Brefeldin A

ATPase inhibitor CAS# 20350-15-6

Brefeldin A

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Chemical structure

Brefeldin A

3D structure

Chemical Properties of Brefeldin A

Cas No. 20350-15-6 SDF Download SDF
PubChem ID 5351204 Appearance Powder
Formula C16H24O4 M.Wt 280.36
Type of Compound N/A Storage Desiccate at -20°C
Synonyms Ascotoxin; Cyanein; Decumbin; Nectrolide; BFA; Synergisidin
Solubility DMSO : 20.83 mg/mL (74.30 mM; Need ultrasonic)
Chemical Name (1S,2E,7S,10E,12S,13R,15S)-12,15-dihydroxy-7-methyl-8-oxabicyclo[11.3.0]hexadeca-2,10-dien-9-one
SMILES CC1CCCC=CC2CC(CC2C(C=CC(=O)O1)O)O
Standard InChIKey KQNZDYYTLMIZCT-PNFJWZTBSA-N
Standard InChI InChI=1S/C16H24O4/c1-11-5-3-2-4-6-12-9-13(17)10-14(12)15(18)7-8-16(19)20-11/h4,6-8,11-15,17-18H,2-3,5,9-10H2,1H3/b6-4+,8-7+/t11-,12+,13-,14+,15-/m0/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Brefeldin A

DescriptionReversible inhibitor of protein translocation from the endoplasmic reticulum (ER) to the Golgi apparatus. Blocks binding of ADP-ribosylation factor to the Golgi apparatus and inhibits GDP-GTP exchange. Can be used to induce autophagy in mammalian cells. Also enhances CRISPR-mediated homology-directed repair (HDR) efficiency ~2-fold when applied at 100 nM, in human induced pluripotent stem cells (iPSCs).

Brefeldin A Dilution Calculator

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Preparing Stock Solutions of Brefeldin A

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 3.5668 mL 17.8342 mL 35.6684 mL 71.3369 mL 89.1711 mL
5 mM 0.7134 mL 3.5668 mL 7.1337 mL 14.2674 mL 17.8342 mL
10 mM 0.3567 mL 1.7834 mL 3.5668 mL 7.1337 mL 8.9171 mL
50 mM 0.0713 mL 0.3567 mL 0.7134 mL 1.4267 mL 1.7834 mL
100 mM 0.0357 mL 0.1783 mL 0.3567 mL 0.7134 mL 0.8917 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Brefeldin A

Brefeldin A (BFA) is an inhibitor of ATPase with IC50 value of 0.2 μM [1]
ATPase is a chemical enzyme which is essential in the ADP/ATP exchange which process provides chemical potential energy. ATP supplies the energy for many physiological activities such as importing metabolites necessary for cell metabolism, exporting toxins, wastes, and solutes that can hinder cellular processes, cell proliferation, ER stress and so forth [2].
Treatment with BFA could attenuate stimulus-dependent hyperalgesia phenomenon via inhibiting vesicular exocytosis which process is important for ATP release [3]. When tested with cell line HEK293 cells (stably express wild-type (wt) CRELD2), BFA treatment nearly abolished the secretion of wtCRELD2 completely via inhibiting the transportation of proteins from the ER to the Golgi apparatus [4]. In MCF-7 cells and Hela cells, treatment with BFA induced p53 expression via inhibiting ATP which enhanced ER stress [5]. When treated with colorectal cancer cell line HCT116 cells, BFA treatment induced cells apoprosis by inhibiting ATP which functioned in the process of cellular vesicle trafficking [1].
BFA also is reported as an inhibitor for GTP/GDP exchange in a dose-dependent way, which is important in vesicular trafficking [6].
References:
[1] P.M. Wierzbicki, M. Kogut, J. Ruczynski, K. Siedlecka-Kroplewska, L. Kaszubowska, A. Rybarczyk, M. Alenowicz, P. Rekowski, Z. Kmiec, Protein and siRNA delivery by transportan and transportan 10 into colorectal cancer cell lines, Folia Histochem Cytobiol, (2014).
[2] M. Westerterp, A.E. Bochem, L. Yvan-Charvet, A.J. Murphy, N. Wang, A.R. Tall, ATP-binding cassette transporters, atherosclerosis, and inflammation, Circulation research, 114 (2014) 157-170.
[3] E.K. Joseph, P.G. Green, J.D. Levine, ATP release mechanisms of endothelial cell-mediated stimulus-dependent hyperalgesia, The journal of pain : official journal of the American Pain Society, 15 (2014) 771-777.
[4] K. Oh-hashi, Y. Kanamori, Y. Hirata, K. Kiuchi, Characterization of V-ATPase inhibitor-induced secretion of cysteine-rich with EGF-like domains 2, Cell biology and toxicology, 30 (2014) 127-136.
[5] W.C. Lin, Y.C. Chuang, Y.S. Chang, M.D. Lai, Y.N. Teng, I.J. Su, C.C. Wang, K.H. Lee, J.H. Hung, Endoplasmic reticulum stress stimulates p53 expression through NF-kappaB activation, PLoS One, 7 (2012) e39120.
[6] D. Prieto, P. Corchete, Transport of flavonolignans to the culture medium of elicited cell suspensions of Silybum marianum, Journal of plant physiology, 171 (2014) 63-68.

