vitamin B6 plays a pivotal role in brain development and functioning. Differences vitamin homeostasis between preterm term newborn infants have been reported. The authors sought to investigate whether vitamers cerebrospinal fluid (CSF) of are different. METHODS: vitamer concentrations were determined 69 CSF samples 36 (26 born 10 term) by ultra performance liquid chromatography-tandem mass spectrometry. samples, taken from subcutaneous intraventricular reservoir,...
Abstract Pyridox (am) ine 5'-phosphate oxidase (PNPO) is a rate-limiting enzyme in converting dietary vitamin B6 (VB6) to pyridoxal (PLP), the biologically active form of VB6 and involved synthesis neurotransmitters including γ-aminobutyric acid (GABA), dopamine, serotonin. In humans, PNPO mutations have been increasingly identified neonatal epileptic encephalopathy more recently also early-onset epilepsy. Till now, little known about neurobiological mechanisms underlying...
Abstract Dravet syndrome is caused by dominant loss-of-function mutations in SCN1A which cause reduced activity of Nav1.1 leading to lack neuronal inhibition. On the other hand, gain-of-function SCN8A can lead a severe epileptic encephalopathy subtype over activating Na V 1.6 channels. These observations suggest that and Nav1.6 represent two opposing sides balance between inhibition activation. Here, we hypothesize may be treated either enhancing or reducing activity. To test this hypothesis...
Abstract Pyridox(am)ine 5’-phosphate oxidase (PNPO) is a rate-limiting enzyme in converting dietary vitamin B6 (VB6) to pyridoxal (PLP), the biologically active form of VB6, and involved synthesis neuro-transmitters including GABA, dopamine, serotonin. In humans, PNPO mutations have been increasingly identified neonatal epileptic encephalopathy more recently also early-onset epilepsy. Till now, little known about neurobiological mechanisms underlying PNPO-deficiency-induced seizures due lack...