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Structural and systems characterization of phosphorylation on metabolic enzymes identifies sex-specific metabolic reprogramming in obesity.
Tamir, Tigist Y; Chaudhary, Shreya; Li, Annie X; Trojan, Sonia E; Flower, Cameron T; Vo, Paula; Cui, Yufei; Davis, Jeffrey C; Mukkamala, Rachit S; Venditti, Francesca N; Hillis, Alissandra L; Toker, Alex; Vander Heiden, Matthew G; Spinelli, Jessica B; Kennedy, Norman J; Davis, Roger J; White, Forest M.
Afiliación
  • Tamir TY; Koch Institute for Integrative Cancer Research.
  • Chaudhary S; Center for Precision Cancer Medicine.
  • Li AX; Department of Biological Engineering.
  • Trojan SE; Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Flower CT; Koch Institute for Integrative Cancer Research.
  • Vo P; Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Cui Y; Koch Institute for Integrative Cancer Research.
  • Davis JC; Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Mukkamala RS; Koch Institute for Integrative Cancer Research.
  • Venditti FN; Department of Biology.
  • Hillis AL; Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Toker A; Koch Institute for Integrative Cancer Research.
  • Vander Heiden MG; Center for Precision Cancer Medicine.
  • Spinelli JB; Program in Computational and Systems Biology.
  • Kennedy NJ; Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Davis RJ; Dana-Farber Cancer Institute, Boston, MA, USA.
  • White FM; Koch Institute for Integrative Cancer Research.
bioRxiv ; 2024 Aug 29.
Article en En | MEDLINE | ID: mdl-39257804
ABSTRACT
Coordination of adaptive metabolism through cellular signaling networks and metabolic response is essential for balanced flow of energy and homeostasis. Post-translational modifications such as phosphorylation offer a rapid, efficient, and dynamic mechanism to regulate metabolic networks. Although numerous phosphorylation sites have been identified on metabolic enzymes, much remains unknown about their contribution to enzyme function and systemic metabolism. In this study, we stratify phosphorylation sites on metabolic enzymes based on their location with respect to functional and dimerization domains. Our analysis reveals that the majority of published phosphosites are on oxidoreductases, with particular enrichment of phosphotyrosine (pY) sites in proximity to binding domains for substrates, cofactors, active sites, or dimer interfaces. We identify phosphosites altered in obesity using a high fat diet (HFD) induced obesity model coupled to multiomics, and interrogate the functional impact of pY on hepatic metabolism. HFD induced dysregulation of redox homeostasis and reductive metabolism at the phosphoproteome and metabolome level in a sex-specific manner, which was reversed by supplementing with the antioxidant butylated hydroxyanisole (BHA). Partial least squares regression (PLSR) analysis identified pY sites that predict HFD or BHA induced changes of redox metabolites. We characterize predictive pY sites on glutathione S-transferase pi 1 (GSTP1), isocitrate dehydrogenase 1 (IDH1), and uridine monophosphate synthase (UMPS) using CRISPRi-rescue and stable isotope tracing. Our analysis revealed that sites on GSTP1 and UMPS inhibit enzyme activity while the pY site on IDH1 induces activity to promote reductive carboxylation. Overall, our approach provides insight into the convergence points where cellular signaling fine-tunes metabolism.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos