PT - JOURNAL ARTICLE AU - Kirk Smith AU - Fangzhou Shen AU - Ho Joon Lee AU - Sriram Chandrasekaran TI - Metabolic signatures of regulation by phosphorylation and acetylation AID - 10.1101/838243 DP - 2021 Jan 01 TA - bioRxiv PG - 838243 4099 - http://biorxiv.org/content/early/2021/06/03/838243.short 4100 - http://biorxiv.org/content/early/2021/06/03/838243.full AB - Acetylation and phosphorylation are highly conserved post-translational modifications (PTMs) that regulate cellular metabolism, yet how metabolic control is shared between these PTMs is unknown. Here we analyze transcriptome, proteome, acetylome, and phosphoproteome datasets in E.coli, S.cerevisiae, and mammalian cells across diverse conditions using CAROM, a new approach that uses genome-scale metabolic networks and machine-learning to classify regulation by PTMs. We built a single machine-learning model that accurately distinguished reactions controlled by each PTM in a condition across all three organisms based on reaction attributes (AUC>0.8). Our model uncovered enzymes regulated by phosphorylation during a mammalian cell-cycle, which we validate using phosphoproteomics. Interpreting the machine-learning model using game-theory uncovered enzyme properties including network connectivity, essentiality, and condition-specific factors such as maximum flux that differentiate regulation by phosphorylation from acetylation. The conserved and predictable partitioning of metabolic regulation identified here between these PTMs can enable rational engineering of regulatory circuits.Competing Interest StatementThe authors have declared no competing interest.