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Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase

Title
Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase
Authors
Keller T.L.Zocco D.Sundrud M.S.Hendrick M.Edenius M.Yum J.Kim Y.-J.Lee H.-K.Cortese J.F.Wirth D.F.Dignam J.D.Rao A.Yeo C.-Y.Mazitschek R.Whitman M.
Ewha Authors
여창열
SCOPUS Author ID
여창열scopus
Issue Date
2012
Journal Title
Nature Chemical Biology
ISSN
1552-4450JCR Link
Citation
vol. 8, no. 3, pp. 311 - 317
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Febrifugine, the bioactive constituent of one of the 50 fundamental herbs of traditional Chinese medicine, has been characterized for its therapeutic activity, though its molecular target has remained unknown. Febrifugine derivatives have been used to treat malaria, cancer, fibrosis and inflammatory disease. We recently demonstrated that halofuginone (HF), a widely studied derivative of febrifugine, inhibits the development of T H 17-driven autoimmunity in a mouse model of multiple sclerosis by activating the amino acid response (AAR) pathway. Here we show that HF binds glutamyl-prolyl-tRNA synthetase (EPRS), inhibiting prolyl-tRNA synthetase activity; this inhibition is reversed by the addition of exogenous proline or EPRS. We further show that inhibition of EPRS underlies the broad bioactivities of this family of natural product derivatives. This work both explains the molecular mechanism of a promising family of therapeutics and highlights the AAR pathway as an important drug target for promoting inflammatory resolution.
DOI
10.1038/nchembio.790
Appears in Collections:
자연과학대학 > 생명과학전공 > Journal papers
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