Brautaset Trygve, Bruheim Per, Sletta Håvard, Hagen Lars, Ellingsen Trond E, Strøm Arne R, Valla Svein, Zotchev Sergey B
Department of Biotechnology, Norwegian University of Science and Technology, N-7491 Trondheim, Norway.
Chem Biol. 2002 Mar;9(3):367-73. doi: 10.1016/s1074-5521(02)00108-4.
Genetic manipulation of the polyketide synthase (PKS) gene nysC involved in the biosynthesis of the tetraene antifungal antibiotic nystatin yielded a recombinant strain producing hexaene nystatin derivatives. Analysis of one such compound, S48HX, by LC-MS/MS suggested that it comprises a 36-membered macrolactone ring completely decorated by the post-PKS modification enzymes. Further characterization by bioassay has shown that S48HX exhibits antifungal activity. Genetic analysis of the hexaene-producing mutant revealed an in-frame deletion within the nysC gene via recombination between two homologous ketoreductase domain-encoding sequences. Apparently, this event resulted in the elimination of one complete module from NysC PKS, subsequently leading to the production of the nystatin derivative with a contracted macrolactone ring. These results represent the first example of manipulation of a PKS gene for the biosynthesis of a polyene antibiotic.
对参与四烯抗真菌抗生素制霉菌素生物合成的聚酮合酶（PKS）基因nysC进行基因操作，得到了一株产生六烯制霉菌素衍生物的重组菌株。通过液相色谱-串联质谱法（LC-MS/MS）对其中一种化合物S48HX进行分析表明，它包含一个36元大环内酯环，该环完全由聚酮合酶后修饰酶修饰。通过生物测定进一步表征表明，S48HX具有抗真菌活性。对产生六烯的突变体进行遗传分析发现，通过两个同源酮还原酶结构域编码序列之间的重组，nysC基因内发生了框内缺失。显然，这一事件导致从NysC聚酮合酶中消除了一个完整模块，随后产生了具有收缩大环内酯环的制霉菌素衍生物。这些结果代表了为多烯抗生素生物合成而对聚酮合酶基因进行操作的首个实例。
