Brefeldin A

Structural formula
General
Surname	Brefeldin A
other names	γ, 4-Dihydroxy-2- (6-hydroxy-1-heptenyl) -4-cyclopentane crotonic acid λ-lactone
Molecular formula	C 16 H 24 O 4
Brief description	white to yellow-white crystalline powder
External identifiers / databases
EC number	606-528-3
ECHA InfoCard	100.127.053
PubChem	5287620
ChemSpider	4449949
DrugBank	DB07348
Wikidata	Q168790
properties
Molar mass	280.36 g mol −1
Physical state	firmly
safety instructions
GHS labeling of hazardous substances danger
H and P phrases	H: 301
	P: 301 + 310
Toxicological data	275 mg kg −1 ( LD 50 , rat , oral )
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Brefeldin A (abbreviation: BFA) is a lactone - antibiotic derived from fungi such Eupenicillium brefeldianum is synthesized and originally as an antiviral agent was isolated. Nowadays it is mainly used in medical and biological research to study protein transport. It has also been used as a substance to improve the CRISPR technique in the field of genome editing since it was first described .

BFA induces retrograde transport from the Golgi apparatus to the endoplasmic reticulum , which leads to an accumulation of proteins ( e.g. interferon γ ) in the endoplasmic reticulum. Brefeldin A seems to attack a certain GTP exchange factor that is responsible for activating the GTPase Arf1p .

history

The substance takes its name from the fungus Eupenicillium brefeldianum . It was first isolated from Penicillium decumbens in 1958 by VL Singleton . It was identified as a metabolite by HP Siggs. Several successful synthetic methods have been described since 1971.

Initially, research was interested in the substance's antiviral activity. Since the discoveries of Takatsuki and Tamara in 1985 and the observation of cytotoxic effects on some cancer cell lines, it has been used more frequently in research. Nowadays it is mostly used in research to study membrane transport and vesicle transport between the endoplasmic reticulum and the Golgi apparatus.

Physical Properties

Solubility :

Clear, colorless solution in 10 mg / ml dichloromethane .
Clear, colorless solution in 10 mg / ml methanol .

The effect of Brefeldin A

Brefeldin A acts as a cell poison in a very short time: the Golgi apparatus disintegrates and changes to the endoplasmic reticulum (ER). Because of this characteristic, Brefeldin is an effective inhibitor of the secretion of a cell: Proteins that are to be secreted are translated in the ER, mature in the Golgi and post-Golgi compartments and are finally released by vesicle fusion with the cell membrane .

Brefeldin A inhibits proteins that activate ADP-ribosylation factors, the so-called Arfs. In the ER, protein complexes, so-called coats, are organized by small, GTP-laden G proteins of the Arf family. The coats help to select the necessary transport molecules and act as a scaffold on which vesicles are pinched off. On the way from the ER to the Golgi, such vesicles are first pinched off by the ER and then stored in the Golgi (cistern maturation or anterograde transport); conversely, proteins in vesicles are also transported back to the ER for reuse from the Golgi (retrograde transport). The formation of such vesicles depends on the COP-I assembly by Arf1-GTP. Brefeldin A inhibition of Arf1 dissolves the COP-I vesicles, causes the Golgi to collapse and stores the affected proteins again in the ER.

The active Arf1-GTP is converted to the inactive Arf1-GDP by GTP- cleaving GTPase . Arf1-GPD in turn exchanges GDP for GTP, mediated by Sec7-GDP-GTP exchange factors. Brefeldin A blocks the GDP-GTP exchange by stabilizing and thus inactivating the Arf1-GDP: Sec7 complex. This was the first example of a toxin trapping a protein, eliminating its function.

Individual evidence

↑ ^a ^b ^c ^d Datasheet Brefeldin A at Sigma-Aldrich , accessed on March 14, 2011 ( PDF ).

↑ Tamura G, Ando K, Suzuki S, Takatsuki A, Arima K: Antiviral activity of brefeldin A and A verrucarin . In: J Antibiot . 21, No. 2, February 1968, pp. 160-161. PMID 4299889 .

↑ Klausner RD , Donaldson JG, Lippincott-Schwartz J: Brefeldin A: insights into the control of membrane traffic and organelle structure . In: J. Cell Biol. . 116, No. 5, March 1992, pp. 1071-80. doi : 10.1083 / jcb.116.5.1071 . PMID 1740466 . PMC 2289364 (free full text).

↑ Chen Yu, Yanxia Liu, Tianhua Ma, Kai Liu, Shaohua Xu, Yu Zhang, Honglei Liu, Marie La Russa, Min Xie, Sheng Ding, Lei S. Qi: Small Molecules Enhance CRISPR Genome Editing in Pluripotent Stem Cells . In: Cell Stem Cell . 16, No. 2, February 2015, pp. 142–147. doi : 10.1016 / j.stem.2015.01.003 .

↑ Rajamahanty S, Alonzo C. Aynehchi S, M Choudhury, Konno S: Growth inhibition of androgen-responsive prostate cancer cells with brefeldin A targeting cell cycle and androgen receptor . In: Journal of Biomedical Science . 17, No. 1, 2010, p. 5. doi : 10.1186 / 1423-0127-17-5 . PMID 20102617 . PMC 2843609 (free full text).