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References on Brefeldin A

Brefeldin A sensitive mechanisms contribute to endocytotic membrane retrieval and vesicle recycling in cerebellar granule cells.[Pubmed:28295320]

J Neurochem. 2017 Jun;141(5):662-675.

The recycling of synaptic vesicle (SV) proteins and transmitter release occur at multiple sites along the axon. These processes are sensitive to inhibition of the small GTP binding protein ARF1, which regulates the adaptor protein 1 and 3 complex (AP-1/AP-3). As the axon matures, SV recycling becomes restricted to the presynaptic bouton, and its machinery undergoes a complex process of maturation. We used the styryl dye FM1-43 to highlight differences in the efficiency of membrane recycling at different sites in cerebellar granule cells cultured for 7 days in vitro. We used Brefeldin A (BFA) to inhibit AP-1/AP-3-mediated recycling and to test the contribution of this pathway to the heterogeneity of the responses when these cells are strongly stimulated. Combining imaging techniques and ultrastructural analyses, we found a significant decrease in the density of functional boutons and an increase in the presence of endosome-like structures within the boutons of cells incubated with BFA prior to FM1-43 loading. Such effects were not observed when BFA was added 5 min after the end of the loading step, when endocytosis was almost fully completed. In this situation, vesicles were found closer to the active zone (AZ) in boutons exposed to BFA. Together, these data suggest that the AP-1/AP-3 pathway contributes to SV recycling, affecting different steps in all boutons but not equally, and thus being partly responsible for the heterogeneity of the different recycling efficiencies. Cover Image for this issue: doi. 10.1111/jnc.13801.

The trans-Golgi Network and the Golgi Stacks Behave Independently During Regeneration After Brefeldin A Treatment in Tobacco BY-2 Cells.[Pubmed:28339924]

Plant Cell Physiol. 2017 Apr 1;58(4):811-821.

The trans-Golgi network (TGN) plays an essential role in intracellular membrane trafficking. In plant cells, recent live-cell imaging studies have revealed the dynamic behavior of the TGN independent from the Golgi apparatus. In order to better understand the relationships between the two organelles, we examined their dynamic responses to the reagent Brefeldin A (BFA) and their recovery after BFA removal. Golgi markers responded to BFA similarly over a range of concentrations, whereas the behavior of the TGN was BFA concentration dependent. The TGN formed aggregates at high concentrations of BFA; however, TGN proteins relocalized to numerous small vesicular structures dispersed throughout the cytoplasm at lower BFA concentrations. During recovery from weak BFA treatment, the TGN started to regenerate earlier than the completion of the Golgi. The regeneration of the two organelles proceeded independently of each other for a while, and eventually was completed by their association. Our data suggest that there is some degree of autonomy for the regeneration of the TGN and the Golgi in tobacco BY-2 cells.

Luman contributes to brefeldin A-induced prion protein gene expression by interacting with the ERSE26 element.[Pubmed:28205568]

Sci Rep. 2017 Feb 13;7:42285.

The cellular prion protein (PrP) is essential for transmissible prion diseases, but its exact physiological function remains unclear. Better understanding the regulation of the human prion protein gene (PRNP) expression can provide insight into this elusive function. Spliced XBP1 (sXBP1) was recently shown to mediate endoplasmic reticulum (ER) stress-induced PRNP expression. In this manuscript, we identify Luman, a ubiquitous, non-canonical unfolded protein response (UPR), as a novel regulator of ER stress-induced PRNP expression. Luman activity was transcriptionally and proteolytically activated by the ER stressing drug Brefeldin A (BFA) in human neurons, astrocytes, and breast cancer MCF-7 cells. Over-expression of active cleaved Luman (DeltaLuman) increased PrP levels, while siRNA-mediated Luman silencing decreased BFA-induced PRNP expression. Site-directed mutagenesis and chromatin immunoprecipitation demonstrated that DeltaLuman regulates PRNP expression by interacting with the ER stress response element 26 (ERSE26). Co-over-expression and siRNA-mediated silencing experiments showed that sXBP1 and DeltaLuman both up-regulate ER stress-induced PRNP expression. Attempts to understand the function of PRNP up-regulation by Luman excluded a role in atorvastatin-induced neuritogenesis, ER-associated degradation, or proteasomal inhibition-induced cell death. Overall, these results refine our understanding of ER stress-induced PRNP expression and function.

