Manipulation of IME4 expression, a global regulation strategy for metabolic engineering in Saccharomyces cerevisiae.
10.1016/j.apsb.2023.01.002
- Author:
Jianxun ZHU
1
;
Tianyue AN
2
;
Wenlong ZHA
1
;
Ke GAO
2
;
Ting LI
2
;
Jiachen ZI
1
Author Information
1. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, CAMS Key Laboratory of Enzyme and Biocatalysis of Natural Drugs, and NHC Key Laboratory of Biosynthesis of Natural Products, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
2. College of Pharmacy, Jinan University, Guangzhou 510632, China.
- Publication Type:Journal Article
- Keywords:
Aromatic compounds;
Isoprenoids;
Metabolic engineering;
RNA m6A modification;
Saccharomyces cerevisiae
- From:
Acta Pharmaceutica Sinica B
2023;13(6):2795-2806
- CountryChina
- Language:English
-
Abstract:
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.
