Selective and brain-penetrant lanosterol synthase inhibitors target glioma stem-like cells by activating a shunt pathway that generates the toxic metabolite 24(S),25-epoxycholesterol
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PROVIDER: PRJNA924316 | ENA |
REPOSITORIES: ENA
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Project description:Glioblastoma (GBM) is a common and aggressive adult brain cancer with few treatment options due in part to the challenges of identifying brain-penetrant drugs. Here, we investigated the mechanism of a tetracyclic dicarboximide (referred to as MM0299) identified in a screen for compounds with anti-glioblastoma activity. MM0299 inhibits lanosterol synthase (LSS) and diverts sterol flux away from cholesterol into a “shunt” pathway that culminates in 24(S),25-epoxycholesterol (EPC). EPC synthesis following MM0299 treatment is both necessary and sufficient to block the growth of mouse and human glioma stem-like cells by depleting cellular cholesterol. In comparison to a known LSS inhibitor, MM0299 exhibits superior selectivity for LSS over other sterol biosynthetic enzymes. Critical for its application in the brain, we report an MM0299 derivative that is orally bioavailable, brain-penetrant and induces the production of EPC in orthotopic GBM tumors but not normal mouse brain. These studies have implications for the development of an LSS inhibitor to treat GBM or other neurologic indications.
2023-01-17 | GSE222971 | GEO
Project description:Cells must cope with toxic or reactive intermediates formed during metabolism. One coping strategy is to sequester reactions that produce such intermediates within specialized compartments or tunnels connecting different active sites. Here, we show that propionyl-CoA synthase (PCS), an ∼ 400-kDa homodimer, three-domain fusion protein and the key enzyme of the 3-hydroxypropionate bi-cycle for CO2 fixation, sequesters its reactive intermediate acrylyl-CoA. Structural analysis showed that PCS forms a multicatalytic reaction chamber. Kinetic analysis suggested that access to the reaction chamber and catalysis are synchronized by interdomain communication. The reaction chamber of PCS features three active sites and has a volume of only 33 nm3. As one of the smallest multireaction chambers described in biology, PCS may inspire the engineering of a new class of dynamically regulated nanoreactors.
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Project description:LUM2_708738 - MM0299-probe bound protein; LUM2_708739 - MM0299 competition; LUM2_850369 - Ro-alkyne bound protein; LUM2_850370 - Ro 48-8071 competition
2023-01-11 | MSV000091046 | MassIVE
Project description:Development of LNA gapmers, antisense oligonucleotides used for efficient inhibition of target RNA expression, is limited by non-target mediated hepatotoxicity issues. In the present study, we investigated hepatic transcription profiles of mice receiving non-toxic and toxic LNA gapmers after a single and repeat administration. To understand the mechanism of LNA gapmer-induced heptotoxicity in mice, we investigated the transcription profiles of liver RNA isolated from mice receiving non-toxic sequence (NTS-1), toxic sequence (TS-2), or severely toxic sequence (HTS-3) of LNA gapmers at 25 mg/kg (dose volume of 10 mL/kg) at 8, 16, or 72 hrs after a single administration (by subcutaneous injection ) using microarray analysis. We also investigated the transcription profiles of liver RNA isolated from mice receiving non-toxic sequence (NTS-1) or toxic sequence (TS-2) of LNA gapmers at 25 mg/kg (dose volume of 10 mL/kg) at 2 weeks after repeated administration (by subcutaneous injection ) using microarray analysis.
2014-01-08 | E-GEOD-53230 | biostudies-arrayexpress
Project description:The goal of this analysis was to profile the gene expression signatures associated to different neuronal doses of IF1. The mitochondrial ATP synthase produces ATP by oxidative phosphorylation and integrates different signals to regulate cellular functions and fate. The ATPase inhibitory factor 1 (IF1) is a structurally-disordered protein that inhibits the ATP synthase, contributing to metabolic reprogramming and signalling through mitochondrial reactive oxygen species (mtROS). mtROS regulate kinases and transcription factors in mitohormetic responses that favour adaptation to toxic insults. IF1 is tissue-specifically expressed and in human and mouse brain is in molar excess over the ATP synthase. Herein, we have used genetic approaches to ablate or overexpress IF1 in neurons to investigate its role in brain functions. IF1 inhibits a fraction of the ATP synthase under physiological conditions and regulates respiration, mtROS production and mitochondrial structure. Transcriptomic, proteomic and metabolomic analyses indicate that IF1 regulates synaptic transmission and cognition. Ablation of IF1 impairs short-term memory whereas IF1 overexpression increases basal synaptic transmission and learning by mtROS-dependent activation of the extracellular signal-regulated kinases 1/2 (ERK 1/2). Overall, we show that IF1 dose plays a fundamental role in the regulation of neuronal function by controlling the fraction of inhibited ATP synthase that acts as source of mitohormetic mtROS, further emphasizing the ATP synthase/IF1 as promising targets to treat cognitive disorders.
