Xylose-Driven Metabolic Reprogramming in <i>Saccharomyces cerevisiae</i> for Enhancing <i>p</i>-Coumaric Acid Production

Xylose, the second most abundant sugar in nature, has garnered increasing attention as a promising carbon source for microbial fermentation in recent years. However, the unpredictable and inefficient metabolism of xylose in <i>Saccharomyces cerevisiae</i> has limited its practical application. In this study, we developed a xylotrophic strain through strategic integration of the xylose isomerase pathway, increasing xylose isomerase activity and identifying optimal transporters. Characterization of the modified strain demonstrated an 11.84-fold increase in ATP content under xylose conditions compared to glucose. This was achieved by redirecting carbon flux away from glycolysis, which resulted in a reduced level of ethanol and glycerol production. To demonstrate the industrial relevance of this platform, we applied the optimized strain to synthesize <i>p</i>-coumaric acid (<i>p</i>-CA). After process refinement, the strain achieved a final titer of 1293.15 mg/L <i>p</i>-CA using xylose as the sole carbon source, representing a 68.29% yield improvement compared to the glucose mode. To the best of our knowledge, this represents the highest reported to date for <i>p</i>-CA production from xylose alone. This study highlights the metabolic advantages of xylotrophic yeast and demonstrates the potential of leveraging these advantages for efficient <i>p</i>-CA synthesis, paving the way for the sustainable valorization of xylose into high-value natural products.