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Protein kinase A controls the hexosamine pathway by tuning the feedback inhibition of GFAT-1

Author

Listed:
  • Sabine Ruegenberg

    (Max Planck Institute for Biology of Ageing
    University of Cologne)

  • Felix A. M. C. Mayr

    (Max Planck Institute for Biology of Ageing)

  • Ilian Atanassov

    (Max Planck Institute for Biology of Ageing)

  • Ulrich Baumann

    (University of Cologne)

  • Martin S. Denzel

    (Max Planck Institute for Biology of Ageing
    University of Cologne
    University of Cologne)

Abstract

The hexosamine pathway (HP) is a key anabolic pathway whose product uridine 5’-diphospho-N-acetyl-D-glucosamine (UDP-GlcNAc) is an essential precursor for glycosylation processes in mammals. It modulates the ER stress response and HP activation extends lifespan in Caenorhabditis elegans. The highly conserved glutamine fructose-6-phosphate amidotransferase 1 (GFAT-1) is the rate-limiting HP enzyme. GFAT-1 activity is modulated by UDP-GlcNAc feedback inhibition and via phosphorylation by protein kinase A (PKA). Molecular consequences of GFAT-1 phosphorylation, however, remain poorly understood. Here, we identify the GFAT-1 R203H substitution that elevates UDP-GlcNAc levels in C. elegans. In human GFAT-1, the R203H substitution interferes with UDP-GlcNAc inhibition and with PKA-mediated Ser205 phosphorylation. Our data indicate that phosphorylation affects the interactions of the two GFAT-1 domains to control catalytic activity. Notably, Ser205 phosphorylation has two discernible effects: it lowers baseline GFAT-1 activity and abolishes UDP-GlcNAc feedback inhibition. PKA controls the HP by uncoupling the metabolic feedback loop of GFAT-1.

Suggested Citation

  • Sabine Ruegenberg & Felix A. M. C. Mayr & Ilian Atanassov & Ulrich Baumann & Martin S. Denzel, 2021. "Protein kinase A controls the hexosamine pathway by tuning the feedback inhibition of GFAT-1," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22320-y
    DOI: 10.1038/s41467-021-22320-y
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