Engineering a Balanced Acetyl Coenzyme A Metabolism in Saccharomyces cerevisiae for Lycopene Production through Rational and Evolutionary Engineering

• Published in: Journal of agricultural and food chemistry Vol. 70; no. 13; pp. 4019 - 4029
• Main Authors: Su, Buli, Lai, Peixuan, Yang, Fan, Li, Anzhang, Deng, Ming-Rong, Zhu, Honghui
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 06.04.2022
• Subjects: acetaldehyde dehydrogenase; acetyl coenzyme A; Acetyl Coenzyme A - metabolism; acetyl-CoA acetyltransferase; acetyl-CoA carboxylase; Biotechnology and Biological Transformations; food chemistry; lycopene; Lycopene - metabolism; Metabolic Engineering - methods; metabolism; mevalonic acid; Mevalonic Acid - metabolism; Saccharomyces cerevisiae; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; dynamic regulation; 2A peptide; acetyl-CoA; acetyl-CoA carboxylase; cho2
• ISSN: 0021-8561; 1520-5118; 1520-5118
• DOI: 10.1021/acs.jafc.2c00531

Saccharomyces cerevisiae is increasingly being used for the production of chemicals derived from acetyl coenzyme A (acetyl-CoA). However, the inadequate supply of cytosolic acetyl-CoA often leads to low yields. Here, we developed a novel strategy for balancing acetyl-CoA metabolism and increasing the amount of the downstream product. First, the combination of acetaldehyde dehydrogenase (eutE) and acetoacetyl-CoA thiolase (AtoB) was optimized to redirect the acetyl-CoA flux toward the target pathway, with a 21-fold improvement in mevalonic acid production. Second, pathway engineering and evolutionary engineering were conducted to attenuate the growth deficiency, and a 10-fold improvement of the maximum productivity was achieved. Third, acetyl-CoA carboxylase (ACC1) was dynamically downregulated as the complementary acetyl-CoA pathway, and the yield was improved more than twofold. Fourth, the most efficient and complementary acetyl-CoA pathways were combined, and the final strain produced 68 mg/g CDW lycopene, which was among the highest yields reported in S. cerevisiae. This study demonstrates a new method of producing lycopene products by regulating acetyl-CoA metabolism.