دورية أكاديمية
Mislocalization and inhibition of acetyl-CoA carboxylase 1 by a synthetic small molecule
| العنوان: | Mislocalization and inhibition of acetyl-CoA carboxylase 1 by a synthetic small molecule |
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| المؤلفون: | Jung, Dongju, Abu-Elheiga, Lutfi, Ayuzawa, Rie, Gu, Ziwei, Shirakawa, Takashi, Fujiki, Yukio, Nakatsuji, Norio, Wakil, Salih J., Uesugi, Motonari |
| المصدر: | Biochemical Journal ; volume 448, issue 3, page 409-416 ; ISSN 0264-6021 1470-8728 |
| بيانات النشر: | Portland Press Ltd. |
| سنة النشر: | 2012 |
| الوصف: | Chromeceptin is a synthetic small molecule that inhibits insulin-induced adipogenesis of 3T3-L1 cells and impairs the function of IGF2 (insulin-like growth factor 2). The molecular target of this benzochromene derivative is MFP-2 (multifunctional protein 2). The interaction between chromeceptin and MFP-2 activates STAT6 (signal transducer and activator of transcription 6), which subsequently induces IGF inhibitory genes. It was not previously known how the binding of chromeceptin with MFP-2 blocks adipogenesis and activates STAT6. The results of the present study show that the chromeceptin–MFP-2 complex binds to and inhibits ACC1 (acetyl-CoA carboxylase 1), an enzyme important for the de novo synthesis of malonyl-CoA and fatty acids. The formation of this ternary complex removes ACC1 from the cytosol and sequesters it in peroxisomes under the guidance of Pex5p (peroxisomal-targeting signal type 1 receptor). As a result, chromeceptin impairs fatty acid synthesis from acetate where ACC1 is a rate-limiting enzyme. Overexpression of malonyl-CoA decarboxylase or siRNA (small interfering RNA) knockdown of ACC1 results in STAT6 activation, suggesting a role for malonyl-CoA in STAT6 signalling. The molecular mechanism of chromeceptin may provide a new pharmacological approach to selective inhibition of ACC1 for biological studies and pharmaceutical development. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1042/bj20121158 |
| الإتاحة: | https://doi.org/10.1042/bj20121158Test https://portlandpress.com/biochemj/article-pdf/448/3/409/672588/bj4480409.pdfTest |
| رقم الانضمام: | edsbas.506EA4F5 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1042/bj20121158 |
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