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Abstract：
A biosynthetic gene cluster for the bioactive fungal sesterterpenoids variecolin (1) and variecolactone (2) was identified in Aspergillus aculeatus ATCC 16872. Heterologous production of 1 and 2 was achieved in Aspergillus oryzae by expressing the sesterterpene synthase VrcA and the cytochrome P450 VrcB. Intriguingly, the replacement of VrcB with homologous P450s from other fungal terpenoid pathways yielded three new variecolin analogues (5-7). Analysis of the compounds\' anticancer activity in vitro and in vivo revealed that although 5 and 1 had comparable activities, 5 was associated with significantly reduced toxic side effects in cancer-bearing mice, indicating its potentially broader therapeutic window. Our study describes the first tests of variecolin and its analogues in animals and demonstrates the utility of synthetic biology for creating molecules with improved biological activities.
摘要：
在刺客曲霉ATCC16872中鉴定出生物活性真菌皮萜类化合物变种林（1）和变种内酯（2）的生物合成基因簇。通过表达酯萜合酶VrcA和细胞色素P450VrcB，在米曲霉中实现了1和2的异源生产。有趣的是，用来自其他真菌萜类途径的同源P450替代VrcB产生了三种新的variecolin类似物(5-7)。对化合物的体外和体内抗癌活性的分析表明，尽管5和1具有相当的活性，5与癌症小鼠的毒副作用显着降低有关，表明其潜在的更广泛的治疗窗口。我们的研究描述了variecolin及其类似物在动物中的首次测试，并证明了合成生物学用于创建具有改善的生物活性的分子的实用性。
