Frank Bettina, Knauber Jens, Steinmetz Heinrich, Scharfe Maren, Blöcker Helmut, Beyer Stefan, Müller Rolf
Pharmaceutical Biotechnology, Saarland University, 66041 Saarbrücken, Germany.
Chem Biol. 2007 Feb;14(2):221-33. doi: 10.1016/j.chembiol.2006.11.013.
Natural products constitute important lead structures in drug discovery. In bacteria, they are often synthesized by large, modular multienzyme complexes. Detailed analysis of the biosynthetic machinery should enable its directed engineering and production of desirable analogs. The myxobacterium Sorangium cellulosum So ce90 produces the cytotoxic spiroketal polyketide spirangien, for which we describe the identification and functional analysis of the biosynthetic pathway. The gene cluster spans 88 kb and encodes 7 type I polyketide synthases and additional enzymes such as a stand-alone thioesterase and 2 methyltransferases. Inactivation of two cytochrome P(450) monooxygenase genes resulted in the production of acyclic spirangien derivatives, providing direct evidence for the involvement of these enzymes in spiroketal formation. The presence of large DNA repeats is consistent with multiple rounds of gene duplication during the evolution of the biosynthetic gene locus.
天然产物是药物发现中重要的先导结构。在细菌中，它们通常由大型模块化多酶复合物合成。对生物合成机制进行详细分析应能实现其定向工程改造并生产出所需的类似物。粘细菌纤维堆囊菌So ce90产生具有细胞毒性的螺环缩酮聚酮化合物螺旋霉素，我们描述了该生物合成途径的鉴定和功能分析。该基因簇跨度为88 kb，编码7种I型聚酮合酶以及其他酶，如一种独立的硫酯酶和2种甲基转移酶。两个细胞色素P(450)单加氧酶基因的失活导致了无环螺旋霉素衍生物的产生，为这些酶参与螺环缩酮形成提供了直接证据。大的DNA重复序列的存在与生物合成基因位点进化过程中的多轮基因复制相一致。
