Effect of the deletion of the genes involved in phospholipid synthesis pathway on gene expression (PAH1 DGK1)
Ontology highlight
ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
PROVIDER: GSE269275 | GEO | 2024/07/25
REPOSITORIES: GEO
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Project description:Phospholipid and nucleotide syntheses are fundamental metabolic processes in eukaryotic organisms, with their dysregulation implicated in various disease states. However, the interplay between these pathways remains elusive. With genetic and metabolic analyses in the yeast S. cerevisiae, we elucidate how cytidine triphosphate utilization and recycling in the Kennedy pathway for phospholipid synthesis influence nucleotide metabolism and redox balance. Deficiencies in the Kennedy pathway impose constraints on nucleotide salvage, prompting compensatory co-activation of de novo nucleotide synthesis and the pentose phosphate pathway. Consequently, this metabolic shift towards alternative nucleotide and phospholipid synthesis pathways fosters the production of antioxidants such as NADPH and glutathione. Additionally, we observe that this oxidation-responsive Kennedy pathway for phospholipid synthesis is inhibited during replicative aging, highlighting its activation as an antioxidative defense mechanism in aged cells. These findings underscore the critical role of pathway choice in phospholipid synthesis in the integrative regulation of nucleotide metabolism, redox balance, and membrane biophysical properties for cellular defense.
2024-07-25 | GSE269277 | GEO
Project description:Tumor cells must rewire nucleotide synthesis to satisfy the demands of unbridled proliferation. Meanwhile, they exhibit augmented reactive oxygen species (ROS) production which paradoxically damages DNA and free dNTPs. How these metabolic processes are integrated to fuel tumorigenesis remains to be investigated. MYC family oncoproteins are central regulators that coordinate nucleotide synthesis and ROS generation to drive the development of numerous human cancers. We herein performed a CRISPR-based functional screen targeting metabolic genes and identified nudix hydrolase 1 (NUDT1) as a MYC-driven metabolic dependency. Mechanistically, MYC orchestrated the balance of two metabolic pathways that act in parallel, the NOX4-ROS pathway and the PLK1-NUDT1 nucleotide-sanitizing pathway. We describe LC-1-40 as the first-in-class degrader that potently and selectively depletes NUDT1 in vivo. Administration of LC-1-40 disrupted MYC-controlled metabolic homeostasis, resulting in excessive nucleotide oxidation, cytotoxicity and therapeutic responses in patient-derived xenografts. Thus, pharmacological targeting of NUDT1 represents an actionable MYC-driven metabolic liability.
2023-12-27 | PXD043444 | Pride
Project description:Many cells in mammals exist in the state of quiescence, which is characterized by reversible exit from the cell cycle. Quiescent cells are widely reported to exhibit reduced size, nucleotide synthesis, and metabolic activity. Much lower glycolytic rates have been reported in quiescent compared with proliferating lymphocytes. In contrast, we show here that primary human fibroblasts continue to exhibit high metabolic rates when induced into quiescence via contact inhibition. By monitoring isotope labeling through metabolic pathways and quantitatively identifying fluxes from the data, we show that contact-inhibited fibroblasts utilize glucose in all branches of central carbon metabolism at rates similar to those of proliferating cells, with greater overflow flux from the pentose phosphate pathway back to glycolysis. Inhibition of the pentose phosphate pathway resulted in apoptosis preferentially in quiescent fibroblasts. By feeding the cells labeled glutamine, we also detected a “backwards” flux in the tricarboxylic acid cycle from α-ketoglutarate to citrate that was enhanced in contact-inhibited fibroblasts; this flux likely contributes to shuttling of NADPH from the mitochondrion to cytosol for redox defense or fatty acid synthesis. The high metabolic activity of the fibroblasts was directed in part toward breakdown and resynthesis of protein and lipid, and in part toward excretion of extracellular matrix proteins. Thus, reduced metabolic activity is not a hallmark of the quiescent state. Quiescent fibroblasts, relieved of the biosynthetic requirements associated with generating progeny, direct their metabolic activity to preservation of self integrity and alternative functions beneficial to the organism as a whole. mRNAs were analyzed by two color microarray from two separate human neonatal dermal fibroblasts cell lines in proliferating, 7 days contact inhibition, or 14 days contact inhibition. Contact inhibited samples were co-hybridized to proliferating samples as a control, while an additional array co-hybridized the two proliferating samples to analyze reproducibility.
