Abstract
This study quantifies metabolic features of engineered Yarrowia lipolytica strains for converting volatile fatty acids (VFAs) into poly-3-hydroxybutyrate (PHB) via 13C-metabolic flux analysis and RNA-Seq. Yarrowia lipolytica is unable to grow with C4∼C6 VFAs due to substrate toxicity, while propionate (C3) metabolism leads to slow growth and minimal PHB production due to enzymatic limitations in substrate assimilation pathways. Acetate is a viable but challenging VFA feedstock. Comparing to glucose, acetate catabolism results in low ATP/ADP ratios, high enzyme usage, substantial CO2 release (>50% of input carbon), and limited NADPH. Several strategies may overcome these roadblocks: 1) glucose-VFA co-catabolism improves energy charge, alleviates metabolic imbalances, reduces flux rigidity, and lowers the enzyme expression burden; 2) overexpressing acetyl-CoA synthetase and nitrogen limitation increase acetate uptake and PHB synthesis during glucose-acetate co-utilization; and 3) repression of oxidase facilitates fluxes towards PHB synthesis. The results provide insights into efficient utilization of acetate as feedstock.
Published Version
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