Identification of the common biosynthetic gene cluster for both antimicrobial streptoaminals and antifungal 5-alkyl-1,2,3,4-tetrahydroquinolines
Identification of the common biosynthetic gene cluster for both antimicrobial streptoaminals and antifungal 5-alkyl-1,2,3,4-tetrahydroquinolines
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DOI：
10.1039/c8ob02846j
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发表时间：
2019-03-07
影响因子：
3.2
通讯作者：
Onaka, Hiroyasu
中科院分区：
文献类型：
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作者：
Ozaki, Taro;Sugiyama, Ryosuke;Onaka, Hiroyasu
5-烷基-1，2，3，4-四氢喹啉（5aTHQs）和链胺醛（STAMs）是从变黑链霉菌HEK 616和肺冢丘菌TP-B 0596的混合培养物中分离得到的天然产物。尽管其结构独特，但其生物合成途径尚未阐明。在本研究中，我们使用C-13标记的乙酸盐进行了饲养实验，并证明了5aTHQs可能是通过聚酮合酶（PKS）的作用合成的。基于这一观察，我们鉴定了5aTHQs的生物合成基因簇。有趣的是，相同的基因簇也负责结构不同的STAM。该基因簇包含9个基因，编码一个酰基载体蛋白，两组酮基转移酶（KS）和链长因子（CLF），一个氨基转移酶/还原酶双功能蛋白，两个酮还原酶，和一个硫酯酶。KS和CLF被分类为与已知的II型PKS不同的进化枝。异源表达的生物合成基因和随后的基因失活清楚地表明，所有的9个基因所需的两种化合物的生物合成。在拟议的生物合成途径中，链延长PKS，还原裂解的硫酯键，和随后的转氨基生成的核心骨架的两种化合物。产物的氧化态的差异导致不同的环化模式以产生5aTHQs和STAM。
5-Alkyl-1,2,3,4-tetrahydroquinolines (5aTHQs) and streptoaminals (STAMs) are natural products isolated from the combined-culture of Streptomyces nigrescens HEK616 and Tsukamurella pulmonis TP-B0596. Despite their unique structures, their biosynthetic pathway has yet to be elucidated. In the present study, we conducted a feeding experiment using C-13-labeled acetates and demonstrated that 5aTHQs are likely synthesized by the action of polyketide synthase (PKS). Based on this observation, we identified the biosynthetic gene cluster for 5aTHQs. Interestingly, the same gene cluster was also responsible for the structurally-distinct STAMs. The gene cluster contains nine genes encoding one acyl carrier protein, two sets of ketosynthases (KSs) and chain length factors (CLFs), one aminotransferase/reductase bifunctional protein, two ketoreductases, and one thioesterase. KSs and CLFs are classified into the phylogenetically distinct clades from those of known type II PKSs. Heterologous expression of the biosynthetic genes and subsequent gene inactivation clearly indicated that all of the nine genes were required for the biosynthesis of both compounds. In the proposed biosynthetic pathway, chain elongation by PKS, reductive cleavage of a thioester bond, and subsequent transamination generate the core skeleton of both compounds. Differences in the oxidation states of the products result in a distinct cyclization mode to yield 5aTHQs and STAMs.