A 61-kb biosynthetic gene cluster (BGC), which is accountable for the biosynthesis of hibarimicin (HBM) B from subsp. TP-A0121, was heterologously expressed in M1154, which generated a trace of the target products but accumulated a large amount of shunt products. Based on rational analysis of the relevant secondary metabolism, directed engineering of the biosynthetic pathways resulted in the high production of HBM B, as well as new HBM derivates with improved antitumor activity. These results not only establish a biosynthetic system to effectively synthesize HBMs-a class of the largest and most complex Type-II polyketides, with a unique pseudo-dimeric structure-but also set the stage for further engineering and deep investigation of this complex biosynthetic pathway toward potent anticancer drugs.

中文翻译：

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异源宿主次级代谢途径的合理工程，以实现具有增强抗黑色素活性的 Hibarimicin 衍生物的生物合成

一个 61 kb 的生物合成基因簇 (BGC)，负责亚种 Hibarimicin (HBM) B 的生物合成。TP-A0121在M1154中异源表达，产生微量目标产物，但积累了大量分流产物。基于对相关次生代谢的合理分析，生物合成途径的定向工程导致了 HBM B 的高产量，以及具有改善的抗肿瘤活性的新 HBM 衍生物。这些结果不仅建立了有效合成HBM（一类最大、最复杂的II型聚酮化合物，具有独特的伪二聚体结构）的生物合成系统，而且为进一步工程化和深入研究这一复杂的生物合成途径奠定了基础走向有效的抗癌药物。