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cycloheximide |
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CHEBI:27641 |
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A dicarboximide that is 4-(2-hydroxyethyl)piperidine-2,6-dione in which one of the hydrogens attached to the carbon bearing the hydroxy group is replaced by a 3,5-dimethyl-2-oxocyclohexyl group. It is an antibiotic produced by the bacterium Streptomyces griseus. |
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This entity has been manually annotated by the ChEBI Team.
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CHEBI:23484, CHEBI:4015
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eMolecules:29817042, eMolecules:474920, ZINC000003872170 |
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Cycloheximide is a naturally occurring fungicide produced by the bacterium Streptomyces griseus. Cycloheximide exerts its effects by interfering with the translocation step in protein synthesis (movement of two tRNA molecules and mRNA in relation to the ribosome), thus blocking eukaryotic translational elongation. Cycloheximide is widely used in biomedical research to inhibit protein synthesis in eukaryotic cells studied in vitro (i.e. outside of organisms). It is inexpensive and works rapidly. Its effects are rapidly reversed by simply removing it from the culture medium.
Due to significant toxic side effects, including DNA damage, teratogenesis, and other reproductive effects (including birth defects and toxicity to sperm), cycloheximide is generally used only in in vitro research applications, and is not suitable for human use as a therapeutic compound. Although it has been used as a fungicide in agricultural applications, this application is now decreasing as the health risks have become better understood.
Because cycloheximide rapidly breaks down in a basic environment, decontamination of work surfaces and containers can be achieved by washing with a non-harmful alkali solution such as soapy water or aqueous sodium bicarbonate.
It is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002), and is subject to strict reporting requirements by facilities which produce, store, or use it in significant quantities. |
Read full article at Wikipedia
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InChI=1S/C15H23NO4/c1-8-3-9(2)15(20)11(4-8)12(17)5-10-6-13(18)16-14(19)7-10/h8-12,17H,3-7H2,1-2H3,(H,16,18,19)/t8-,9-,11-,12+/m0/s1 |
YPHMISFOHDHNIV-FSZOTQKASA-N |
[H][C@]1(C[C@@H](C)C[C@H](C)C1=O)[C@H](O)CC1CC(=O)NC(=O)C1 |
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bacterial metabolite
Any prokaryotic metabolite produced during a metabolic reaction in bacteria.
protein synthesis inhibitor
A compound, usually an anti-bacterial agent or a toxin, which inhibits the synthesis of a protein.
anticoronaviral agent
Any antiviral agent which inhibits the activity of coronaviruses.
ferroptosis inhibitor
Any substance that inhibits the process of ferroptosis (a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides) in organisms.
antimicrobial agent
A substance that kills or slows the growth of microorganisms, including bacteria, viruses, fungi and protozoans.
(via heterocyclic antibiotic )
fungicide
A substance used to destroy fungal pests.
(via antibiotic fungicide )
antifungal agent
An antimicrobial agent that destroys fungi by suppressing their ability to grow or reproduce.
(via antibiotic antifungal agent )
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neuroprotective agent
Any compound that can be used for the treatment of neurodegenerative disorders.
fungicide
A substance used to destroy fungal pests.
