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Inhibition of p-aminobenzoate and folate syntheses in plants and apicomplexan parasites by natural product rubreserine

Djeneb Camara, Cordelia Bisanz, Caroline Barette, Jeroen Van Daele, Esmare Human, Bernice Barnard, Dominique Van Der Straeten UGent, Christophe Stove UGent, Willy Lambert, Roland Douce, et al. (2012) JOURNAL OF BIOLOGICAL CHEMISTRY. 287(26). p.22367-22376
abstract
Glutamine amidotransferase/aminodeoxychorismate synthase (GAT-ADCS) is a bifunctional enzyme involved in the synthesis of p-aminobenzoate, a central component part of folate cofactors. GAT-ADCS is found in eukaryotic organisms autonomous for folate biosynthesis, such as plants or parasites of the phylum Apicomplexa. Based on an automated screening to search for new inhibitors of folate biosynthesis, we found that rubreserine was able to inhibit the glutamine amidotransferase activity of the plant GAT-ADCS with an apparent IC50 of about 8 mu M. The growth rates of Arabidopsis thaliana, Toxoplasma gondii, and Plasmodium falciparum were inhibited by rubreserine with respective IC50 values of 65, 20, and 1 mu M. The correlation between folate biosynthesis and growth inhibition was studied with Arabidopsis and Toxoplasma. In both organisms, the folate content was decreased by 40-50% in the presence of rubreserine. In both organisms, the addition of p-aminobenzoate or 5-formyltetrahydrofolate in the external medium restored the growth for inhibitor concentrations up to the IC50 value, indicating that, within this range of concentrations, rubreserine was specific for folate biosynthesis. Rubreserine appeared to be more efficient than sulfonamides, antifolate drugs known to inhibit the invasion and proliferation of T. gondii in human fibroblasts. Altogether, these results validate the use of the bifunctional GAT-ADCS as an efficient drug target in eukaryotic cells and indicate that the chemical structure of rubreserine presents interesting anti-parasitic (toxoplasmosis, malaria) potential.
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author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
rubreserine, CHORISMATE-UTILIZING ENZYMES, anti-parasitic drugs, pABA biosynthesis, apicomplexan parasites, folate synthesis, DE-NOVO SYNTHESIS, PLASMODIUM-FALCIPARUM, TOXOPLASMA-GONDII, AMINODEOXYCHORISMATE SYNTHASE, ANTHRANILATE SYNTHASE, 4-AMINO-4-DEOXYCHORISMATE SYNTHASE, ISOCHORISMATE SYNTHASE, GMP SYNTHETASE, GLUCOSE ESTER
journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
J. Biol. Chem.
volume
287
issue
26
pages
22367 - 22376
Web of Science type
Article
Web of Science id
000306418600073
JCR category
BIOCHEMISTRY & MOLECULAR BIOLOGY
JCR impact factor
4.651 (2012)
JCR rank
61/288 (2012)
JCR quartile
1 (2012)
ISSN
0021-9258
DOI
10.1074/jbc.M112.365833
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
3164473
handle
http://hdl.handle.net/1854/LU-3164473
date created
2013-03-14 09:30:36
date last changed
2016-12-19 15:39:25
@article{3164473,
  abstract     = {Glutamine amidotransferase/aminodeoxychorismate synthase (GAT-ADCS) is a bifunctional enzyme involved in the synthesis of p-aminobenzoate, a central component part of folate cofactors. GAT-ADCS is found in eukaryotic organisms autonomous for folate biosynthesis, such as plants or parasites of the phylum Apicomplexa. Based on an automated screening to search for new inhibitors of folate biosynthesis, we found that rubreserine was able to inhibit the glutamine amidotransferase activity of the plant GAT-ADCS with an apparent IC50 of about 8 mu M. The growth rates of Arabidopsis thaliana, Toxoplasma gondii, and Plasmodium falciparum were inhibited by rubreserine with respective IC50 values of 65, 20, and 1 mu M. The correlation between folate biosynthesis and growth inhibition was studied with Arabidopsis and Toxoplasma. In both organisms, the folate content was decreased by 40-50\% in the presence of rubreserine. In both organisms, the addition of p-aminobenzoate or 5-formyltetrahydrofolate in the external medium restored the growth for inhibitor concentrations up to the IC50 value, indicating that, within this range of concentrations, rubreserine was specific for folate biosynthesis. Rubreserine appeared to be more efficient than sulfonamides, antifolate drugs known to inhibit the invasion and proliferation of T. gondii in human fibroblasts. Altogether, these results validate the use of the bifunctional GAT-ADCS as an efficient drug target in eukaryotic cells and indicate that the chemical structure of rubreserine presents interesting anti-parasitic (toxoplasmosis, malaria) potential.},
  author       = {Camara, Djeneb and Bisanz, Cordelia and Barette, Caroline and Van Daele, Jeroen and Human, Esmare and Barnard, Bernice and Van Der Straeten, Dominique and Stove, Christophe and Lambert, Willy and Douce, Roland and Mar{\'e}chal, Eric and Birkholtz, Lyn-Marie and Cesbron-Delauw, Marie-France and Dumas, Renaux and R{\'e}beill{\'e}, Fabrice},
  issn         = {0021-9258},
  journal      = {JOURNAL OF BIOLOGICAL CHEMISTRY},
  keyword      = {rubreserine,CHORISMATE-UTILIZING ENZYMES,anti-parasitic drugs,pABA biosynthesis,apicomplexan parasites,folate synthesis,DE-NOVO SYNTHESIS,PLASMODIUM-FALCIPARUM,TOXOPLASMA-GONDII,AMINODEOXYCHORISMATE SYNTHASE,ANTHRANILATE SYNTHASE,4-AMINO-4-DEOXYCHORISMATE SYNTHASE,ISOCHORISMATE SYNTHASE,GMP SYNTHETASE,GLUCOSE ESTER},
  language     = {eng},
  number       = {26},
  pages        = {22367--22376},
  title        = {Inhibition of p-aminobenzoate and folate syntheses in plants and apicomplexan parasites by natural product rubreserine},
  url          = {http://dx.doi.org/10.1074/jbc.M112.365833},
  volume       = {287},
  year         = {2012},
}

Chicago
Camara, Djeneb, Cordelia Bisanz, Caroline Barette, Jeroen Van Daele, Esmare Human, Bernice Barnard, Dominique Van Der Straeten, et al. 2012. “Inhibition of P-aminobenzoate and Folate Syntheses in Plants and Apicomplexan Parasites by Natural Product Rubreserine.” Journal of Biological Chemistry 287 (26): 22367–22376.
APA
Camara, D., Bisanz, C., Barette, C., Van Daele, J., Human, E., Barnard, B., Van Der Straeten, D., et al. (2012). Inhibition of p-aminobenzoate and folate syntheses in plants and apicomplexan parasites by natural product rubreserine. JOURNAL OF BIOLOGICAL CHEMISTRY, 287(26), 22367–22376.
Vancouver
1.
Camara D, Bisanz C, Barette C, Van Daele J, Human E, Barnard B, et al. Inhibition of p-aminobenzoate and folate syntheses in plants and apicomplexan parasites by natural product rubreserine. JOURNAL OF BIOLOGICAL CHEMISTRY. 2012;287(26):22367–76.
MLA
Camara, Djeneb, Cordelia Bisanz, Caroline Barette, et al. “Inhibition of P-aminobenzoate and Folate Syntheses in Plants and Apicomplexan Parasites by Natural Product Rubreserine.” JOURNAL OF BIOLOGICAL CHEMISTRY 287.26 (2012): 22367–22376. Print.