The cycloaspeptides: uncovering a new model for methylated nonribosomal peptide biosynthesis†,Chemical Science

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The cycloaspeptides: uncovering a new model for methylated nonribosomal peptide biosynthesis†
Chemical Science ( IF 7.6 ) Pub Date : 2018-04-10 00:00:00 , DOI: 10.1039/c8sc00717a
Kate M. J. de Mattos-Shipley _{1,

2,

3,

4} , Claudio Greco _{1,

2,

3,

4} , David M. Heard _{1,

2,

3,

4} , Gemma Hough _{4,

5,

6} , Nicholas P. Mulholland _{4,

5,

6} , Jason L. Vincent _{4,

5,

6} , Jason Micklefield _{1,

4,

7,

8} , Thomas J. Simpson _{1,

2,

3,

4} , Christine L. Willis _{1,

2,

3,

4} , Russell J. Cox _{9,

10,

11,

12,

13} , Andrew M. Bailey _{2,

3,

4,

14}

Affiliation

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.

中文翻译：

环肽：发现甲基化非核糖体肽生物合成的新模型†

环肽是由各种丝状真菌产生的具有生物活性的五肽，由于报道了次要代谢物环肽E的杀虫活性，已引起农业界的兴趣。基因组测序，生物信息学和异源表达证实环肽基因簇中至少含有5种-module非核糖体肽合成酶（NRPS）和新类型的反式作用ñ -methyltransferase（ñ -Met）。删除N -MeT编码基因并随后进行喂养研究，确定NRPS的两个模块优先接受并掺入N-甲基化氨基酸。这一发现使系统的开发可以对底物的供应和输出进行前所未有的控制，既可以提高特定代谢产物的产量，又可以生产新型的氟化类似物。此外，显示出另一种真菌性非核糖体肽双色芬那碱的生物合成途径相似，因为双色芬那林NRPS接受甲基化的苯丙氨酸。再次，这允许通过馈入突变体菌株来直接进行氟化类似物的生物合成。这些发现代表了通过选择性掺入N-甲基化的游离氨基酸来生产N-甲基化的环肽的新范例。

更新日期：2018-04-10

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