Antitumor polyketide biosynthesis by an uncultivated bacterial symbiont of the marine sponge Theonella swinhoei
Antitumor polyketide biosynthesis by an uncultivated bacterial symbiont of the marine sponge Theonella swinhoei
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DOI：
10.1073/pnas.0405976101
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发表时间：
2004-11-16
影响因子：
11.1
通讯作者：
Matsunaga, S
中科院分区：
文献类型：
--
作者：
Piel, J;Hui, DQ;Matsunaga, S
长期以来，细菌共生体一直被怀疑是许多从海洋无脊椎动物中分离出的候选药物的真正生产者。海绵是最重要的海洋生物活性天然产物来源，经常被假设含有细菌来源的化合物。然而，这种共生体假说仍然没有得到证实，因为一般无法培养可疑的生产者。然而，我们最近已经确定了一个未培养的假单胞菌属共生体作为最有可能的生产者的防御性抗肿瘤聚酮pederin在褐天牛甲虫通过克隆推定的生物合成基因。在这里，我们报告密切相关的基因分离的高度复杂的宏基因组的海绵Theonella swinhoei，这是onnamides和theopederins，一组聚酮化合物，结构类似pederin的来源。分离的基因的序列特征清楚地表明，它属于原核基因组，并应负责与抗肿瘤活性相关的聚酮结构的几乎整个部分的生物合成。除了进一步证明相关的甲虫共生体衍生基因的作用，这些发现提出了有趣的生态和进化问题，并具有重要的一般性影响，否则无法使用生物技术战略的海洋药物的可持续生产。
Bacterial symbionts have long been suspected to be the true producers of many drug candidates isolated from marine invertebrates. Sponges, the most important marine source of biologically active natural products, have been frequently hypothesized to contain compounds of bacterial origin. This symbiont hypothesis, however, remained unproven because of a general inability to cultivate the suspected producers. However, we have recently identified an uncultured Pseudomonas sp. symbiont as the most likely producer of the defensive antitumor polyketide pederin in Paederus fuscipes beetles by cloning the putative biosynthesis genes. Here we report closely related genes isolated from the highly complex metagenome of the marine sponge Theonella swinhoei, which is the source of the onnamides and theopederins, a group of polyketides that structurally resemble pederin. Sequence features of the isolated genes clearly indicate that it belongs to a prokaryotic genome and should be responsible for the biosynthesis of almost the entire portion of the polyketide structure that is correlated with antitumor activity. Besides providing further proof for the role of the related beetle symbiont-derived genes, these findings raise intriguing ecological and evolutionary questions and have important general implications for the sustainable production of otherwise inaccessible marine drugs by using biotechnological strategies.