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ABSTRACT:
PROVIDER: PRJNA594462 | ENA |
REPOSITORIES: ENA
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Project description:In this experiment we performed the transcriptional profiling of the wild type yeast Saccharomyces cerevisiae upon treatment with lovastatin or zaragozic acid. These drugs are known to exert a repressing effect on the sterol branch of the isoprenoid pathway, but their action differs at the level of FPP biosynthesis. While lovastatin decreases FPP availability because it is an inhibitor of HMGR, zaragozic acid increases this level because it inhibits squalene synthase. In this work, we were interested especially in genes, whose expression would be oppositely regulated in the presence of lovastatin or zaragozic acid, since these genes could be affected by variation in FPP level and thus related somehow to the isoprenoid pathway.
2009-09-01 | GSE12984 | GEO
Project description:The statins are a family of inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase enzyme, which converts acetyl-CoA into mevalonic acid. Since HMG-CoA reductase catalyzes the rate-limiting step in the mevalonate pathway of cholesterol biosynthesis, it was thought that the major clinical benefit of statins was to reduce cholesterol levels in the bloodstream; statins are thus in wide clinical use for the prevention and treatment of cardiovascular disease. Nonetheless, mevalonate is also the precursor of isoprenoid compounds, which are substrates for the post-translational modification of many proteins involved in cell signaling. The blockade of isoprenoid synthesis might explain the pleiotropic effects described for statins in extrahepatic tissues, including inhibition of pathogen infection and anti-inflammatory and immunomodulatory activities. We used microarrays to find differentially expressed genes in spontaneous breast tumors from mice treated with lovastatin (Lov) or vehicle (ethanol) as control.
2015-05-19 | GSE42787 | GEO
Project description:The statins are a family of inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase enzyme, which converts acetyl-CoA into mevalonic acid. Since HMG-CoA reductase catalyzes the rate-limiting step in the mevalonate pathway of cholesterol biosynthesis, it was thought that the major clinical benefit of statins was to reduce cholesterol levels in the bloodstream; statins are thus in wide clinical use for the prevention and treatment of cardiovascular disease. Nonetheless, mevalonate is also the precursor of isoprenoid compounds, which are substrates for the post-translational modification of many proteins involved in cell signaling. The blockade of isoprenoid synthesis might explain the pleiotropic effects described for statins in extrahepatic tissues, including inhibition of pathogen infection and anti-inflammatory and immunomodulatory activities. We used microarrays to find differentially expressed genes in spontaneous breast tumors from mice treated with lovastatin (Lov) or vehicle (ethanol) as control. Standard single channel experimental design with biological replicates: gene expression signals from 5 treated tumor samples were compared to 5 non-treated tumor samples using Affymetrix GeneChips (MG430 v2.0).
2015-05-19 | E-GEOD-42787 | biostudies-arrayexpress
Project description:Plasmodium falciparum is the etiological agent of human malaria, one of the most widespread diseases in tropical and subtropical world regions. One of the biggest problems in controlling the disease is the emergence of drug resistance, which leads to the need to discover new antimalarial compounds. One of the most promissory drugs purposed is fosmidomycin, an inhibitor of the biosynthesis of isoprene units by the methylerythritol 4-phosphate (MEP) pathway which in some cases failed in clinic studies. Once formed, isoprene units are condensed to form longer structures such as farnesyl and geranylgeranyl pyrophosphate (GGPP), which are necessary for heme O and A formation, ubiquinone, and dolichyl phosphate biosynthesis as well as for protein isoprenylation. Even though the natural substrates of polyprenyl transferases and syntheses are polyprenyl pyrophosphates, it was already demonstrated that isoprenoid alcohols (polyprenols) such as farnesol (FOH) and geranylgeraniol (GGOH) can rescue parasites from fosmidomycin. This study better investigated how this rescue phenomenon occurs by performing drug-rescue assays. By this, it was observed that phytol (POH), a 20-carbon plant isoprenoid, rescues parasites from the fosmidomycin effect, similarly to FOH or GGOH. Contrarily, neither dolichols nor nonaprenol rescue parasites from fosmidomycin. Considering this, here we characterized the transport of FOH, GGOH, and POH. Once incorporated, it was observed that these substances are phosphorylated, condensed into longer isoprenoid alcohols, and incorporated into proteins and dolichyl phosphates. Through proteomic and radiolabelling approaches, it was found that prenylated proteins are naturally attached to several isoprenoids including GGOH, dolichol, and POH if exogenously added. Furthermore, results suggest the presence of at least two promiscuous protein prenyltransferases in the parasite: one enzyme which can use FPP among other unidentified substrates and another enzyme that can use GGOH, POH, and dolichols among other substrates not identified here. Thus, was obtained further evidence for dolichols and other isoprenoid products attached to proteins. This study helps better understand apicoplast-targeting antimalarials mechanism of action as well as novel posttranslational modifications of proteins.
