Combining multiplex metabolic engineering with adaptive evolution strategies for high-level succinic acid production in Yarrowia lipolytica
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Succinic acid, an essential platform chemical with extensive utility in biodegradable materials, pharmaceuticals, and the food industry, faces challenges of high energy consumption and environmental pollution in traditional chemical synthesis. Here, we employed multiplex metabolic engineering and adaptive laboratory evolution to enhance succinic acid biosynthesis in Yarrowia lipolytica. By attenuating succinate dehydrogenase (Sdh) activity, mitigating by-product accumulation, and enhancing the succinate synthesis pathway, engineered strains showed efficient succinic acid production from glycerol. The titer reached 130.99 g/L under unregulated pH conditions, translating to a yield of 0.35 g/g and a productivity of 0.70 g/(L·h). Subsequently, transporter engineering and adaptive evolution strategies were applied to enhance glucose utilization for succinic acid synthesis, yielding an evolved strain that eliminated the growth lag phase and produced 106.68 g/L succinic acid from glucose, which translated to a yield of 0.32 g/g and a productivity of 0.64 g/(L·h). Additionally, transcriptomic analysis and inverse metabolic engineering revealed that 4-hydroxyphenylpyruvate dioxygenase (4-Hppd) in the tyrosine degradation pathway partially restored the growth of Sdh-deficient strains on glucose, offering new insights for subsequent succinic acid biomanufacturing using Y. lipolytica.
Date Issued
2026-03-01
Date Acceptance
2025-08-23
Citation
Synthetic and Systems Biotechnology, 2026, 11, pp.48-58
ISSN
2405-805X
Publisher
KeAi Communications Co., Ltd.
Start Page
48
End Page
58
Journal / Book Title
Synthetic and Systems Biotechnology
Volume
11
Copyright Statement
© 2025 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Subjects
Adaptive laboratory evolution
Biotechnology & Applied Microbiology
Inverse metabolic engineering
Life Sciences & Biomedicine
Science & Technology
Succinic acid
Transcriptomic analysis
Yarrowia lipolytica
Publication Status
Published
Date Publish Online
2025-08-30