(via antibiotic fungicide )
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View more via ChEBI Ontology
4-{(2R)-2-[(1S,3S,5S)-3,5-dimethyl-2-oxocyclohexyl]-2-hydroxyethyl}piperidine-2,6-dione
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cicloheximida
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ChemIDplus
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cicloheximide
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WHO MedNet
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cicloheximide
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WHO MedNet
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cicloheximidum
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ChemIDplus
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3-((R)-2-((1S,3S,5S)-3,5-dimethyl-2-oxocyclohexyl)-2-hydroxyethyl)glutarimide
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ChemIDplus
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Cycloheximid
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ChEBI
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Cycloheximide
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KEGG COMPOUND
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cycloheximide
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UniProt
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naramycin
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ChemIDplus
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naramycin A
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ChemIDplus
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Zykloheximid
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ChEBI
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66-81-9
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CAS Registry Number
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KEGG COMPOUND
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66-81-9
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CAS Registry Number
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ChemIDplus
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88868
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Reaxys Registry Number
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Reaxys
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Grubbs KJ, Surup F, Biedermann PHW, McDonald BR, Klassen JL, Carlson CM, Clardy J, Currie CR (2020) Cycloheximide-Producing Streptomyces Associated With Xyleborinus saxesenii and Xyleborus affinis Fungus-Farming Ambrosia Beetles. Frontiers in microbiology 11, 562140 [PubMed:33101237] [show Abstract] Symbiotic microbes help a myriad of insects acquire nutrients. Recent work suggests that insects also frequently associate with actinobacterial symbionts that produce molecules to help defend against parasites and predators. Here we explore a potential association between Actinobacteria and two species of fungus-farming ambrosia beetles, Xyleborinus saxesenii and Xyleborus affinis. We isolated and identified actinobacterial and fungal symbionts from laboratory reared nests, and characterized small molecules produced by the putative actinobacterial symbionts. One 16S rRNA phylotype of Streptomyces (XylebKG-1) was abundantly and consistently isolated from the galleries and adults of X. saxesenii and X. affinis nests. In addition to Raffaelea sulphurea, the symbiont that X. saxesenii cultivates, we also repeatedly isolated a strain of Nectria sp. that is an antagonist of this mutualism. Inhibition bioassays between Streptomyces griseus XylebKG-1 and the fungal symbionts from X. saxesenii revealed strong inhibitory activity of the actinobacterium toward the fungal antagonist Nectria sp. but not the fungal mutualist R. sulphurea. Bioassay guided HPLC fractionation of S. griseus XylebKG-1 culture extracts, followed by NMR and mass spectrometry, identified cycloheximide as the compound responsible for the observed growth inhibition. A biosynthetic gene cluster putatively encoding cycloheximide was also identified in S. griseus XylebKG-1. The consistent isolation of a single 16S phylotype of Streptomyces from two species of ambrosia beetles, and our finding that a representative isolate of this phylotype produces cycloheximide, which inhibits a parasite of the system but not the cultivated fungus, suggests that these actinobacteria may play defensive roles within these systems. | Buschauer R, Matsuo Y, Sugiyama T, Chen YH, Alhusaini N, Sweet T, Ikeuchi K, Cheng J, Matsuki Y, Nobuta R, Gilmozzi A, Berninghausen O, Tesina P, Becker T, Coller J, Inada T, Beckmann R (2020) The Ccr4-Not complex monitors the translating ribosome for codon optimality. Science (New York, N.Y.) 368, eaay6912 [PubMed:32299921] [show Abstract] Control of messenger RNA (mRNA) decay rate is intimately connected to translation elongation, but the spatial coordination of these events is poorly understood. The Ccr4-Not complex initiates mRNA decay through deadenylation and activation of decapping. We used a combination of cryo-electron microscopy, ribosome profiling, and mRNA stability assays to examine the recruitment of Ccr4-Not to the ribosome via specific interaction of the Not5 subunit with the ribosomal E-site in Saccharomyces cerevisiae This interaction occurred when the ribosome lacked accommodated A-site transfer RNA, indicative of low codon optimality. Loss of the interaction resulted in the inability of the mRNA degradation machinery to sense codon optimality. Our findings elucidate a physical