2012-11-30 | E-GEOD-42612 | biostudies-arrayexpress
Project description:The mitochondrial respiratory chain assembles into higher order complexes termed supercomplexes (SCs) under certain physiological or metabolic stimuli. A small molecule screen developed by the lab identified DHODH inhibitors as potent activators of SC assembly in cancer cells. To investigate the proteomic regulation of SCs under nucleotide deficiency, we treated U2OS cells for 48 hours with Brequinar (500 nM). Proteomic analysis highlighted strong signatures of respiratory chain subunit abundance and peroxisomal-derived ether phospholipid synthesis enzymes. Bypassing DHODH inhibition through uridine supplementation prevented these alterations. These findings establish a coordinated cellular response to reduced nucleotide pools that stimulates ether phospholipid synthesis and respiratory chain supra-assembly.
2022-02-16 | PXD023882 | Pride
Project description:Sen2013 - Phospholipid Synthesis in P.knowlesi
The model describes the multiple phospholipid synthetic pathways in Plasmodium knowlesi.
This model is described in the article:
Kinetic modelling of phospholipid synthesis in Plasmodium knowlesi unravels crucial steps and relative importance of multiple pathways.
Sen P, Vial HJ, Radulescu O.
BMC Syst Biol 2013 Nov; 7(1): 123
Abstract:
BACKGROUND: Plasmodium is the causal parasite of malaria, infectious disease responsible for the death of up to one million people each year. Glycerophospholipid and consequently membrane biosynthesis are essential for the survival of the parasite and are targeted by a new class of antimalarial drugs developed in our lab. In order to understand the highly redundant phospholipid synthethic pathways and eventual mechanism of resistance to various drugs, an organism specific kinetic model of these metabolic pathways need to be developed in Plasmodium species. RESULTS: Fluxomic data were used to build a quantitative kinetic model of glycerophospholipid pathways in Plasmodium knowlesi. In vitro incorporation dynamics of phospholipids unravels multiple synthetic pathways. A detailed metabolic network with values of the kinetic parameters (maximum rates and Michaelis constants) has been built. In order to obtain a global search in the parameter space, we have designed a hybrid, discrete and continuous, optimization method. Discrete parameters were used to sample the cone of admissible fluxes, whereas the continuous Michaelis and maximum rates constants were obtained by local minimization of an objective function.The model was used to predict the distribution of fluxes within the network of various metabolic precursors.The quantitative analysis was used to understand eventual links between different pathways. The major source of phosphatidylcholine (PC) is the CDP-choline Kennedy pathway.In silico knock-out experiments showed comparable importance of phosphoethanolamine-N-methyltransferase (PMT) and phosphatidylethanolamine-N-methyltransferase (PEMT) for PC synthesis.The flux values indicate that, major part of serine derived phosphatidylethanolamine (PE) is formed via serine decarboxylation, whereas major part of phosphatidylserine (PS) is formed by base-exchange reactions.Sensitivity analysis of CDP-choline pathway shows that the carrier-mediated choline entry into the parasite and the phosphocholine cytidylyltransferase reaction have the largest sensitivity coefficients in this pathway, but does not distinguish a reaction as an unique rate-limiting step.
CONCLUSION: We provide a fully parametrized kinetic model for the multiple phospholipid synthetic pathways in P. knowlesi. This model has been used to clarify the relative importance of the various reactions in these metabolic pathways. Future work extensions of this modelling strategy will serve to elucidate the regulatory mechanisms governing the development of Plasmodium during its blood stages, as well as the mechanisms of action of drugs on membrane biosynthetic pathways and eventual mechanisms of resistance.
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2024-09-02 | BIOMD0000000495 | BioModels
Project description:Many cells in mammals exist in the state of quiescence, which is characterized by reversible exit from the cell cycle. Quiescent cells are widely reported to exhibit reduced size, nucleotide synthesis, and metabolic activity. Much lower glycolytic rates have been reported in quiescent compared with proliferating lymphocytes. In contrast, we show here that primary human fibroblasts continue to exhibit high metabolic rates when induced into quiescence via contact inhibition. By monitoring isotope labeling through metabolic pathways and quantitatively identifying fluxes from the data, we show that contact-inhibited fibroblasts utilize glucose in all branches of central carbon metabolism at rates similar to those of proliferating cells, with greater overflow flux from the pentose phosphate pathway back to glycolysis. Inhibition of the pentose phosphate pathway resulted in apoptosis preferentially in quiescent fibroblasts. By feeding the cells labeled glutamine, we also detected a “backwards” flux in the tricarboxylic acid cycle from α-ketoglutarate to citrate that was enhanced in contact-inhibited fibroblasts; this flux likely contributes to shuttling of NADPH from the mitochondrion to cytosol for redox defense or fatty acid synthesis. The high metabolic activity of the fibroblasts was directed in part toward breakdown and resynthesis of protein and lipid, and in part toward excretion of extracellular matrix proteins. Thus, reduced metabolic activity is not a hallmark of the quiescent state. Quiescent fibroblasts, relieved of the biosynthetic requirements associated with generating progeny, direct their metabolic activity to preservation of self integrity and alternative functions beneficial to the organism as a whole.
