論文 - 詳細
| RRC ID | 15728 |
|---|---|
| 著者 | Kim W, Lee D, Hong SS, Na Z, Shin JC, Roh SH, Wu CZ, Choi O, Lee K, Shen YM, Paik SG, Lee JJ, Hong YS. |
| タイトル | Rational biosynthetic engineering for optimization of geldanamycin analogues. |
| ジャーナル | Chembiochem |
| Abstract |
Tailor made: We report the rational biosynthesis of C15 hydroxylated non-quinone geldanamycin analogues by site-directed mutagenesis of the geldanamycin polyketide synthase (PKS), together with a combination of post-PKS tailoring genes. Rational biosynthetic engineering allowed the generation of geldanamycin derivatives, such as DHQ3 illustrated in the figure, which had superior pharmacological properties in comparison to the parent compound. A rational biosynthetic engineering approach was applied to the optimization of the pharmacological properties of the benzoquinone ansamycin, geldanamycin. Geldanamycin and its natural or semisynthetic derivatives have the potential to serve as anticancer chemotherapeutic agents. However, these first-generation Hsp90 inhibitors share an unfavorable structural feature that causes both reduced efficacy and toxicity during clinical evaluation. We report the rationally designed biosynthesis of C15 hydroxylated non-quinone geldanamycin analogues by site-directed mutagenesis of the geldanamycin polyketide synthase (PKS), together with a combination of post-PKS tailoring genes. A 15-hydroxyl-17-demethoxy non-quinone analogue, DHQ3, exhibited stronger inhibition of Hsp90 ATPase activity (4.6-fold) than geldanamycin. Taken together, the results of the present study indicate that rational biosynthetic engineering allows the generation of derivatives of geldanamycin with superior pharmacological properties. |
| 巻・号 | 10(7) |
| ページ | 1243-51 |
| 公開日 | 2009-5-4 |
| DOI | 10.1002/cbic.200800763 |
| PMID | 19308924 |
| MeSH | Amino Acid Sequence Amino Acid Substitution Antibiotics, Antineoplastic / chemistry* Antibiotics, Antineoplastic / metabolism Antibiotics, Antineoplastic / pharmacology Benzoquinones / chemistry* Benzoquinones / metabolism* Benzoquinones / pharmacology Genetic Engineering HSP90 Heat-Shock Proteins / antagonists & inhibitors HSP90 Heat-Shock Proteins / metabolism Lactams, Macrocyclic / chemistry* Lactams, Macrocyclic / metabolism* Lactams, Macrocyclic / pharmacology Molecular Sequence Data Multigene Family Mutagenesis, Site-Directed Polyketide Synthases / genetics Polyketide Synthases / metabolism Sequence Alignment |
| IF | 2.576 |
| 引用数 | 35 |
| WOS 分野 | CHEMISTRY, MEDICINAL 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 | Wikipedia |
| 各媒体での言及数の合計 | 4 |
| 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 | |
| 一般微生物 | JCM 4427 |