CAS Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, 164 West Xingang Road, Guangzhou 510301, China.
College of Oceanography, University of Chinese Academy of Sciences, Beijing 100049, China.
Mar Drugs. 2019 Apr 23;17(4):240. doi: 10.3390/md17040240.
Bioactive secondary metabolites from are important sources of lead compounds in current drug development. SCSIO ZS0073, a mangrove-derived actinomycete, produces actinomycin D, a clinically used therapeutic for Wilm's tumor of the kidney, trophoblastic tumors and rhabdomyosarcoma. In this work, we identified the actinomycin biosynthetic gene cluster (BGC) by detailed analyses of the SCSIO ZS0073 genome. This organism produces actinomycin D with a titer of ~69.8 μg mL along with traces of actinomycin X. The cluster localized to a 39.8 kb length region consisting of 25 open reading frames (ORFs), including a set of four genes that drive the construction of the 4-methyl-3-hydroxy-anthranilic acid (4-MHA) precursor and three non-ribosomal peptide synthetases (NRPSs) that generate the 4-MHA pentapeptide semi-lactone, which, upon dimerization, affords final actinomycin D. Furthermore, the cluster contains four positive regulatory genes , which were identified by in vivo gene inactivation studies. Our data provide insights into the genetic characteristics of this new mangrove-derived actinomycin D bioproducer, enabling future metabolic engineering campaigns to improve both titers and the structural diversities possible for actinomycin D and related analogues.
来源于 的生物活性次生代谢产物是当前药物开发中铅类化合物的重要来源。海洋来源放线菌 SCSIO ZS0073 产生放线菌素 D，这是一种临床上用于治疗肾母细胞瘤、滋养层肿瘤和横纹肌肉瘤的治疗药物。在这项工作中，我们通过对 SCSIO ZS0073 基因组的详细分析，鉴定出了放线菌素生物合成基因簇（BGC）。该生物产生的放线菌素 D 产量约为 69.8μg/mL，同时还存在少量的放线菌素 X。该 BGC 定位于一个 39.8kb 的长度区域，由 25 个开放阅读框（ORFs）组成，包括一组四个基因，这些基因驱动 4-甲基-3-羟基-邻氨基苯甲酸（4-MHA）前体的构建，以及三个非核糖体肽合成酶（NRPSs），这些酶生成 4-MHA 五肽半内酯，经二聚化后得到最终的放线菌素 D。此外，该 BGC 还包含四个正调控基因 ，这些基因是通过体内基因失活研究鉴定的。我们的数据提供了对这种新的海洋来源放线菌素 D 生物产生菌的遗传特征的深入了解，为未来的代谢工程改造提供了可能，以提高放线菌素 D 和相关类似物的产量和结构多样性。
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