link between the Ccr4-Not complex and the ribosome and provide mechanistic insight into the coupling of decoding efficiency with mRNA stability. | Santos DA, Shi L, Tu BP, Weissman JS (2019) Cycloheximide can distort measurements of mRNA levels and translation efficiency. Nucleic acids research 47, 4974-4985 [PubMed:30916348] [show Abstract] Regulation of the efficiency with which an mRNA is translated into proteins represents a key mechanism for controlling gene expression. Such regulation impacts the number of actively translating ribosomes per mRNA molecule, referred to as translation efficiency (TE), which can be monitored using ribosome profiling and RNA-seq, or by evaluating the position of an mRNA in a polysome gradient. Here we show that in budding yeast, under nutrient limiting conditions, the commonly used translation inhibitor cycloheximide induces rapid transcriptional upregulation of hundreds of genes involved in ribosome biogenesis. Cycloheximide also prevents translation of these newly transcribed messages, leading to an apparent drop in TE of these genes under conditions that include key transitions during the yeast metabolic cycle, meiosis, and amino acid starvation; however, this effect is abolished when cycloheximide pretreatment is omitted. This response requires TORC1 signaling, and is modulated by the genetic background as well as the vehicle used to deliver the drug. The present work highlights an important caveat to the use of translation inhibitors when measuring TE or mRNA levels, and will hopefully aid in future experimental design as well as interpretation of prior results. | Elliott A, Shaw SL (2018) A Cycloheximide-Sensitive Step in Transverse Microtubule Array Patterning. Plant physiology 178, 684-698 [PubMed:30154175] [show Abstract] The growth properties of individual cells within a tissue determine plant morphology, and the organization of the cytoskeleton, particularly the microtubule arrays, determines cellular growth properties. We investigated the mechanisms governing the formation of transverse microtubule array patterns in axially growing Arabidopsis (Arabidopsis thaliana) epidermal hypocotyl cells. Using quantitative imaging approaches, we mapped the transition of the cortical microtubule arrays into a transverse coaligned pattern after induction with auxin and gibberellic acid. Hormone induction led to an early loss of microtubule plus end density and a rotation toward oblique patterns. Beginning 30 min after induction, transverse microtubules appeared at the cell's midzone concurrently with the loss of longitudinal polymers, eventually progressing apically and basally to remodel the array pattern. Based on the timing and known hormone-signaling pathways, we tested the hypothesis that the later events require de novo gene expression and, thus, constitute a level of genetic control over transverse patterning. We found that the presence of the translation inhibitor cycloheximide (CHX) resulted in a selective and reversible loss of transverse patterns that were replaced with radial-like pinwheel arrays exhibiting a split bipolar architecture centered at the cell's midzone. Experiments using hormone induction and CHX revealed that pinwheel arrays occur when transverse microtubules increase at the midzone but longitudinal microtubules in the split bipolar architecture are not suppressed. We propose that a key regulatory mechanism for creating the transverse microtubule coalignment in axially growing hypocotyls involves the expression of a CHX-sensitive factor that acts to suppress the nucleation of the longitudinally oriented polymers. | Darvishi E, Woldemichael GM (2016) Cycloheximide Inhibits Actin Cytoskeletal Dynamics by Suppressing Signaling via RhoA. Journal of cellular biochemistry 117, 2886-2898 [PubMed:27192630] [show Abstract] Genome-wide screening of the yeast Saccharomyces cerevisiae knockout collection was used to characterize chemical-genetic interactions of cycloheximide (CHX). The results showed that while the act1Δ mutant was the only deletion mutant in the heterozygous essential gene deletion collection that showed hypersensitivity to sub-inhibitory concentrations of CHX, deletion of nonessential genes that work in concert with either cytoplasmic or nuclear actin in the homozygous deletion collection also highly sensitized yeast to CHX. Fluorescence microscopy analysis revealed that CHX disrupts filamentous actin structures and fluid phase endocytosis in the yeast cell. It also showed that CHX disrupts transforming growth factor-β1 (TGF-β1)-induced actin reorganization and polygonal architecture of microfilaments in mammalian cells. This inhibitory effect is mediated, at least in part, through the actin dynamics signaling pathway via suppression of activation of the small GTPase RhoA. J. Cell. Biochem. 