Zhang Weike, Wang Lu, Kong Lingxin, Wang Tao, Chu Yiwen, Deng Zixin, You Delin
State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, China.
Chem Biol. 2012 Mar 23;19(3):422-32. doi: 10.1016/j.chembiol.2012.01.016.
Xantholipin from Streptomyces flavogriseus is a curved hexacyclic aromatic polyketide antitumor antibiotic. The entire 52 kb xantholipin (xan) biosynthetic gene cluster was sequenced, and bioinformatic analysis revealed open reading frames encoding type II polyketide synthases, regulators, and polyketide tailoring enzymes. Individual in-frame mutagenesis of five tailoring enzymes lead to the production of nine xantholipin analogs, revealing that the xanthone scaffold formation was catalyzed by the FAD binding monooxygenase XanO4, the δ-lactam formation by the asparagine synthetase homolog XanA, the methylenedioxy bridge generation by the P450 monooxygenase XanO2 and the hydroxylation of the carbon backbone by the FAD binding monooxygenase XanO5. These findings may also apply to other polycyclic xanthone antibiotics, and they form the basis for genetic engineering of the xantholipin and similar biosynthetic gene clusters for the generation of compounds with improved antitumor activities.
来自黄色灰链霉菌的黄脂素是一种弯曲的六环芳香族聚酮类抗肿瘤抗生素。对整个52 kb的黄脂素（xan）生物合成基因簇进行了测序，生物信息学分析揭示了编码II型聚酮合酶、调控因子和聚酮修饰酶的开放阅读框。对五种修饰酶进行单个框内诱变导致产生了九种黄脂素类似物，这表明呫吨酮支架的形成由FAD结合单加氧酶XanO4催化，δ-内酰胺的形成由天冬酰胺合成酶同源物XanA催化，亚甲二氧基桥的生成由P450单加氧酶XanO2催化，碳骨架的羟基化由FAD结合单加氧酶XanO5催化。这些发现可能也适用于其他多环呫吨酮抗生素，它们构成了对黄脂素和类似生物合成基因簇进行基因工程以产生具有改善抗肿瘤活性的化合物的基础。
