A5026042283- Metabolism and Genetic Disorders
- Metabolomics and Mass Spectrometry Studies
- Drug Transport and Resistance Mechanisms
- Alcoholism and Thiamine Deficiency
- Erythrocyte Function and Pathophysiology
- Folate and B Vitamins Research
- Fatty Acid Research and Health
- Amino Acid Enzymes and Metabolism
- Epigenetics and DNA Methylation
- Cancer, Hypoxia, and Metabolism
- Mitochondrial Function and Pathology
- Diet and metabolism studies
- FOXO transcription factor regulation
- Cancer, Lipids, and Metabolism
- Pancreatic function and diabetes
- Neonatal Health and Biochemistry
- Hemoglobin structure and function
- Hemoglobinopathies and Related Disorders
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Analytical Chemistry and Chromatography
- MicroRNA in disease regulation
- Lysosomal Storage Disorders Research
- PARP inhibition in cancer therapy
- Kidney Stones and Urolithiasis Treatments
- Steroid Chemistry and Biochemistry
University Medical Center Utrecht
2016-2025
Utrecht University
2017-2020
Netherlands Metabolomics Centre
2011-2013
Ziekenhuis Groep Twente
1997
University of Groningen
1987
University of Amsterdam
1961
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...
Abstract Phenotypic and biochemical categorization of humans with detrimental variants can provide valuable information on gene function. We illustrate this the identification two different homozygous resulting in enzymatic loss-of-function LDHD , encoding lactate dehydrogenase D, unrelated patients elevated D-lactate urinary excretion plasma concentrations. establish role by demonstrating that zebrafish results increased concentrations D-lactate. levels are rescued wildtype but not...
In metabolic diagnostics, there is an emerging need for a comprehensive test to acquire complete view of metabolite status. Here, we describe non-quantitative direct-infusion high-resolution mass spectrometry (DI-HRMS) based metabolomics method and evaluate the both dried blood spots (DBS) plasma. 110 DBS 42 patients harboring 23 different inborn errors metabolism (IEM) 86 plasma samples 38 21 IEM were analyzed using DI-HRMS. A peak calling pipeline developed in R programming language...
The nuclear receptor subfamily 1 group H member 4 (NR1H4 or farnesoid X [FXR]) regulates bile acid synthesis, transport, and catabolism. FXR also postprandial lipid glucose metabolism. We performed quantitative proteomic analyses of liver tissues from mice to evaluate these functions investigate whether amino metabolism.To study the role in mouse liver, we used with a disruption Nr1h4 (FXR-knockout mice) compared them floxed control mice. Mice were gavaged agonist obeticholic vehicle for 11...
Our research group previously identified specific endogenous platinum-induced fatty acids (PIFAs) that, in picomolar quantities, activate splenic macrophages leading to resistance chemotherapy mouse models. Fish oil was shown contain the PIFA 16:4(n-3) (hexadeca-4,7,10,13-tetraenoic acid) and when administered mice neutralized activity.Because patients with cancer frequently use fish supplements, we set out determine exposure after intake of or oil.(1) In November 2011, 400 undergoing...
Abstract Pyridoxal 5′‐phosphate (PLP), the metabolically active form of vitamin B6, plays an essential role in brain metabolism as a cofactor numerous enzyme reactions. PLP deficiency brain, either genetic or acquired, results severe drug‐resistant seizures that respond to B6 supplementation. The pathogenesis is largely unknown. To shed more light on metabolic consequences we performed untargeted metabolomics B6‐deprived Neuro‐2a cells. Significant alterations were observed range...
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),...
Next-generation sequencing and next-generation metabolic screening are, independently, increasingly applied in clinical diagnostics of inborn errors metabolism (IEM). Integrated into a single bioinformatic method, these two –omics technologies can potentially further improve the diagnostic yield for IEM. Here, we present cross-omics: method that uses untargeted metabolomics results patient’s dried blood spots (DBSs), indicated by Z-scores mapped onto human pathways, to prioritize affected...
Correct identification and quantification of different sterol biomarkers can be used as a first-line diagnostic approach for inherited metabolic disorders (IMD). The main drawbacks current methodologies are related to lack selectivity sensitivity some these compounds. To address this, we developed validated two sensitive selective assays six cholesterol biosynthesis pathway intermediates (total amount (free esterified form) 7-dehydrocholesterol (7-DHC), 8-dehydrocholesterol (8-DHC),...
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...
For inborn errors of metabolism (IEM), metabolomics is performed for three main purposes: 1) development next generation metabolic screening platforms, 2) identification new biomarkers in predefined patient cohorts and 3) IEM. To date, plasma, urine dried blood spots are used. We anticipate that cerebrospinal fluid (CSF) holds additional - valuable information, especially IEM with neurological involvement. expand to CSF, we here tested whether direct-infusion high-resolution mass...
Metabolomics studies aiming to find biomarkers frequently make use of historical or multicenter cohorts. These samples often have different pre-analytical conditions that potentially affect metabolite concentrations. We studied the effect storage on stability small-molecule metabolites in cerebrospinal fluid aid a reliable interpretation metabolomics data. Three pools were prepared from surplus Amsterdam Dementia Cohort biobank. Aliquoted exposed assess temperature and freeze/thaw before...
Direct infusion–high-resolution mass spectrometry (DI-HRMS) allows for rapid profiling of complex mixtures metabolites in blood, cerebrospinal fluid, tissue samples and cultured cells. Here, we present a DI-HRMS method suitable the determination metabolic fluxes isotopically labeled substrates cells organoids. We adapted an automated annotation pipeline by selecting adducts that best represent majority 13C and/or 15N-labeled glycolytic tricarboxylic acid cycle intermediates as well number...
NAD synthetase 1 (encoded by the gene NADSYN1) is a cytosolic enzyme that catalyzes final step in biosynthesis of nicotinamide adenine dinucleotide (NAD+) from tryptophan and nicotinic acid. NADSYN1 deficiency has recently been added to spectrum congenital NAD+ disorders. To gain insight into metabolic consequences deficiency, encoding was disrupted A549 HEK293T cells, metabolome profiled presence different precursors, including tryptophan, We demonstrate when precursors salvage pathway form...