The cycloaspeptides: uncovering a new model for methylated nonribosomal peptide biosynthesis.
The cycloaspeptides: uncovering a new model for methylated nonribosomal peptide biosynthesis.
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DOI：
10.1039/c8sc00717a
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发表时间：
2018-05-07
期刊：
影响因子：
8.4
通讯作者：
Bailey AM
中科院分区：
文献类型：
--
作者：
de Mattos-Shipley KMJ;Greco C;Heard DM;Hough G;Mulholland NP;Vincent JL;Micklefield J;Simpson TJ;Willis CL;Cox RJ;Bailey AM
环肽基因簇包括途径特异性N-甲基转移酶。它的破坏允许掺入培养基中提供的 N-甲基化氨基酸，从而能够有效生产环肽 E 和新型相关产品。环冬肽是由各种丝状真菌产生的具有生物活性的五肽，由于其次要代谢物环肽E的杀虫活性而引起了农业界的兴趣。基因组测序、生物信息学和异源表达证实环冬肽基因簇含有最小的5模块非核糖体肽合成酶（NRPS）和新型反式作用N-甲基转移酶(N-MeT)。 N-MeT 编码基因的删除和随后的喂养研究确定 NRPS 的两个模块优先接受并掺入 N-甲基化氨基酸。这一发现使得能够开发出一种对底物供应和产量进行前所未有的控制的系统，既增加了特定代谢物的产量，又允许生产新型氟化类似物。此外，另一种真菌非核糖体肽二色苯丙氨酸的生物合成途径也被证明是相似的，因为甲基化苯丙氨酸被二色苯丙氨酸NRPS所接受。同样，这允许通过喂养突变菌株来定向生物合成氟化类似物。这些发现代表了通过选择性掺入 N-甲基化游离氨基酸来生产 N-甲基化环肽的新范例。
The cycloaspeptide gene cluster includes a pathway-specific N-methyl transferase. Its disruption allowed incorporation of N-methylated amino acids provided in the culture medium, allowing efficient production of cycloaspeptide E and novel related products. The cycloaspeptides are bioactive pentapeptides produced by various filamentous fungi, which have garnered interest from the agricultural industry due to the reported insecticidal activity of the minor metabolite, cycloaspeptide E. Genome sequencing, bioinformatics and heterologous expression confirmed that the cycloaspeptide gene cluster contains a minimal 5-module nonribosomal peptide synthetase (NRPS) and a new type of trans-acting N-methyltransferase (N-MeT). Deletion of the N-MeT encoding gene and subsequent feeding studies determined that two modules of the NRPS preferentially accept and incorporate N-methylated amino acids. This discovery allowed the development of a system with unprecedented control over substrate supply and thus output, both increasing yields of specific metabolites and allowing the production of novel fluorinated analogues. Furthermore, the biosynthetic pathway to ditryptophenaline, another fungal nonribosomal peptide, was shown to be similar, in that methylated phenylalanine is accepted by the ditryptophenaline NRPS. Again, this allowed the directed biosynthesis of a fluorinated analogue, through the feeding of a mutant strain. These discoveries represent a new paradigm for the production of N-methylated cyclic peptides via the selective incorporation of N-methylated free amino acids.
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影响因子：
14.8
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