Fischer Carsten, Lipata Fredilyn, Rohr Jürgen
Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 907 Rose Street, Lexington, KY 40536-0082, USA.
J Am Chem Soc. 2003 Jul 2;125(26):7818-9. doi: 10.1021/ja034781q.
Gilvocarcin V, an antitumor agent produced by the bacterium Streptomyces griseoflavus Gö 3592, is the most studied representative of the distinct family of benzo[d]naphtho[1,2-b]pyran-6-one aryl C-glycoside antibiotics, which show excellent antitumor activity and a remarkably low toxicity. Its biosynthesis contains many intriguing steps, including an oxidative rearrangement, the C-glycosylation, and the generation of a vinyl side chain. These steps all contribute to structural elements of the drug, which are essential for its biological activity, but only poorly understood. Herein we report the cloning and characterization of the gilvocarcin (gil) gene cluster from S. griseoflavus Gö 3592, and its heterologous expression in a foreign host (S. lividans). This is the first reported gene cluster encoding the biosynthesis of a benzo[d]naphtho[1,2-b]pyran-6-one aryl C-glycoside antibiotic, which not only provides insights regarding the biosynthesis of gilvocarcin V but also lays the foundation for the detailed studies of its intriguing biosynthetic steps and possibly for the generation of gilvocarcin analogues with improved biological activities through combinatorial biosynthesis.
吉尔vocarcin V是由灰色黄链霉菌Gö 3592产生的一种抗肿瘤剂，是苯并[d]萘并[1,2 - b]吡喃 - 6 - 酮芳基C - 糖苷抗生素独特家族中研究最多的代表，这类抗生素显示出优异的抗肿瘤活性和极低的毒性。其生物合成包含许多有趣的步骤，包括氧化重排、C - 糖基化以及乙烯基侧链的生成。这些步骤都对药物的结构元件有贡献，而这些结构元件对其生物活性至关重要，但目前了解甚少。在此，我们报道了从灰色黄链霉菌Gö 3592中克隆和鉴定吉尔vocarcin（gil）基因簇，并在异源宿主（变铅青链霉菌）中进行异源表达。这是首次报道的编码苯并[d]萘并[1,2 - b]吡喃 - 6 - 酮芳基C - 糖苷抗生素生物合成的基因簇，它不仅为吉尔vocarcin V的生物合成提供了见解，也为详细研究其有趣的生物合成步骤奠定了基础，并且可能通过组合生物合成产生具有改善生物活性的吉尔vocarcin类似物。