2021-05-24 | GSE154064 | GEO
Project description:Quisinostat is a brain-penetrant radiosensitizer in glioblastoma
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Project description:Development of LNA gapmers, antisense oligonucleotides used for efficient inhibition of target RNA expression, is limited by non-target mediated hepatotoxicity issues. In the present study, we investigated hepatic transcription profiles of mice receiving non-toxic and toxic LNA gapmers after a single and repeat administration.
2014-01-08 | GSE53230 | GEO
Project description:Biological systems must possess mechanisms that prevent inappropriate responses to spurious environmental inputs. Caenorhabditis elegans has two breakdown pathways for the short-chain fatty acid propionate: a canonical, vitamin B12-dependent pathway and a propionate-shunt that is used when vitamin B12 levels are low. The shunt pathway is kept off when there is sufficient flux through the canonical pathway, likely to avoid generating shunt-specific toxic intermediates. Here, we discover a transcriptional regulatory circuit that activates shunt gene expression upon propionate buildup. The nuclear hormone receptors NHR-10 and NHR-68 function together as a ‘persistence detector’ in a type 1, coherent feed-forward loop with an AND-logic gate to delay shunt activation upon propionate accumulation, and to avoid spurious shunt activation in response to a non-sustained pulse of propionate. Together, our findings identify the first persistence detector in an animal, which transcriptionally rewires propionate metabolism to maintain homeostasis.
2018-12-08 | GSE123507 | GEO
Project description:Fusicoccadiene synthase from Phomopsis amygdali (PaFS) catalyzes the first committed step in the biosynthesis of Fusicoccin A, a diterpene glycoside and a a potential therapeutic agent. PaFS contains a C-terminal prenyltransferase domain that generates geranylgeranyl diphosphate (GGPP) and an N-terminal cyclase domain that utilizes GGPP to generate fusicoccadiene, which comprises the complex 5-8-5 tricyclic hydrocarbon skeleton of Fusicoccin A. The C-termimal domain octamerizes to form a central core, with the eight cyclase domains radiating outward via flexible linker segments with variable extended conformations. Crosslinking-mass spectrometry (XL-MS) experiments affirm and reveal inter-domain interactions, showing that compact conformations can be achieved. These studies, complemented by cryo-EM and functional studies, provide a framework for understanding substrate channeling between consecutive catalytic domains.
2021-07-07 | PXD021007 | Pride
Project description:Cyanide is stoichiometrically produced as a co-product of the ethylene biosynthesis pathway, and it is detoxified by the b-cyanoalanine synthase enzyme. The molecular and phenotypical analysis of T-DNA insertional mutants of the mitochondrial b-cyanoalanine synthase CYS-C1 suggests that discrete accumulation of cyanide is not toxic for the plant and does not alter mitochondrial respiration rates, but does act as a strong inhibitor of root hair development. The cys-c1 null allele is defective in root hair formation and accumulates cyanide in root tissues. The root hair defect is phenocopied in wild type plants by the exogenous addition of cyanide to the growth medium and is reversed by the addition of hydroxocobalamin. Hydroxocobalamin not only recovers the root phenotype of the mutant, but also the formation of ROS at the initial step of the root hair tip. Transcriptional profile analysis of the cys-c1 mutant reveals that cyanide accumulation acts as a repressor signal for several genes encoding enzymes involved in cell wall rebuilding and the formation of the root hair tip, as well as genes involved in ethylene signaling and metabolism. Our results demonstrate that mitochondrial b-cyanoalanine synthase activity is essential to maintain a low level of cyanide for proper root hair development.
2010-10-01 | GSE19242 | GEO