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

Nat Commun. 2021 Apr 12;12(1):2176. doi: 10.1038/s41467-021-22320-y.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution / genetics
  • Animals
  • Caenorhabditis elegans / enzymology*
  • Caenorhabditis elegans Proteins / chemistry
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Endoplasmic Reticulum Stress
  • Feedback, Physiological*
  • Gain of Function Mutation
  • Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / chemistry
  • Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / genetics
  • Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / metabolism*
  • Hexosamines / metabolism*
  • Kinetics
  • Phosphorylation
  • Protein Binding
  • Protein Domains
  • Serine / genetics
  • Uridine Diphosphate N-Acetylglucosamine / metabolism


  • Caenorhabditis elegans Proteins
  • Hexosamines
  • Serine
  • Uridine Diphosphate N-Acetylglucosamine
  • GFAT1 protein, C elegans
  • Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)
  • Cyclic AMP-Dependent Protein Kinases