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Extension of the substrate range is among one of the metabolic engineering goals for microorganisms used in biotechnological processes because it enables the use of a wide range of raw materials as substrates. One of the most prominent examples is the engineering of baker’s yeast  Saccharomyces cerevisiae  for the utilization of  d- xylose, a five-carbon sugar found in high abundance in lignocellulosic biomass and a key substrate to achieve good process economy in chemical production from renewable and non-edible plant feedstocks. Despite many excellent engineering strategies that have allowed recombinant  S. cerevisiae  to ferment  d- xylose to ethanol at high yields, the consumption rate of  d -xylose is still significantly lower than that of its preferred sugar  d -glucose. In mixed  d -glucose/ d -xylose cultivations,  d -xylose is only utilized after  d -glucose depletion, which leads to prolonged process times and added costs. Due to this limitation, the response on  d -xylose in the native sugar signaling pathways has emerged as a promising next-level engineering target. Here we review the current status of the knowledge of the response of  S. cerevisiae  signaling pathways to  d -xylose. To do this, we first summarize the response of the native sensing and signaling pathways in  S. cerevisiae  to  d -glucose (the preferred sugar of the yeast). Using the  d -glucose case as a point of reference, we then proceed to discuss the known signaling response to  d -xylose in  S. cerevisiae  and current attempts of improving the response by signaling engineering using native targets and synthetic (non-native) regulatory circuits.

D-Xylose Sensing in Saccharomyces cerevisiae: Insights from D-Glucose Signaling and Native D-Xylose Utilizers