Biotechnology and Bioprocess Engineering 2024; 29(1): 129-140  
Enhanced fermentative γ‑aminobutyric acid production by a metabolic engineered Corynebacterium glutamicum
Jingbai Wen1 · Wanli Sun1 · Guihua Leng1 · Dan Li1 · Changyan Feng1 · Zhide Tian1 · Xin Wang1
1 College of Chemistry and Bioengineering, Yichun University, Jiangxi 336000, China
Correspondence to: Jingbai Wen
Received: July 7, 2023; Revised: October 16, 2023; Accepted: November 6, 2023; Published online: February 12, 2024.
© The Korean Society for Biotechnology and Bioengineering. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
γ-Aminobutyric acid (GABA) is a non-proteinogenic amino acid with important physiological functions, which has been widely used in food, pharmaceuticals, and polyamides production. The fermentative GABA production by Corynebacterium glutamicum was recognized as one of the most promising methods. However, the problems of low catalytic activity of the heterologously expressed glutamate decarboxylase (GAD) and the imbalanced carbon flux between cell growth and GABA synthesis severely limited the GABA production by C. glutamicum. This study applied combinational metabolic engineering and catalytic condition optimization strategies to solve these two major obstacles. The secretory expression of GAD was enhanced using a bicistronic-designed expression cassette. This bicistronic expression cassette was further triply inserted into the genome by substituting the ldhA, pqo, and ack genes, thus stabilizing the expression of GAD and reducing the accumulation of by-products of lactate and acetate. A growth-regulated promoter PCP_2836 was applied to dynamically control the expression of odhA, thus controlling the α-oxoglutarate dehydrogenase complex activity for balanced cell growth and GABA production. The glutamate precursor synthesis and pyridoxal 5′-phosphate supply were also strengthened by promoter substitution. Finally, through a two-stage pH-controlled fed-batch fermentation under optimized conditions, the engineered strain reached GABA titer of 81.31 ± 1.31 g/L with a yield and productivity of 0.50 ± 0.01 g/g and 1.36 ± 0.23 g L−1 h−1, which was 4.8%, 13.6%, and 11.2% higher than that of the original strain. This study laid a solid foundation for industrial fermentative GABA production by engineered C. glutamicum.
Keywords: γ-Aminobutyric acid · Corynebacterium glutamicum · Metabolic engineering · Glutamate decarboxylase

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