Metabolic engineering has been widely used for production of natural medicinal molecules. However, engineering high-yield platforms is hindered in large part by limited knowledge of complex regulatory machinery of metabolic network. N⁶-Methyladenosine (m⁶A) modification of RNA plays critical roles in regulation of gene expression. Herein, we identify 1470 putatively m⁶A peaks within 1151 genes from the haploid Saccharomyces cerevisiae strain. Among them, the transcript levels of 94 genes falling into the pathways which are frequently optimized for chemical production, are remarkably altered upon overexpression of IME4 (the yeast m⁶A methyltransferase). In particular, IME4 overexpression elevates the mRNA levels of the methylated genes in the glycolysis, acetyl-CoA synthesis and shikimate/aromatic amino acid synthesis modules. Furthermore, ACS1 and ADH2, two key genes responsible for acetyl-CoA synthesis, are induced by IME4 overexpression in a transcription factor-mediated manner. Finally, we show IME4 overexpression can significantly increase the titers of isoprenoids and aromatic compounds. Manipulation of m⁶A therefore adds a new layer of metabolic regulatory machinery and may be broadly used in bioproduction of various medicinal molecules of terpenoid and phenol classes.

代谢工程已广泛用于天然药物分子的生产。然而，设计高产平台在很大程度上受到对代谢网络复杂调节机制的有限了解的阻碍。RNA 的N ⁶ -甲基腺苷 (m ⁶ A) 修饰在基因表达调控中发挥着关键作用。在此，我们在单倍体酿酒酵母菌株的 1151 个基因中鉴定出 1470 个推定的 m ⁶ A 峰。其中，属于经常为化学生产而优化的途径的 94 个基因的转录水平在 IME4 过表达后显着改变（酵母 m ⁶甲基转移酶）。特别是，IME4 过表达会提高糖酵解、乙酰辅酶A 合成和莽草酸/芳香氨基酸合成模块中甲基化基因的 mRNA 水平。此外，负责乙酰辅酶A合成的两个关键基因ACS1和ADH2是由IME4以转录因子介导的方式过度表达诱导的。最后，我们发现 IME4 过表达可以显着增加类异戊二烯和芳香族化合物的滴度。因此， m ⁶ A 的操作增加了一层新的代谢调节机制，可广泛用于萜类和酚类各种药用分子的生物生产。