Brefeldin A-Inhibited Guanine Nucleotide-Exchange Factor 1 (BIG1) Governs the Recruitment of Tumor Necrosis Factor Receptor-Associated Factor 2 (TRAF2) to Tumor Necrosis Factor Receptor 1 (TNFR1) Signaling Complexes.[Pubmed:27834853]

Int J Mol Sci. 2016 Nov 9;17(11). pii: ijms17111869.

Tumor necrosis factor receptor-associated factor 2 (TRAF2) is a critical mediator of tumor necrosis factor-alpha (TNF-alpha) signaling. However, the regulatory mechanisms of TRAF2 are not fully understood. Here we show evidence that TRAF2 requires Brefeldin A-inhibited guanine nucleotide-exchange factor 1 (BIG1) to be recruited into TNF receptor 1 (TNFR1) signaling complexes. In BIG1 knockdown cells, TNF-alpha-induced c-Jun N-terminal kinase (JNK) activation was attenuated and the sensitivity to TNF-alpha-induced apoptosis was increased. Since these trends correlated well with those of TRAF2 deficient cells as previously demonstrated, we tested whether BIG1 functions as an upstream regulator of TRAF2 in TNFR1 signaling. As expected, we found that knockdown of BIG1 suppressed TNF-alpha-dependent ubiquitination of TRAF2 that is required for JNK activation, and impaired the recruitment of TRAF2 to the TNFR1 signaling complex (complex I). Moreover, we found that the recruitment of TRAF2 to the death-inducing signaling complex termed complex II was also impaired in BIG1 knockdown cells. These results suggest that BIG1 is a key component of the machinery that drives TRAF2 to the signaling complexes formed after TNFR1 activation. Thus, our data demonstrate a novel and unexpected function of BIG1 that regulates TNFR1 signaling by targeting TRAF2.

Small molecules enhance CRISPR genome editing in pluripotent stem cells.[Pubmed:25658371]

Cell Stem Cell. 2015 Feb 5;16(2):142-7.

The bacterial CRISPR-Cas9 system has emerged as an effective tool for sequence-specific gene knockout through non-homologous end joining (NHEJ), but it remains inefficient for precise editing of genome sequences. Here we develop a reporter-based screening approach for high-throughput identification of chemical compounds that can modulate precise genome editing through homology-directed repair (HDR). Using our screening method, we have identified small molecules that can enhance CRISPR-mediated HDR efficiency, 3-fold for large fragment insertions and 9-fold for point mutations. Interestingly, we have also observed that a small molecule that inhibits HDR can enhance frame shift insertion and deletion (indel) mutations mediated by NHEJ. The identified small molecules function robustly in diverse cell types with minimal toxicity. The use of small molecules provides a simple and effective strategy to enhance precise genome engineering applications and facilitates the study of DNA repair mechanisms in mammalian cells.

Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival.[Pubmed:17135238]

J Biol Chem. 2007 Feb 16;282(7):4702-10.

Autophagy is a cellular response to adverse environment and stress, but its significance in cell survival is not always clear. Here we show that autophagy could be induced in the mammalian cells by chemicals, such as A23187, tunicamycin, thapsigargin, and Brefeldin A, that cause endoplasmic reticulum stress. Endoplasmic reticulum stress-induced autophagy is important for clearing polyubiquitinated protein aggregates and for reducing cellular vacuolization in HCT116 colon cancer cells and DU145 prostate cancer cells, thus mitigating endoplasmic reticulum stress and protecting against cell death. In contrast, autophagy induced by the same chemicals does not confer protection in a normal human colon cell line and in the non-transformed murine embryonic fibroblasts but rather contributes to cell death. Thus the impact of autophagy on cell survival during endoplasmic reticulum stress is likely contingent on the status of cells, which could be explored for tumor-specific therapy.

Isolation of a brefeldin A-inhibited guanine nucleotide-exchange protein for ADP ribosylation factor (ARF) 1 and ARF3 that contains a Sec7-like domain.[Pubmed:8917509]

Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):12856-60.

