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Metabolic signatures of regulation by phosphorylation and acetylation

Kirk Smith, Fangzhou Shen, View ORCID ProfileHo Joon Lee, View ORCID ProfileSriram Chandrasekaran
doi: https://doi.org/10.1101/838243
Kirk Smith
1Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA, 48109
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Fangzhou Shen
1Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA, 48109
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Ho Joon Lee
3Department of Genetics, Yale University, New Haven, CT 06510, USA
4Yale Center for Genome Analysis, Yale University, New Haven, CT 06510, USA
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Sriram Chandrasekaran
1Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA, 48109
2Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA, 48109
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  • For correspondence: csriram@umich.edu
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Abstract

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.

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Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted June 03, 2021.
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Metabolic signatures of regulation by phosphorylation and acetylation
Kirk Smith, Fangzhou Shen, Ho Joon Lee, Sriram Chandrasekaran
bioRxiv 838243; doi: https://doi.org/10.1101/838243
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Metabolic signatures of regulation by phosphorylation and acetylation
Kirk Smith, Fangzhou Shen, Ho Joon Lee, Sriram Chandrasekaran
bioRxiv 838243; doi: https://doi.org/10.1101/838243

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