Genome Mining of Streptomyces sp Tu 6176: Characterization of the Nataxazole Biosynthesis Pathway
Genome Mining of Streptomyces sp Tu 6176: Characterization of the Nataxazole Biosynthesis Pathway
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DOI：
10.1002/cbic.201500153
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发表时间：
2015-07-06
期刊：
影响因子：
3.2
通讯作者：
Olano, Carlos
中科院分区：
文献类型：
--
作者：
Cano-Prieto, Carolina;Garcia-Salcedo, Raul;Olano, Carlos
链霉菌属TU 6176生产具有细胞毒性的苯并恶唑他他唑。对该微生物基因组的生物信息学分析预测存在38个可能的次生代谢物生物合成基因簇，包括参与AJI9561及其衍生物他他唑、抗生素潮霉素B和离子载体enterobactin和coelibactin的生物合成的基因簇。鉴定和鉴定了他他唑生物合成基因簇：它缺乏将AJI9561转化为他他唑所需的O-甲基转移酶基因。这种O-甲基转移酶的活性可能是一种耐药机制，因为AJI9561显示出抗生素活性，而他他唑则没有活性。此外，他他唑生物合成基因簇在变铅青链霉菌JT46中的异源表达导致了AJI9561的产生。他他唑的生物合成需要莽草酸途径生成3-羟基邻氨基苯甲酸酯，需要I型PKS迭代生成6-甲基水杨酸。通过干扰该簇中的一个调控基因，他他唑的产量提高了四倍。链霉菌产生了另外一种苯并恶唑--5-羟基他恶唑。图6176。5-羟基他他唑是通过一种未知的加氧酶的活性从他他唑衍生而来的，这意味着他他唑的生物合成途径和未知途径之间存在串扰。
Streptomyces sp. Tu 6176 produces the cytotoxic benzoxazole nataxazole. Bioinformatic analysis of the genome of this organism predicts the presence of 38 putative secondary-metabolite biosynthesis gene clusters, including those involved in the biosynthesis of AJI9561 and its derivative nataxazole, the antibiotic hygromycin B, and ionophores enterobactin and coelibactin. The nataxazole biosynthesis gene cluster was identified and characterized: it lacks the O-methyltransferase gene required to convert AJI9561 into nataxazole. This O-methyltransferase activity might act as a resistance mechanism, as AJI9561 shows antibiotic activity whereas nataxazole is inactive. Moreover, heterologous expression of the nataxazole biosynthesis gene cluster in S. lividans JT46 resulted in the production of AJI9561. Nataxazole biosynthesis requires the shikimate pathway to generate 3-hydroxyanthranilate and an iterative type I PKS to generate 6-methylsalicylate. Production of nataxazole was improved up to fourfold by disrupting one regulatory gene in the cluster. An additional benzoxazole, 5-hydroxynataxazole is produced by Streptomyces sp. Tu 6176. 5-Hydroxynataxazole derives from nataxazole by the activity of an as yet unidentified oxygenase; this implies cross-talk between the nataxazole biosynthesis pathway and an unknown pathway.