Genome Mining Reveals a Minimum Gene Set for the Biosynthesis of 32-Membered Macrocyclic Thiopeptides Lactazoles
Genome Mining Reveals a Minimum Gene Set for the Biosynthesis of 32-Membered Macrocyclic Thiopeptides Lactazoles
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DOI：
10.1016/j.chembiol.2014.03.008
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发表时间：
2014-05-22
影响因子：
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通讯作者：
Onaka, Hiroyasu
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文献类型：
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作者：
Hayashi, Shohei;Ozaki, Taro;Onaka, Hiroyasu
虽然已经发现了100个硫肽，但参与其生物合成的经过验证的基因簇的数量是滞后的。我们使用基因组挖掘来鉴定一个沉默的硫肽生物合成基因簇，负责内酰胺唑的生物合成。内酰胺唑是一种结构独特的硫肽，具有32元大环和2-恶唑-6-噻唑吡啶核。我们证明了内酰胺唑起源于最简单的簇，只包含6个单向基因（lazA到lazF）。我们发现lazC参与了大环化过程，导致中心吡啶部分的形成。用强启动子替代内源性启动子导致lactazole a产量增加约30倍，并且在两种类似物的生产中导致lazC前体基因突变。乳酸唑类不具有抗菌活性，但可能调节骨形态发生蛋白引发的信号级联反应。我们的方法有助于生产更多样化的硫肽结构，增加药物开发中使用的半合成曲目。
Although >100 thiopeptides have been discovered, the number of validated gene clusters involved in their biosynthesis is lagging. We use genome mining to identify a silent thiopeptide biosynthetic gene cluster responsible for biosynthesis of lactazoles. Lactazoles are structurally unique thiopeptides with a 32-membered macrocycle and a 2-oxazolyl-6-thiazolyl pyridine core. We demonstrate that lactazoles originate from the simplest cluster, containing only six unidirectional genes (lazA to lazF). We show that lazC is involved in the macrocyclization process, leading to central pyridine moiety formation. Substitution of the endogenous promoter with a strong promoter results in an approximately 30-fold increase in lactazole A production and mutagenesis of lazC precursor gene in production of two analogs. Lactazoles do not exhibit antimicrobial activity but may modulate signaling cascades triggered by bone morphogenetic protein. Our approach facilitates the production of a more diverse set of thiopeptide structures, increasing the semisynthetic repertoire for use in drug development.