Oligomycin A
(Synonyms: 寡霉素A; MCH 32) 目录号 : GC16859
Oligomycin A 是一种 ATP 合酶抑制剂，可抑制线粒体偶联膜上依赖 ATP 和氧化磷酸化的过程。
Cas No.:579-13-5
Sample solution is provided at 25 µL, 10mM.
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- Purity: >98.00%
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| Cell experiment [1]: | |
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Cell lines |
P3 cells |
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Preparation Method |
Oxygen consumption was measured at 37 °C in cell culture medium. The oxygen consumption rate was measured under 3 different conditions: phosphorylating state (endogenous respiratory condition), non-phosphorylating state with addition of oligomycin A (50 ng/mL), and uncoupled state by the successive addition of carbonyl cyanide m-chlorophenyl hydrazone (CCCP 0.5 µM) to reach the maximal respiration. |
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Reaction Conditions |
50 ng/mL for 3days |
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Applications |
Additional oxygen consumption analysis was performed using the Oroboros oxygraph methodology and showed no difference in endogenous oxygen consumption rate at oligomycin A or CCCP, even with a long-term DCA treatment (3 days) |
| Animal experiment [2]: | |
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Animal models |
Wt and Tg mice |
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Preparation Method |
Oligomycin A (1mg/kg ) was given by i.v. for 2h before lipopolysaccharide (LPS) and galactosamine (GalN) treatment |
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Dosage form |
intravenous injection (i.v.), 1mg/kg, |
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Applications |
Wt mice treated with oligomycin A have decreased ATP levels in the liver. Concomitantly, these mice showed an enhanced apoptosis in hepatocytes as Tg mice after LPS/GalN administration. |
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References: [1]: Larrieu, CM; Storevik, S, et al. Refining the Role of Pyruvate Dehydrogenase Kinases in Glioblastoma Development. 2022. Cancers,14(15). DOI: 10.3390/cancers14153769 |
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Oligomycin A is an inhibitor of ATP synthase, which inhibits the process taking place on mitochondria coupling membrane that depended on ATP and oxidative phosphorylation [1].
Oligomycin A produced a concentration-dependent block of Icrac with similar characteristics, but with lower potency than oligomycin B. Fits of averaged concentration-response data to a logistic function yielded IC50 values and slope factor coefficients (respectively) of 13.5 μM and 0.85 for oligomycin A, and 2.3 μM and 0.82 for oligomycin B. A two-way analysis of variance confirmed a significantly greater inhibition by oligomycin B over the concentration range tested [2].
Oligomycin A treated Wt(widetype) mice have decreased ATP levels in the liver. Concomitantly, these mice showed an enhanced apoptosis in hepatocytes as Tg mice after LPS/GalN administration [3]. Further activation of AMPK was detected in Wt mice after treatment with oligomycin A. Collectively, these data demonstrated that UCP2 expression in hepatocytes could alter mitochondrial parameters leading to activation of AMPK [3].
References:
[1]. Jastroch M, Divakaruni AS, Mookerjee S, et al. Mitochondrial proton and electron leaks. Essays Biochemistry, 2010, 47:53-67.
[2]. Cho, J.H., M. Balasubramanyam, G. Chernaya, J.P. Gardner, A. Aviv, J.P. Reeves, P.G. Dargis, and E.P. Christian. Oligomycin inhibits storeoperated channels by a mechanism independent of its effects on mitochondrial ATP. Biochem. J. 1997.324:971-980.
[3]. Shang Y, Liu Y, Du L, Wang Y, et al. Targeted expression of uncoupling protein 2 to mouse liver increases the susceptibility to lipopolysaccharide/galactosamine-induced acute liver injury. Hepatology 2009, 50: 1204-1216
Oligomycin A 是一种 ATP 合酶抑制剂，可抑制线粒体偶联膜上依赖 ATP 和氧化磷酸化的过程[1]。
Oligomycin A 产生了 Icrac 的浓度依赖性块，具有相似的特性，但效力低于寡霉素 B。平均浓度-响应数据与逻辑函数的拟合产生 IC50 值和斜率系数（分别）为 13.5 μM 和寡霉素 A 为 0.85，寡霉素 B 为 2.3 μM 和 0.82。双向方差分析证实寡霉素 B 在测试的浓度范围内具有显着更强的抑制作用[2]。
寡霉素 A 处理的 Wt（宽型）小鼠肝脏中的 ATP 水平降低。同时，这些小鼠在 LPS/GalN 给药后表现出与 Tg 小鼠一样肝细胞凋亡增强 [3]。在用寡霉素 A 处理后的 Wt 小鼠中检测到 AMPK 的进一步激活。总的来说，这些数据表明肝细胞中 UCP2 的表达可以改变线粒体参数，从而导致 AMPK 激活 [3]。
| Cas No. | 579-13-5 | SDF | |
| 别名 | 寡霉素A; MCH 32 | ||
| 化学名 | 4-ethyl-11,12,15,19-tetrahydroxy-6'-(2-hydroxypropyl)-5',10,12,14,16,18,20,26,29-nonamethylspiro[24,28-dioxabicyclo[23.3.1]nonacosa-5,7,21-triene-27,2'-oxane]-13,17,23-trione | ||
| Canonical SMILES | CCC1CCC2C(C(C(C3(O2)CCC(C(O3)CC(C)O)C)C)OC(=O)C=CC(C(C(C(=O)C(C(C(C(=O)C(C(C(CC=CC=C1)C)O)(C)O)C)O)C)C)O)C)C | ||
| 分子式 | C45H74O11 | 分子量 | 791.06 |
| 溶解度 | ≥ 9.9mg/mL in DMSO, ≥ 17.43 mg/mL in EtOH | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.2641 mL | 6.3206 mL | 12.6413 mL |
| 5 mM | 0.2528 mL | 1.2641 mL | 2.5283 mL |
| 10 mM | 0.1264 mL | 0.6321 mL | 1.2641 mL |
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动物平均体重 | g | |
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动物数量 | 只 |
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2.
