Manipulation of IME4 expression, a global regulation strategy for metabolic engineering in Saccharomyces cerevisiae

作     者：Jianxun Zhu Tianyue An Wenlong Zha Ke Gao Ting Li Jiachen Zi Jianxun Zhu;Tianyue An;Wenlong Zha;Ke Gao;Ting Li;Jiachen Zi

作者机构：State Key Laboratory of Bioactive Substance and Function of Natural MedicinesCAMS Key Laboratory of Enzyme and Biocatalysis of Natural Drugsand NHC Key Laboratory of Biosynthesis of Natural ProductsInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China College of PharmacyJinan UniversityGuangzhou 510632China 

出 版 物：《药学学报:英文版》 (Acta Pharmaceutica Sinica B)

年 卷 期：2023年第13卷第6期

页      面：2795-2806页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 07[理学] 070303[理学-有机化学] 0703[理学-化学] 

基　　金：supported by the National Key Research and Development Program of China [2022YFF1100304 (2022YFF1100300), China] National Natural Science Foundation of China [82293682 (82293680), China] Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2021-RC350-009, China) the CAMS Innovation Fund for Medical Sciences (2021-I2M-1-029, China)。 

主　　题：RNA m^(6)A modification Metabolic engineering Saccharomyces cerevisiae Isoprenoids Aromatic compounds 

摘      要：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. N~6-Methyladenosine(m^(6)A) modification of RNA plays critical roles in regulation of gene expression. Herein, we identify 1470 putatively m^(6)A 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 m^(6)A 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 m^(6)A 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.