Dürr Clemens, Schnell Hans-Jörg, Luzhetskyy Andriy, Murillo Renato, Weber Monika, Welzel Katrin, Vente Andreas, Bechthold Andreas
Albert-Ludwigs-Universität, Institut für Pharmazeutische Wissenschaften, Stefan-Meier-Strasse 19, 79104 Freiburg, Germany.
Chem Biol. 2006 Apr;13(4):365-77. doi: 10.1016/j.chembiol.2006.01.011.
Phenalinolactones are terpene glycosides with antibacterial activity. A striking structural feature is a highly oxidized gamma-butyrolactone of elusive biosynthetic origin. To investigate the genetic basis of the phenalinolactones biosynthesis, we cloned and sequenced the corresponding gene cluster from the producer strain Streptomyces sp. Tü6071. Spanning a 42 kbp region, 35 candidate genes could be assigned to putatively encode biosynthetic, regulatory, and resistance-conferring functions. Targeted gene inactivations were carried out to specifically manipulate the phenalinolactones pathway. The inactivation of a sugar methyltransferase gene and a cytochrome P450 monoxygenase gene led to the production of modified phenalinolactone derivatives. The inactivation of a Fe(II)/alpha-ketoglutarate-dependent dioxygenase gene disrupted the biosynthetic pathway within gamma-butyrolactone formation. The structure elucidation of the accumulating intermediate indicated that pyruvate is the biosynthetic precursor of the gamma butyrolactone moiety.
苯那内酯是具有抗菌活性的萜烯糖苷。一个显著的结构特征是具有难以捉摸的生物合成起源的高度氧化的γ-丁内酯。为了研究苯那内酯生物合成的遗传基础，我们从产生菌链霉菌属菌株Tü6071中克隆并测序了相应的基因簇。该基因簇跨越42 kbp区域，35个候选基因可被指定为假定编码生物合成、调控和赋予抗性的功能。进行了靶向基因失活以特异性操纵苯那内酯途径。糖甲基转移酶基因和细胞色素P450单加氧酶基因的失活导致了修饰的苯那内酯衍生物的产生。Fe(II)/α-酮戊二酸依赖性双加氧酶基因的失活破坏了γ-丁内酯形成过程中的生物合成途径。对积累的中间体的结构解析表明，丙酮酸是γ-丁内酯部分的生物合成前体。
