Brefeldin A

Brefeldin A is a lactone antiviral produced by the fungus Penicillium brefeldianum.[1] Brefeldin A inhibits protein transport from the endoplasmic reticulum to the golgi complex indirectly by preventing association of COP-I coat [2] to the Golgi membrane. Brefeldin A was initially isolated with hopes to become an antiviral drug[3] but is now primarily used in research to study protein transport.

Brefeldin A
Names
Preferred IUPAC name
(1R,2E,6S,10E,11aS,13S,14aR)-1,13-Dihydroxy-6-methyl-1,6,7,8,9,11a,12,13,14,14a-decahydro-4H-cyclopenta[f][1]oxacyclotridecin-4-one
Other names
γ,4-Dihydroxy-2-(6-hydroxy-1-heptenyl)-4-cyclopentanecrotonic acid λ-lactone
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.127.053
UNII
  • 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 checkY
    Key: KQNZDYYTLMIZCT-KQPMLPITSA-N checkY
  • InChI=1/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
    Key: KQNZDYYTLMIZCT-KQPMLPITBH
  • O=C/1O[C@H](CCC/C=C/[C@H]2[C@H]([C@H](O)/C=C\1)C[C@@H](O)C2)C
Properties
C16H24O4
Molar mass 280.36 g/mol
Appearance White to off-white crystalline powder
Melting point 204 to 205 °C (399 to 401 °F; 477 to 478 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)
Infobox references

History

The compound gets its name from a species of anamorph fungus of the Penicillium genus known as Eupenicillium brefeldianum, though it is found in a variety of species that span several genera.[4] It was first isolated from Penicillium decumbens in 1958 by V.L. Singleton who initially called it Decumbin.[5] It was later identified as a metabolite by H.P. Siggs who then went on to identify the chemical structure of the compound in 1971.[5] Since then several successful total synthesis methods have been described.[5] Interest in researching brefeldin A was initially lacking due to poor antiviral activity.[5] However, upon discovery of its mechanism involving disruption of protein transport by Takatsuki and Tamura in 1985 and the cytotoxic effects observed in certain cancer cell lines, research efforts were revitalized.[5] It is currently used solely in research mainly as an assay tool for studying membrane traffic and vesicle transport dynamics between the endoplasmic reticulum and Golgi apparatus.

Physical properties and storage information

Brefeldin A is found naturally as a white to off-white crystalline solid. It forms a clear colorless solution when dissolved. It is soluble in methanol (10 mg/mL), ethanol (5 mg/mL), DMSO (20 mg/mL), acetone, and ethyl acetate (1 mg/mL) without the aid of heating.[6] It is poorly soluble in water (slightly miscible).[6] It is sold commercially with a purity of 98% or greater.[6] It is recommended that it be stored desiccate at -20 °C away from direct sunlight.> Its suggested shelf life for use is 6 months as a solid and 1 month as a solution with tightly sealed storage at -20 °C. Since the compound is combustible, contamination with oxidizing agents should be avoided to prevent the risk of fire. Direct contact should be avoided as well.

Mechanism of action
Brefeldin A inhibits vesicle formation and transport between the endoplasmic reticulum and the Golgi apparatus which ultimately results in collapse of the Golgi apparatus into the endoplasmic reticulum via membrane fusion.

In mammalian and yeast cells, the main target of brefeldin A appears to be a guanine nucleotide exchange factor (GEF) called GBF1.[7] GBF1 is a member of the Arf family of GEFs which are recruited to membranes of the Golgi.[8] It is responsible for the regulation of Arf1p GTPase.[8] It does this through converting the inactive GDP-bound form of Arf1p to the active GTP-bound form.[8] The nucleotide exchange occurs at the catalytic Sec7 domain of GBF1. Activated Arf1p then recruits coat protein β-COP, a subunit of the COP-I complex, to cargo-bound receptors on the membrane.[8] Coat protein recruitment is necessary for proper vesicle formation and transport. Brefeldin A reversibly inhibits the function of GBF1 uncompetitively by binding to the complex it forms with GDP-bound Arf1p and preventing conversion to the GTP-bound form.[8] The lack of active Arf1p prevents coat protein recruitment, which then ultimately induces the fusion of neighboring ER and Golgi membranes due to lack of vesicle formation. This is because lack of vesicle formation results in a buildup of SNARE proteins in the Golgi which would otherwise be bound to coat protein-coated vesicles and removed with the vesicles once they bud off.[9] SNARE proteins mediate membrane fusion and it is postulated that the described SNARE build up in the Golgi increases the chances of aberrant fusion of the Golgi membrane with that of the ER.[9] The collapse of the Golgi into the ER triggers activation of unfolded protein response (UPR) (or ER stress)[10][11] which can result in apoptosis.