Brefeldin A (BFA) inhibited the exchange of ADP ribosylation factor (ARF)-bound GDP for GTP by a Golgi-associated guanine nucleotide-exchange protein (GEP) [Helms, J.B. & Rothman, J.E. (1992) Nature (London) 360, 352-354; Donaldson, J.G., Finazzi, D. & Klausner, R.D. (1992) Nature (London) 360, 350-352]. Cytosolic ARF GEP was also inhibited by BFA, but after purification from bovine brain and rat spleen, it was no longer BFA-sensitive [Tsai, S.-C., Adamik, R., Moss, J. & Vaughan, M. (1996) Proc. Natl. Acad. Sci. USA 93, 305-309]. We describe here purification from bovine brain cytosol of a BFA-inhibited GEP. After chromatography on DEAE-Sephacel, hydroxylapatite, and Mono Q and precipitation at pH 5.8, GEP was eluted from Superose 6 as a large molecular weight complex at the position of thyroglobulin (approximately 670 kDa). After SDS/PAGE of samples from column fractions, silver-stained protein bands of approximately 190 and 200 kDa correlated with activity. BFA-inhibited GEP activity of the 200-kDa protein was demonstrated following electroelution from the gel and renaturation by dialysis. Four tryptic peptides from the 200-kDa protein had amino acid sequences that were 47% identical to sequences in Sec7 from Saccharomyces cerevisiae (total of 51 amino acids), consistent with the view that the BFA-sensitive 200-kDa protein may be a mammalian counterpart of Sec7 that plays a similar role in cellular vesicular transport and Sec7 may be a GEP for one or more yeast ARFs.

Identification of a brefeldin A-insensitive guanine nucleotide-exchange protein for ADP-ribosylation factor in bovine brain.[Pubmed:8159707]

Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3063-6.

ADP-ribosylation factors (ARFs) are approximately 20-kDa guanine nucleotide-binding proteins that participate in vesicular transport in the Golgi and other intracellular compartments and stimulate cholera toxin ADP-ribosyltransferase activity. ARFs are active in the GTP-bound form; hydrolysis of bound GTP to GDP, possibly with the assistance of a GTP hydrolysis (GTPase)-activating protein results in inactivation. Exchange of GDP for GTP and reactivation were shown by other workers to be enhanced by Golgi membranes in a Brefeldin A-sensitive reaction, leading to the proposal that the guanine nucleotide-exchange protein (GEP) was a target of Brefeldin A. In the studies reported here, a soluble GEP was partially purified from bovine brain. Exchange of nucleotide on ARFs 1 and 3, based on increased ARF activity in a toxin assay and stimulation of binding of guanosine 5'-[gamma-[35S]thio]triphosphate, was dependent on phospholipids, with phosphatidylserine being more effective than cardiolipin. GEP appeared to increase the rate of nucleotide exchange but did not affect the affinity of ARF for GTP. Whereas the crude GEP had a size of approximately 700 kDa, the partially purified GEP behaved on Ultrogel AcA 54 as a protein of 60 kDa. With purification, the GEP activity became insensitive to Brefeldin A, consistent with the conclusion that, in contrast to earlier inferences, the exchange protein is not itself the target of Brefeldin A.

Action of brefeldin A blocked by activation of a pertussis-toxin-sensitive G protein.[Pubmed:1549178]

Nature. 1992 Mar 26;356(6367):344-6.

In many mammalian cells Brefeldin A interferes with mechanisms that keep the Golgi appartus separate from the endoplasmic reticulum. The earliest effect of Brefeldin A is release of the coat protein beta-COP from the Golgi. This release is blocked by pretreatment with GTP-gamma S or AlF4- (ref. 12). The AlF4- ion activates heterotrimeric G proteins but not proteins of the ras superfamily, suggesting that a heterotrimeric G protein might control membrane transfer from the endoplasmic reticulum to the Golgi. We report here that mastoparan, a peptide that activates heterotrimeric G proteins, promotes binding of beta-COP to Golgi membranes in vitro and antagonizes the effect of Brefeldin A on beta-COP in perforated cells and on isolated Golgi membranes. This inhibition is greatly diminished if cells are pretreated with pertussis toxin before perforation. Thus, a heterotrimeric G protein of the Gi/Go subfamily regulates association of coat components with Golgi membranes.

Description

Brefeldin A (BFA) is a lactone antibiotic and a specific inhibitor of protein trafficking. Brefeldin A blocks the transport of secreted and membrane proteins from endoplasmic reticulum to Golgi apparatus. Brefeldin A is also an autophagy and mitophagy inhibitor. Brefeldin A is a CRISPR/Cas9 activator. Brefeldin A inhibits HSV-1 and has anti-cancer activity.

Keywords:

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