2022-11-28 | PXD036092 | Pride
Project description:Within this study, the non-model organism Myriophyllum spicatum was used to evaluate ecotoxic modes of action at the gene expression level. M. spicatum was exposed to low-effect concentrations of bentazone and atorvastatin in a shortened and modified version of the OECD guideline test No. 239, followed by RNA extraction of the shoot tip tissue and a subsequent RNA-seq analysis utilizing a de novo assembly of the transcriptome. While the herbicide bentazone is an inhibitor of photosynthesis, the widely spread pharmaceutical atorvastatin acts as an inhibitor of the hydroxymethylglutaryl-CoA reductase and thus the isoprenoid biosynthesis. The aim of this study was to determine molecular fingerprints and biomarkers distinguishing these distinct modes of action at a molecular level.
2024-03-20 | E-MTAB-13702 | biostudies-arrayexpress
Project description:Isovaleryl-CoA (IV-CoA) is usually derived from the degradation of leucine using the Bkd (branched-chain ketoacid dehydrogenase) complex. In myxobacteria we have previously identified an alternative pathway for IV-CoA formation that branches from the well-known mevalonate dependent isoprenoid biosynthesis pathway and we could already identify the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (MvaS) to be involved in this pathway in Myxococcus xanthus which is induced under leucine limiting conditions like in mutants impaired in leucine degradation or during myxobacterial fruiting body formation. Here we show that proteins involved in leucine degradation are also involved in the alternative IV-CoA biosynthesis by catalyzing the reverse reactions of that used in leucine degradation. Moreover, we conducted a global gene expression experiment comparing vegetative cells of wild type and a bkd mutant. Thus we could identify a five-gene operon which was highly upregulated in a bkd mutant and that contains the mvaS gene and other genes which might be involved in a mevalonate-shunt pathway leading from mevalonate to 3-methylglutaconyl-CoA. Additionally, several genes involved in outer membrane biosynthesis and a plethora of genes encoding regulatory proteins are decreased explaining the complex phenotype of a bkd mutant that includes a lack of adhesion in developmental submers culture. 6 independent biological replicates. Normalized ratios to Cy3.
2008-05-01 | E-GEOD-10818 | biostudies-arrayexpress
Project description:Gram-negative bacteria in the order Rickettsiales are obligate intracellular parasites that cause human diseases such typhus and spotted fever. They have evolved a dependence on essential nutrients and metabolites from the host cell as a consequence of extensive genome streamlining. However, it remains largely unknown which nutrients they require and whether their metabolic dependency can be exploited therapeutically. Here, we describe a genetic rewiring of bacterial isoprenoid biosynthetic pathways in the Rickettsiales that has resulted from reductive genome evolution. We further investigated whether the spotted fever group Rickettsia species Rickettsia parkeri scavenges isoprenoid precursors directly from the host. Using targeted mass spectrometry in uninfected and infected cells, we found decreases in host isoprenoid products and concomitant increases in bacterial isoprenoid metabolites. Additionally, we report that bacterial growth is prohibited by inhibition of the host isoprenoid pathway with the statins class of drugs. We show that growth inhibition correlates with changes in bacterial size and shape that mimic those caused by antibiotics that inhibit peptidoglycan biosynthesis, suggesting statins inhibit cell wall synthesis. Altogether, our results describe an Achilles' heel of obligate intracellular pathogens that can be exploited with host-targeted therapeutics that interfere with metabolic pathways required for bacterial growth.
2019-10-31 | MTBLS846 | MetaboLights
Project description:Zymomonas mobilis is an aerotolerant anaerobe and prolific ethanologen with attractive characteristics for industrial bioproduct generation. However, there is currently insufficient knowledge of the impact that environmental factors have on flux through industrially relevant biosynthetic pathways. Here, we examine the effect of oxygen exposure on metabolism and gene expression in Z. mobilis by combining targeted metabolomics, mRNA sequencing, and shotgun proteomics. We found that exposure to oxygen profoundly influenced metabolism, inducing both transient metabolic bottlenecks and long-term metabolic remodeling. In particular, oxygen induced a severe but temporary metabolic bottleneck in the methyl erythritol 4-phosphate pathway for isoprenoid biosynthesis caused by oxidative damage to the iron-sulfur co-factors of the final two enzymes of the pathway. This bottleneck was resolved with minimal changes in expression of isoprenoid biosynthetic enzymes. Instead, it was associated with pronounced upregulation of enzymes related to iron-sulfur cluster maintenance and biogenesis (i.e., flavodoxin reductase and the suf operon). We also detected major changes in glucose utilization in the presence of oxygen. Specifically, we observed increased gluconate production following exposure to oxygen, accounting for 18% of glucose uptake. Our results suggest that under aerobic conditions, electrons derived from the oxidation of glucose to gluconate are diverted to the electron transport chain where they can minimize oxidative damage by reducing reactive oxygen species such as H2O2. This model is supported by the simultaneous upregulation of three membrane-bound dehydrogenases, cytochrome c peroxidase, and a cytochrome bd oxidase following exposure to oxygen.
2019-01-21 | GSE125123 | GEO