2012-11-30 | GSE42612 | GEO
Project description:Oxygen limitation is regarded as a useful strategy to improve enzyme production by mycelial fungus like Aspergillus niger. However, the intracellular metabolic response of A. niger to oxygen limitation is still obscure. To address this, the metabolism of A. niger was studied using multi-omics integrated analysis based on the latest GEMs (genome-scale metabolic model), including metabolomics, fluxomics and transcriptomics. Upon sharp reduction of the oxygen supply, A. niger metabolism shifted to higher redox level status, as well as lower energy supply, characterized by the accumulation of intermediates from the TCA cycle, down-regulation of genes for fatty acid synthesis and a rapid decrease of the specific growth rate. The gene expression of the glyoxylate bypass was activated, consistent with the increasing flux, which was assumed to reduce the NADH formation from TCA cycle and benefit maintenance of the cellular redox balance under hypoxic conditions. In addition, the relative fluxes of the EMP pathway were increased, which possibly relieved the energy demand for cell metabolism.
2020-01-30 | GSE109525 | GEO
Project description:The malaria parasite Plasmodium falciparum contains the apicoplast organelle that synthesize isoprenoids, which are metabolites necessary for post-translational modification of Plasmodium proteins. We used fosmidomycin, an antibiotic that inhibits isoprenoid biosynthesis, to identify mechanisms that underlie the development of the parasite’s adaptation to the drug at sub-lethal concentrations. We first determined a concentration of fosmidomycin that reduced parasite growth by ~50% over one intraerythrocytic developmental cycle (IDC). At this dose, we maintained synchronous parasite cultures for one full IDC, and collected metabolomic and transcriptomic data at multiple time points to capture global and stage-specific alterations. We integrated the data with a genome-scale metabolic model of P. falciparum to characterize the metabolic adaptations of the parasite in response to fosmidomycin treatment. Our simulations showed that, in treated parasites, the synthesis of purine-based nucleotides increased, whereas the synthesis of phosphatidylcholine during the trophozoite and schizont stages decreased. Specifically, the increased polyamine synthesis led to increased nucleotide synthesis, while the reduced methyl-group cycling led to reduced phospholipid synthesis and methyltransferase activities. These results indicate that fosmidomycin-treated parasites compensate for the loss of prenylation modifications by directly altering processes that affect nucleotide synthesis and ribosomal biogenesis to control the rate of RNA translation during the IDC. This also suggests that combination therapies with antibiotics that target the compensatory response of the parasite, such as nucleotide synthesis or ribosomal biogenesis, may be more effective than treating the parasite with fosmidomycin alone.
2021-01-27 | GSE159516 | GEO
Project description:Cells must appropriately sense and integrate multiple metabolic resources to commit to proliferation. Here, we report that cells regulate nitrogen (amino acid) and carbon metabolic homeostasis through tRNA U34-thiolation. Despite amino acid sufficiency, tRNA-thiolation deficient cells appear amino acid starved. In these cells, carbon flux towards nucleotide synthesis decreases, and trehalose synthesis increases, resulting in metabolic a starvation-signature. Thiolation mutants have only minor translation defects. However, these cells exhibit strongly decreased expression of phosphate homeostasis genes, mimicking a phosphate-limited state. Reduced phosphate enforces a metabolic switch, where glucose-6-phosphate is routed towards storage carbohydrates. Notably, trehalose synthesis, which releases phosphate and thereby restores phosphate availability, is central to this metabolic rewiring. Thus, cells use thiolated tRNAs to perceive amino acid sufficiency, and balance amino acid and carbon metabolic flux to maintain metabolic homeostasis, by controlling phosphate availability. These results further biochemical explain how phosphate availability determines a switch to a ‘starvation-state’.
2018-12-28 | GSE124428 | GEO
Project description:Cytidine diphosphate (CDP)-ethanolamine pathway of phospholipid metabolism coordinates metabolic programming of Tfh cell responses and humoral immunity.
2021-05-26 | GSE147190 | GEO