論文 - 詳細
| RRC ID | 4922 |
|---|---|
| 著者 | Guianvarc'h D, Guangqi E, Drujon T, Rey C, Wang Q, Ploux O. |
| タイトル | Identification of inhibitors of the E. coli cyclopropane fatty acid synthase from the screening of a chemical library: In vitro and in vivo studies. |
| ジャーナル | Biochim Biophys Acta |
| Abstract |
Using an automated coupled colorimetric assay for the Escherichia coli cyclopropane fatty acid synthase (CFAS), we have screened an academic chemical library of 3040 compounds, to identify new inhibitors of this enzyme. We identified 8 compounds as potent inhibitors of this enzyme, with IC(50) ranging from 1 to 10 microM, in the presence of 750 microM S-adenosyl-l-methionine and 1 mg/mL phospholipids. We conducted kinetic analyses of the inhibition of the CFAS using dioctylamine and three inhibitors identified in this report: sinefungin, 1, a synthetic S-adenosyl-l-homocysteine analog, 2, and an indoloquinolizine derivative, 3. The inhibition patterns observed were interpreted assuming that the E. coli CFAS operated via an ordered Bi Bi mechanism with binding of S-adenosyl-l-methionine first. Dioctylamine was the most potent inhibitor with a competitive inhibition constant of 130 nM with respect to the phospholipids. Compound 2 bound to the two substrate-binding sites of the enzyme suggesting that it acted as a bisubstrate analog (apparent inhibition constant, K(I)=6 microM). Compound 2 was also found to completely inhibit cyclopropanation of the phospholipids in growing E. coli cells, at 150 microM. This molecule is thus the first inhibitor of a cyclopropane synthase that is active in vivo, contrary to sinefungin and other analogs that are only active on the isolated enzyme. |
| 巻・号 | 1784(11) |
| ページ | 1652-8 |
| 公開日 | 2008-11-1 |
| DOI | 10.1016/j.bbapap.2008.04.019 |
| PII | S1570-9639(08)00143-X |
| PMID | 18501724 |
| MeSH | Adenosine / analogs & derivatives Adenosine / pharmacology Anti-Bacterial Agents / pharmacology Catalysis / drug effects Drug Evaluation, Preclinical Enzyme Inhibitors / isolation & purification* Enzyme Inhibitors / pharmacology Escherichia coli / enzymology* Escherichia coli Proteins / antagonists & inhibitors Fatty Acids / metabolism Methyltransferases / antagonists & inhibitors* Methyltransferases / metabolism Models, Biological Small Molecule Libraries / analysis* |
| IF | 3.411 |
| 引用数 | 11 |
| WOS 分野 | BIOPHYSICS BIOCHEMISTRY & MOLECULAR BIOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 原核生物(大腸菌) | JW1653 |