Nature Chemical Biology ( IF 12.9 ) Pub Date : 2019-01-14 , DOI: 10.1038/s41589-018-0203-4
Yeon Hee Ban 1 , Myoung Chong Song 1 , Jae-Yeon Hwang 1 , Hea-Lyung Shin 1 , Hak Joong Kim 2 , Seung Kon Hong 1 , Na Joon Lee 3 , Je Won Park 4 , Sun-Shin Cha 1 , Hung-Wen Liu 2 , Yeo Joon Yoon 1
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Gentamicin B (GB), a valuable starting material for the preparation of the semisynthetic aminoglycoside antibiotic isepamicin, is produced in trace amounts by the wild-type Micromonospora echinospora. Though the biosynthetic pathway to GB has remained obscure for decades, we have now identified three hidden pathways to GB production via seven hitherto unknown intermediates in M. echinospora. The narrow substrate specificity of a key glycosyltransferase and the C6′-amination enzymes, in combination with the weak and unsynchronized gene expression of the 2′-deamination enzymes, limits GB production in M. echinospora. The crystal structure of the aminotransferase involved in C6′-amination explains its substrate specificity. Some of the new intermediates displayed similar premature termination codon readthrough activity but with reduced toxicity compared to the natural aminoglycoside G418. This work not only led to the discovery of unknown biosynthetic routes to GB, but also demonstrated the potential to mine new aminoglycosides from nature for drug discovery.
中文翻译:
![](https://scdn.x-mol.com/jcss/images/paperTranslation.png)
庆大霉素B生物合成的各种途径的完全重建。
庆大霉素B(GB)是用于制备半合成氨基糖苷类抗生素异帕米星的有价值的起始原料,它是由野生型Micromonospora echinospora微量生产的。尽管数十年来GB的生物合成途径一直不为人所知,但我们现在已经通过棘孢棘孢菌中的七个迄今未知的中间体鉴定出了三个隐藏的GB产生途径。一个关键糖基转移酶和C6'-胺化的酶,在与2'-脱氨酶的弱和非同步的基因表达组合的窄的底物特异性,限制了GB生产M.棘。参与C6'氨基化的氨基转移酶的晶体结构说明了其底物特异性。与天然氨基糖苷G418相比,某些新中间体显示出相似的过早终止密码子通读活性,但毒性降低。这项工作不仅导致发现了通往GB的未知生物合成途径,而且证明了从自然界开采新的氨基糖苷类药物的潜力。