Toxicity

The toxological effects of brefeldin A have not been studied extensively yet.[12] Some animal LD50 values have been reported including 250 mg/kg in mice (interperitoneal) and 275 mg/kg in rats (oral).[12] Generally, antibiotic macrolides that share a similar macrocyclic lactone ring to that of brefeldin A have been shown to produce gastrointestinal discomfort as the most common side effect.[13] Some macrolides have been shown to produce allergic reactions and though uncommon this possibility in the case of brefeldin A cannot be disregarded as of yet.[13] The compound may bind to hemoglobin and inhibit oxygen uptake resulting in methemoglobinemia, a form of oxygen starvation, though this is not confirmed.[13] Brefeldin A is not considered to be harmful from direct skin or eye exposure other than transient irritation.[13] It may cause irritation of the respiratory system if inhaled.[13]

See also

References
  1. Hutchinson, C. R.; Shu-Wen, L.; McInnes, A. G.; Walter, J. A. (1983). "Comparative biochemistry of fatty acid and macrolide antibiotic (brefeldin a). Formation in penicillium brefeldianum". Tetrahedron. 39 (21): 3507. doi:10.1016/S0040-4020(01)88660-9.
  2. Helms, J. Bernd; Rothman, James E. (1992). "Inhibition by brefeldin A of a Golgi membrane enzyme that catalyses exchange of guanine nucleotide bound to ARF". Nature. 360 (6402): 352–354. Bibcode:1992Natur.360..352H. doi:10.1038/360352a0. PMID 1448152. S2CID 4306100.
  3. Tamura G, Ando K, Suzuki S, Takatsuki A, Arima K (February 1968). "Antiviral activity of brefeldin A and verrucarin A". J. Antibiot. 21 (2): 160–1. doi:10.7164/antibiotics.21.160. PMID 4299889.
  4. Wang, Jianfeng; Huang, Yaojian; Fang, Meijuan; Zhang, Yongjie; Zheng, Zhonghui; Zhao, Yufen; Su, Wenjin (2002-09-01). "Brefeldin A, a cytotoxin produced by Paecilomyces sp. and Aspergillus clavatus isolated from Taxus mairei and Torreya grandis". FEMS Immunology & Medical Microbiology. 34 (1): 51–57. doi:10.1111/j.1574-695X.2002.tb00602.x. ISSN 0928-8244. PMID 12208606.
  5. McCloud, T. G.; Burns, M. P.; Majadly, F. D.; Muschik, G. M.; Miller, D. A.; Poole, K. K.; Roach, J. M.; Ross, J. T.; Lebherz, W. B. (1995-07-01). "Production of brefeldin-A". Journal of Industrial Microbiology. 15 (1): 5–9. doi:10.1007/BF01570006. ISSN 0169-4146. PMID 7662298. S2CID 8511645.
  6. "Brefeldin A (CAS 20350-15-6)". Santa Cruz Biotechnology. 8 May 2017.
  7. "GBF1 Gene - GeneCards | GBF1 Protein | GBF1 Antibody". www.genecards.org.
  8. Niu, Ting-Kuang; Pfeifer, Andrea C.; Lippincott-Schwartz, Jennifer; Jackson, Catherine L. (2005-03-01). "Dynamics of GBF1, a Brefeldin A-Sensitive Arf1 Exchange Factor at the Golgi". Molecular Biology of the Cell. 16 (3): 1213–1222. doi:10.1091/mbc.E04-07-0599. ISSN 1059-1524. PMC 551486. PMID 15616190.
  9. Nebenführ, Andreas; Ritzenthaler, Christophe; Robinson, David G. (2002-11-01). "Brefeldin A: Deciphering an Enigmatic Inhibitor of Secretion". Plant Physiology. 130 (3): 1102–1108. doi:10.1104/pp.011569. ISSN 1532-2548. PMC 1540261. PMID 12427977.
  10. Pahl HL, Baeuerle (Jun 1995). "A novel signal transduction pathway from the endoplasmic reticulum to the nucleus is mediated by transcription factor NF-kappa B". EMBO J. 14 (11): 2580–8. doi:10.1002/j.1460-2075.1995.tb07256.x. PMC 398372. PMID 7781611.
  11. Kober L, Zehe C, Bode J (October 2012). "Development of a novel ER stress based selection system for the isolation of highly productive clones". Biotechnol. Bioeng. 109 (10): 2599–611. doi:10.1002/bit.24527. PMID 22510960. S2CID 25858120.
  12. "SAFETY DATA SHEET Brefeldin A" (PDF). Cayman Chemical. 6 February 2015.
  13. "Material Safety Data Sheet. Brefeldin A (BFA) sc-200861" (PDF). Santa Cruz Biotechnology. 20 January 2009.
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