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Oligomycin A promotes radioresistance in HT29 colorectal cancer cells and its mechanisms
Objectives: Radiotherapy is one of the main therapies for colorectal cancer, but radioresistance often leads to radiotherapy failure. To improve the radioresistance, we explore the effect of oligomycin A, the H+-ATP synthase inhibitor, on the sensitivity of HT29 colorectal cancer cells to irradiation and its underlying mechanisms. Methods: The effects of different concentrations of oligomycin A on the survival rate and glycolysis of HT29 colorectal cancer cells at different time points were investigated via MTT and glycolysis assay. siRNA-PFK1 was synthesized in vitro and transfected into HT29 cells. The effects of oligomycin A on radiosensitivity of HT29 colorectal cancer cells were measured via MTT and colony formation assay. Western blotting was used to detect the effect of oligomycin A on the expression of glycolytic enzyme PFK1. We compared difference between the effects of siRNA-PFK1 group and oligomycin A combined with siRNA-PFK1 group on cell survival and glycolysis. After 4 Gy X-ray irradiation, the effects of cell survival and glycolysis between the siRNA-PFK1 group and the oligomycin A combined with siRNA-PFK1 group were compared. Results: Compared with the 0 μmol/L oligomycin A group, the cell survival rate of HT29 cells treated with 4 μmol/L oligomycin A was significantly increased (P<0.05), and the glucose uptake, the lactic acid, and the ATP production were also significantly increased (all P<0.01). After X-ray irradiation at different doses (0, 2, 4, 6, and 8 Gy), the colony formation rate and cell survival rate of the 4 μmol/L oligomycin A treated group were significantly higher than those in the 0 μmol/L oligomycin A group (both P<0.01). The sensitization enhancement ratio of oligomycin A on HT29 colorectal cancer cells was 0.4886. The expression of PFK1 in the 4 μmol/L oligomycin A group was significantly higher than that in the 0 μmol/L oligomycin A group (P<0.001). The glycolysis level, colony formation rate, and cell survival rate of the siRNA-PFK1 HT29 cells group were significantly lower than those in the 0 μmol/L oligomycin A group (all P<0.05), while the results in the 4 μmol/L oligomycin A combined with siRNA-PFK1 group were significantly higher than those in the siRNA-PFK1 group (all P<0.001). After 4 Gy X-ray irradiation, the colony formation rate and cell survival rate in the siRNA-PFK1 group were decreased compared with those in the irradiation group (P<0.01 or P<0.001), while the results of the 4 μmol/L oligomycin A combined with siRNA-PFK1 group were significantly higher than those in the siRNA-PFK1 group (both P<0.001). Conclusions: Oligomycin A can promote the radioresistance of HT29 colorectal cancer cells, which may be related to up-regulation of the PFK1 expression and increase of cell glycolysis.
Stereochemistries and Biological Properties of Oligomycin A Diels-Alder Adducts
Oligomycin A is a potent antibiotic and antitumor agent. However, its applications are restricted by its high toxicity and low bioavailability. In this study, we obtained Oligomycin A Diels-Alder adducts with benzoquinone and N-benzylmaleimide and determined their absolute configurations by combining 1H and ROESY NMR data with molecular mechanics conformational analysis and quantum chemical reaction modeling. The latter showed that adduct stereochemistry is controlled by hydrogen bonding of the Oligomycin A side-chain isopropanol moiety with the carbonyl group of the dienophile. Biological studies showed that the Diels-Alder modification of the Oligomycin A diene system resulted in a complex antiproliferative potential pattern. The synthesized adducts were determined to be more active against the triple-negative (ERα, PR, and HER2 negative) breast cancer cell line MDA-MB-231 and lung carcinoma cell line A-549 compared to Oligomycin A. Meanwhile, Oligomycin A was more potent against myeloid leukemia cell line K-562 and breast carcinoma cell line MCF-7 than its derivatives. Thus, modification of the diene moiety of Oligomycin A is a promising strategy for developing novel antitumor agents based on its scaffold.
