A polyketide synthase-peptide synthetase gene cluster from an uncultured bacterial symbiont of Paederus beetles
A polyketide synthase-peptide synthetase gene cluster from an uncultured bacterial symbiont of Paederus beetles
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DOI：
10.1073/pnas.222481399
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发表时间：
2002-10-29
影响因子：
11.1
通讯作者：
Piel, J
中科院分区：
文献类型：
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作者：
Piel, J
许多来自海洋和陆地无脊椎动物的候选药物被怀疑是未经培养的细菌共生体的代谢物。从甲虫和海绵中分离出的pederin家族的抗肿瘤聚酮就是一个例子。这种来源的药物开发通常受到产量低和维持无脊椎动物培养的困难的阻碍。为了深入了解这些稀有候选药物的真正生产者和替代供应，从使用这种化合物进行化学防御的Paederus fuscipes甲虫的总DNA中克隆了推测的pederin生物合成基因。基因簇和邻近区域的序列分析显示存在典型的细菌结构和同源性的ORF。ped簇，只存在于高pederin含量的甲虫标本中，位于一个54-kb的区域，由转座酶假基因接壤，编码混合模块化聚酮合成酶/非核糖体肽合成酶。值得注意的是，这些模块都不包含与酰基转移酶结构域同源的区域，但在集群的上游端发现了两个分离的单结构域酰基转移酶基因拷贝。由于参与了菊酯类化合物的生物合成，上游集群区域完美地反映了菊酯类化合物的结构。额外的聚酮合成酶/非核糖体肽合成酶模块的意外存在揭示了甲虫和海绵中pederintype通路之间进化关系的惊人见解。
Many drug candidates from marine and terrestrial invertebrates are suspected metabolites of uncultured bacterial symbionts. The antitumor polyketides of the pederin family, isolated from beetles and sponges, are an example. Drug development from such sources is commonly hampered by low yields and the difficulty of sustaining invertebrate cultures. To obtain insight into the true producer and find alternative supplies of these rare drug candidates, the putative pederin biosynthesis genes were cloned from total DNA of Paederus fuscipes beetles, which use this compound for chemical defense. Sequence analysis of the gene cluster and adjacent regions revealed the presence of ORF's with typical bacterial architecture and homologies. The ped cluster, which is present only in beetle specimens with high pederin content, is located on a 54-kb region bordered by transposase pseudogenes and encodes a mixed modular polyketide synthase/nonribosomal peptide synthetase. Notably, none of the modules contains regions with homology to acyltransferase domains, but two copies of isolated monodomain acyltransferase genes were found at the upstream end of the cluster. In line with an involvement in pederin biosynthesis, the upstream cluster region perfectly mirrors pederin structure. The unexpected presence of additional polylketide synthase/nonribosomal peptide synthetase modules reveals surprising insights into the evolutionary relationship between pederintype pathways in beetles and sponges.