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Exploring Fungal Polyketide C-Methylation through Combinatorial Domain Swaps
ACS Chemical Biology ( IF 4 ) Pub Date : 2018-10-23 00:00:00 , DOI: 10.1021/acschembio.8b00429
Philip A. Storm 1 , Paramita Pal 1 , Callie R. Huitt-Roehl 1 , Craig A. Townsend 1
Affiliation  

Polyketide C-methylation occurs during a programmed sequence of dozens of reactions carried out by multidomain polyketide synthases (PKSs). Fungal PKSs perform these reactions iteratively, where a domain may be exposed to and act upon multiple enzyme-tethered intermediates during biosynthesis. We surveyed a collection of C-methyltransferase (CMeT) domains from nonreducing fungal PKSs to gain insight into how different methylation patterns are installed. Our in vitro results show that control of methylation resides primarily with the CMeT, and CMeTs can intercept and methylate intermediates from noncognate nonreducing PKS domains. Furthermore, the methylation pattern is likely imposed by a competition between methylation or ketosynthase-catalyzed extension for each intermediate. Understanding site-specific polyketide C-methylation may facilitate targeted C–C bond formation in engineered biosynthetic pathways.

中文翻译:

通过组合域交换研究真菌聚酮化合物C-甲基化

聚酮化合物C-甲基化发生在由多域聚酮化合物合酶(PKS)进行的数十个反应的程序化序列中。真菌PKS反复进行这些反应,在生物合成过程中,结构域可能会暴露于多种酶链连接的中间体并对其起作用。我们调查了来自非还原性真菌PKS的C-甲基转移酶(CMeT)域的集合,以了解如何安装不同的甲基化模式。我们的体外结果表明,甲基化的控制主要在于CMeT,而CMeTs可以拦截非甲基化非还原性PKS结构域的中间体并使之甲基化。此外,甲基化模式可能是由于每种中间体的甲基化或酮合酶催化的延伸之间的竞争所引起的。了解特定位置的聚酮化合物的C-甲基化可能有助于在工程化的生物合成途径中形成有针对性的C–C键。
更新日期:2018-10-23
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