A Cuproptosis Activation Scoring model predicts neoplasm-immunity interactions and personalized treatments in glioma
Gliomas are malignant tumors in the central nervous system. Cuproptosis is a newly discovered cell death mechanism targeting lipoylated tricarboxylic acid cycle proteins. Previous studies have found that cuproptosis participates in tumor progression, but its role in gliomas is still elusive. Here, we systematically explored the bulk-tumor and single-cell transcriptome data to reveal its role in gliomas. The cuproptosis activity score (CuAS) was constructed based on cuproptosis-related genes, and machine learning techniques validated the score stability. High CuAS gliomas were more likely to have a poor prognosis and an aggressive mesenchymal (MES) subtype. Subsequently, the SCENIC algorithm predicted 20 CuAS-related transcription factors (TFs) in gliomas. Function enrichment and microenvironment analyses found that CuAS was associated with tumor immune infiltration. Accordingly, intercellular communications between neoplasm and immunity were explored by the R package "Cellchat". Five signaling pathways and 8 ligand-receptor pairs including ICAM1, ITGAX, ITGB2, ANXA1-FRR1, and the like, were identified to suggest how cuproptosis activity connected neoplastic and immune cells. Critically, 13 potential drugs targeting high CuAs gliomas were predicted according to the CTRP and PRISM databases, including oligomycin A, dihydroartemisinin, and others. Taken together, cuproptosis is involved in glioma aggressiveness, neoplasm-immune interactions, and may be used to assist in drug selection.
Synthesis, antimicrobial and antiproliferative properties of epi-oligomycin A, the (33 S)-diastereomer of oligomycin A
We describe the synthesis of epi-oligomycin A, a (33S)-diastereomer of the antibiotic oligomycin A. The structure of (33S)-oligomycin A was determined by elemental analysis, spectroscopic studies, including 1D and 2D NMR spectroscopy, and mass spectrometry. Isomerization of C33 hydroxyl group led to minor changes in the potency against Aspergillus niger, Candida spp., and filamentous fungi whereas the activity against Streptomyces fradiae decreased by approximately 20-fold compared to oligomycin A. We observed that 33-epi-oligomycin A had the same activity on the human leukemia cell line K562 as oligomycin A but was more potent for the multidrug resistant subline K562/4. Non-malignant cells were less sensitive to both oligomycin isomers. Finally, our results pointed at the dependence of the cytotoxicity of oligomycins on oxygen supply.
LC3 subfamily in cardiolipin-mediated mitophagy: a comparison of the LC3A, LC3B and LC3C homologs
Externalization of the phospholipid cardiolipin (CL) to the outer mitochondrial membrane has been proposed to act as a mitophagy trigger. CL would act as a signal for binding the LC3 macroautophagy/autophagy proteins. As yet, the behavior of the LC3-subfamily members has not been directly compared in a detailed way. In the present contribution, an analysis of LC3A, LC3B and LC3C interaction with CL-containing model membranes, and of their ability to translocate to mitochondria, is described. Binding of LC3A to CL was stronger than that of LC3B; both proteins showed a similar ability to colocalize with mitochondria upon induction of CL externalization in SH-SY5Y cells. Besides, the double silencing of LC3A and LC3B proteins was seen to decrease CCCP-induced mitophagy. Residues 14 and 18 located in the N-terminal region of LC3A were shown to be important for its recognition of damaged mitochondria during rotenone- or CCCP-induced mitophagy. Moreover, the in vitro results suggested a possible role of LC3A, but not of LC3B, in oxidized-CL recognition as a counterweight to excessive apoptosis activation. In the case of LC3C, even if this protein showed a stronger CL binding than LC3B or LC3A, the interaction was less specific, and colocalization of LC3C with mitochondria was not rotenone dependent. These results suggest that, at variance with LC3A, LC3C does not participate in cargo recognition during CL-mediated-mitophagy. The data support the notion that the various LC3-subfamily members might play different roles during autophagy initiation, identifying LC3A as a novel stakeholder in CL-mediated mitophagy. Abbreviations: ACTB/β-actin: actin beta; Atg8: autophagy-related 8; CL: cardiolipin; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; DMSO: dimethyl sulfoxide; DOPE: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine; DTT: DL-dithiothreitol; FKBP8: FKBP prolyl isomerase 8; GABARAP: GABA type A receptor associated protein; GABARAPL1: GABA type A receptor associated protein like 1; GABARAPL2: GABA type A receptor associated protein like 2; GFP: green fluorescent protein; IMM: inner mitochondrial membrane; LUV/LUVs: large unilamellar vesicle/s; MAP1LC3A/LC3A: microtubule associated protein 1 light chain 3 alpha; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAP1LC3C/LC3C: microtubule associated protein 1 light chain 3 gamma; NME4/NDPK-D/Nm23-H4: NME/NM23 nucleoside diphosphate kinase 4; O/A: oligomycin A + antimycin A; OMM: outer mitochondrial membrane; PA: phosphatidic acid; PC: phosphatidylcholine; PG: phosphatidylglycerol; PINK1: PTEN induced putative kinase 1; PtdIns4P: phosphatidylinositol-4-phosphate; Rho-PE: lissamine rhodamine phosphatidylethanolamine; SUV/SUVs: small unilamellar vesicle/s.