117: 2886-2898, 2016. © 2016 Wiley Periodicals, Inc. | Myasnikov AG, Kundhavai Natchiar S, Nebout M, Hazemann I, Imbert V, Khatter H, Peyron JF, Klaholz BP (2016) Structure-function insights reveal the human ribosome as a cancer target for antibiotics. Nature communications 7, 12856 [PubMed:27665925] [show Abstract] Many antibiotics in clinical use target the bacterial ribosome by interfering with the protein synthesis machinery. However, targeting the human ribosome in the case of protein synthesis deregulations such as in highly proliferating cancer cells has not been investigated at the molecular level up to now. Here we report the structure of the human 80S ribosome with a eukaryote-specific antibiotic and show its anti-proliferative effect on several cancer cell lines. The structure provides insights into the detailed interactions in a ligand-binding pocket of the human ribosome that are required for structure-assisted drug design. Furthermore, anti-proliferative dose response in leukaemic cells and interference with synthesis of c-myc and mcl-1 short-lived protein markers reveals specificity of a series of eukaryote-specific antibiotics towards cytosolic rather than mitochondrial ribosomes, uncovering the human ribosome as a promising cancer target. | Schmidt C, Becker T, Heuer A, Braunger K, Shanmuganathan V, Pech M, Berninghausen O, Wilson DN, Beckmann R (2016) Structure of the hypusinylated eukaryotic translation factor eIF-5A bound to the ribosome. Nucleic acids research 44, 1944-1951 [PubMed:26715760] [show Abstract] During protein synthesis, ribosomes become stalled on polyproline-containing sequences, unless they are rescued in archaea and eukaryotes by the initiation factor 5A (a/eIF-5A) and in bacteria by the homologous protein EF-P. While a structure of EF-P bound to the 70S ribosome exists, structural insight into eIF-5A on the 80S ribosome has been lacking. Here we present a cryo-electron microscopy reconstruction of eIF-5A bound to the yeast 80S ribosome at 3.9 Å resolution. The structure reveals that the unique and functionally essential post-translational hypusine modification reaches toward the peptidyltransferase center of the ribosome, where the hypusine moiety contacts A76 of the CCA-end of the P-site tRNA. These findings would support a model whereby eIF-5A stimulates peptide bond formation on polyproline-stalled ribosomes by stabilizing and orienting the CCA-end of the P-tRNA, rather than by directly contributing to the catalysis. | Garreau de Loubresse N, Prokhorova I, Holtkamp W, Rodnina MV, Yusupova G, Yusupov M (2014) Structural basis for the inhibition of the eukaryotic ribosome. Nature 513, 517-522 [PubMed:25209664] [show Abstract] The ribosome is a molecular machine responsible for protein synthesis and a major target for small-molecule inhibitors. Compared to the wealth of structural information available on ribosome-targeting antibiotics in bacteria, our understanding of the binding mode of ribosome inhibitors in eukaryotes is currently limited. Here we used X-ray crystallography to determine 16 high-resolution structures of 80S ribosomes from Saccharomyces cerevisiae in complexes with 12 eukaryote-specific and 4 broad-spectrum inhibitors. All inhibitors were found associated with messenger RNA and transfer RNA binding sites. In combination with kinetic experiments, the structures suggest a model for the action of cycloheximide and lactimidomycin, which explains why lactimidomycin, the larger compound, specifically targets the first elongation cycle. The study defines common principles of targeting and resistance, provides insights into translation inhibitor mode of action and reveals the structural determinants responsible for species selectivity which could guide future drug development. | Tsuchida T, Kato T, Yamada A, Kawamoto K (2002) Cycloheximide induces apoptosis of astrocytes. Pathology international 52, 181-185 [PubMed:11972861] [show Abstract] Cultured rat astrocytes were incubated in the presence of cycloheximide (CHX; 20 microg/mL), a potent neuroprotective agent. Then cells were subjected to DNA gel electrophoresis. Electrophoresis showed DNA ladder formation, which is characteristic of apoptosis. Inhibitors of interleukin-1beta-converting enzyme (ICE) and caspase 32(CPP32), which play critical roles in certain apoptotic pathways, did not block the cycloheximide-induced apoptosis of cultured astrocytes. This observation indicates that the role of ICE and CPP32 is not significant in the CHX-induced astrocyte apoptosis process. When the blood-brain barrier was disrupted in the rat, the number of brain cells undergoing apoptosis was significantly higher after cycloheximide administration, in contrast to controls. Of the cells that produced glial fibrillary acidic protein, some were observed to undergo apoptosis. Although CHX has been shown to be useful as a neuroprotective agent against ischemic neuronal death, astroglial toxicity may be problematic, depending on CHX concentration. Therefore, a prudent use of this compound is recommended. | McMahon D (1975) Cycloheximide is not a specific inhibitor of protein synthesis in vivo. Plant physiology 55, 815-821 [PubMed:16659174] [show Abstract] Cycloheximide is frequently presumed to inhibit specifically the cytoplasmic protein synthesis of eukaryotes. Although previous investigators have shown that it had other effects on the cells of a variety of organisms, these results were frequently presumed to be secondary effects of the inhibition of protein synthesis. This paper shows that a wide range of deleterious effects are produced by cycloheximide on a single organism, Chlamydomonas reinhardi Dangeard. If, protein synthesis is inhibited by nonpermissive conditions in temperature-sensitive mutants or with other treatments these "secondary" effects are not produced. Instead, cycloheximide appears to have two or three independent inhibitory effects on the cell. Moreover, in contrast to a number of previous investigations, these results show that protein synthesis is not required for RNA synthesis. Instead the rate of RNA synthesis is actually increased by interference with protein synthesis. |
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