Advances in metabolic engineering for enhanced acetyl-CoA availability in yeast

Acetyl-CoA is an intermediate metabolite in cellular central metabolism. It's a precursor for various valuable commercial products, including: terpenoids, fatty acids, and polyketides. With the advancement of metabolic and synthetic biology tools, microbial cell factories have been constructed for the efficient synthesis of acetyl-CoA and derivatives, with the Saccharomyces cerevisiae and Yarrowia lipolytica as two prominent chassis. This review summarized the recent developments in the biosynthetic pathways and metabolic engineering approaches for acetyl-CoA and its derivatives synthesis in these two yeasts. First, the metabolic routes involved in the biosynthesis of acetyl-CoA and derived products were outlined. Then, the advancements in metabolic engineering strategies for channeling acetyl-CoA toward the desired products were summarized, with particular emphasis on: enhancing metabolic flux in different organelles, refining precursor CoA synthesis, optimizing substrate utilization, and modifying protein acetylation level. Finally, future developments in advancing the metabolic engineering strategies for acetyl-CoA and related derivatives synthesis, including: reducing CO₂ emissions, dynamically regulating metabolic pathways, and exploring the regulatory functions between acetyl-CoA levels and protein acetylation, are highlighted. This review provided new insights into regulating acetyl-CoA synthesis to create more effective microbial cell factories for bio-manufacturing.