↑ Jianfeng Wang, Yaojian Huang, Meijuan Fang, Yongjie Zhang, Zhonghui Zheng: Brefeldin A, a cytotoxin produced by Paecilomyces sp. and Aspergillus clavatus isolated from Taxus mairei and Torreya grandis . In: FEMS Immunology & Medical Microbiology . tape 34 , no. 1 , September 1, 2002, ISSN 0928-8244 , p. 51–57 , doi : 10.1111 / j.1574-695X.2002.tb00602.x ( oup.com [accessed May 12, 2018]).

^ ^A ^b T. G. McCloud, MP Burns, FD Majadly, GM Muschik, DA Miller: Production of brefeldin-A . In: Journal of Industrial Microbiology . tape 15 , no. 1 , July 1, 1995, ISSN 0169-4146 , p. 5–9 , doi : 10.1007 / BF01570006 ( springer.com [accessed May 12, 2018]).

↑ Physical properties: Brefeldin A ( Memento of the original from June 26, 2006 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. - Product information from Fermentek @1@ 2
^ ^A ^b N. Sciaky, J. Presley, C. Smith, KJ Zaal, N. Cole, JE Moreira, M. Terasaki, E. Siggia, J. Lippincott-Schwartz: Golgi tubule traffic and the effects of brefeldin A visualized in living cells. In: Journal of Cell Biology . Volume 139, Number 5, December 1997, pp. 1137-1155, PMID 9382862 , PMC 2140213 (free full text).
↑ Randy Schekman , L. Orci: Coat proteins and vesicle budding. In: Science. Volume 271, Number 5255, March 1996, pp. 1526-1533, PMID 8599108 (review).
^ BS Glick, V. Malhotra: The curious status of the Golgi apparatus. In: Cell. Volume 95, Number 7, December 1998, pp. 883-889, PMID 9875843 .
↑ A. Peyroche, B. Antonny, S. Robineau, J. Acker, J. Cherfils, CL Jackson: Brefeldin A acts to stabilize at abortive ARF-GDP-Sec7 domain protein complex: involvement of specific residues of the Sec7 domain. In: Molecular cell. Volume 3, Number 3, March 1999, pp. 275-285, PMID 10198630 .
^ P. Chardin, F. McCormick: Brefeldin A: The advantage of being uncompetitive. In: Cell. Volume 97, Number 2, April 1999, pp. 153-155, PMID 10219235 (review).

Web links

Commons : Brefeldin A - collection of images, videos and audio files

NCI Frederick: Structure and Data for Brefeldin A (NSC 56310) (structural formula)

[Sigma-1] Datasheet Brefeldin A at Sigma-Aldrich , accessed on March 14, 2011 ( PDF ).

[2] Tamura G, Ando K, Suzuki S, Takatsuki A, Arima K: Antiviral activity of brefeldin A and A verrucarin . In: J Antibiot . 21, No. 2, February 1968, pp. 160-161. PMID 4299889 .

[3] Klausner RD , Donaldson JG, Lippincott-Schwartz J: Brefeldin A: insights into the control of membrane traffic and organelle structure . In: J. Cell Biol. . 116, No. 5, March 1992, pp. 1071-80. doi : 10.1083 / jcb.116.5.1071 . PMID 1740466 . PMC 2289364 (free full text).

[4] Chen Yu, Yanxia Liu, Tianhua Ma, Kai Liu, Shaohua Xu, Yu Zhang, Honglei Liu, Marie La Russa, Min Xie, Sheng Ding, Lei S. Qi: Small Molecules Enhance CRISPR Genome Editing in Pluripotent Stem Cells . In: Cell Stem Cell . 16, No. 2, February 2015, pp. 142–147. doi : 10.1016 / j.stem.2015.01.003 .

[pmid20102617-5] Rajamahanty S, Alonzo C. Aynehchi S, M Choudhury, Konno S: Growth inhibition of androgen-responsive prostate cancer cells with brefeldin A targeting cell cycle and androgen receptor . In: Journal of Biomedical Science . 17, No. 1, 2010, p. 5. doi : 10.1186 / 1423-0127-17-5 . PMID 20102617 . PMC 2843609 (free full text).

[6] Jianfeng Wang, Yaojian Huang, Meijuan Fang, Yongjie Zhang, Zhonghui Zheng: Brefeldin A, a cytotoxin produced by Paecilomyces sp. and Aspergillus clavatus isolated from Taxus mairei and Torreya grandis . In: FEMS Immunology & Medical Microbiology . tape 34 , no. 1 , September 1, 2002, ISSN 0928-8244 , p. 51–57 , doi : 10.1111 / j.1574-695X.2002.tb00602.x ( oup.com [accessed May 12, 2018]).

[:0-7] A ^b T. G. McCloud, MP Burns, FD Majadly, GM Muschik, DA Miller: Production of brefeldin-A . In: Journal of Industrial Microbiology . tape 15 , no. 1 , July 1, 1995, ISSN 0169-4146 , p. 5–9 , doi : 10.1007 / BF01570006 ( springer.com [accessed May 12, 2018]).