Yeast-MetaTwin for Systematically Exploring Yeast Metabolism through Retrobiosynthesis and Deep Learning

Underground metabolism plays a crucial role in understanding enzyme promiscuity, cellular metabolism, and biological evolution, yet experimental exploration of underground metabolism is often sparse. Even though yeast genome-scale metabolic models have been reconstructed and curated for over 20 years, more than 90% of the yeast metabolome is still not covered by these models. To address this gap, we have developed a workflow based on retrobiosynthesis and deep learning methods to comprehensively explore yeast underground metabolism. We integrated the predicted underground network into the yeast consensus genome-scale model, Yeast8, to reconstruct the yeast metabolic twin model, Yeast-MetaTwin, covering 16,244 metabolites (92% of the total yeast metabolome), 2,057 metabolic genes and 59,914 reactions. We revealed that Km parameters differ between the known and underground network, identified hub molecules connecting the underground network and pinpointed the underground percentages for yeast metabolic pathways. Moreover, the Yeast-MetaTwin can predict the by-products of chemicals produced in yeast, offering valuable insights to guide metabolic engineering designs.