Reprogramming Yarrowia lipolytica metabolism for efficient synthesis of itaconic acid from flask to semipilot scale
Journal article, 2024
Itaconic acid is an emerging platform chemical with extensive applications. Itaconic acid is currently produced by Aspergillus terreus through biological fermentation. However, A. terreus is a fungal pathogen that needs additional morphology controls, making itaconic acid production on industrial scale problematic. Here, we reprogrammed the Generally Recognized As Safe (GRAS) yeast Yarrowia lipolytica for competitive itaconic acid production. After preventing carbon sink into lipid accumulation, we evaluated itaconic acid production both inside and outside the mitochondria while fine-tuning its biosynthetic pathway. We then mimicked the regulation of nitrogen limitation in nitrogen-replete conditions by down-regulating NAD+-dependent isocitrate dehydrogenase through weak promoters, RNA interference, or CRISPR interference. Ultimately, we optimized fermentation parameters for fed-batch cultivations and produced itaconic acid titers of 130.1 grams per liter in 1-liter bioreactors and 94.8 grams per liter in a 50-liter bioreactor on semipilot scale. Our findings provide effective approaches to harness the GRAS microorganism Y. lipolytica for competitive industrial-scale production of itaconic acid.
Author
Jing Fu
Chalmers, Life Sciences, Systems and Synthetic Biology
Imperial College London
Simone Zaghen
Chalmers, Life Sciences, Systems and Synthetic Biology
Hongzhong Lu
State Key Laboratory of Microbial Metabolism
Oliver Konzock
Chalmers, Life Sciences, Systems and Synthetic Biology
Naghmeh Poorinmohammad
Chalmers, Life Sciences, Systems and Synthetic Biology
Alexander Kornberg
Student at Chalmers
R. Ledesma-Amaro
Imperial College London
Deni Koseto
Sintef Foundation for Scientific and Industrial Research At the Norwegian Institute of Technology
Alexander Wentzel
Sintef Foundation for Scientific and Industrial Research At the Norwegian Institute of Technology
Francesca Di Bartolomeo
Sintef Foundation for Scientific and Industrial Research At the Norwegian Institute of Technology
Eduard Kerkhoven
Novo Nordisk Foundation
Chalmers, Life Sciences, Systems and Synthetic Biology
Science advances
2375-2548 (eISSN)
Vol. 10 32 eadn0414-Subject Categories
Biochemistry and Molecular Biology
Microbiology
DOI
10.1126/sciadv.adn0414
PubMed
39121230