New Simocyclinones: Surprising Evolutionary and Biosynthetic Insights
New Simocyclinones: Surprising Evolutionary and Biosynthetic Insights
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DOI：
10.1021/acschembio.5b00669
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发表时间：
2016-01-01
影响因子：
4
通讯作者：
Luzhetskyy, Andriy
中科院分区：
文献类型：
--
作者：
Bilyk, Oksana;Broetz, Elke;Luzhetskyy, Andriy
Simocyclinone D8 （1, SD8）因其高度复杂的杂化结构和通过阻止DNA结合抑制细菌DNA回转酶的独特方式而备受关注。虽然先前提出了一种解释西莫环酮生物合成的假设，但由于产生菌株的遗传不可接近性，很少在体内得到证实。本文报道了在Kitasatospora sp.和Streptomyces sp. NRRL B-24484中发现的3个新的d型simocyclinone (D9、D10和D11)，并对其生物合成基因簇进行了鉴定和注释。出乎意料的是，新发现的生物合成基因簇的排列与之前发表的基因簇截然不同，尽管D8和D9的结构几乎相同。基因失活和表达研究已经证明了模块化聚酮合成酶（PKS）系统在线性二羧酸组装中的作用。相反，新的独立酮合酶基因被证明参与了四烯链的生物合成。此外，我们确定了负责将西莫环酮D9 （2,sd9）转化为D8的基因。
Simocyclinone D8 (1, SD8) has attracted attention due to its highly complex hybrid structure and the unusual way it inhibits bacterial DNA gyrase by preventing DNA binding to the enzyme. Although a hypothesis explaining simocyclinone biosynthesis has been previously proposed, little was proven in vivo due to the genetic inaccessibility of the producer strain. Herein, we report discovery of three new D-type simocyclinones (D9, D10, and D11) produced by Kitasatospora sp. and Streptomyces sp. NRRL B-24484, as well as the identification and annotation of their biosynthetic gene clusters. Unexpectedly, the arrangement of the newly discovered biosynthetic gene clusters is starkly different from the previously published one, despite the nearly identical structures of D8 and D9 simocyclinones. The gene inactivation and expression studies have disproven the role of a modular polyketide synthase (PKS) system in the assembly of the linear dicarboxylic acid. Instead, the new stand-alone ketosynthase genes were shown to be involved in the biosynthesis of the tetraene chain. Additionally, we identified the gene responsible for the conversion of simocyclinone D9 (2, SD9) into D8.