Protein kinase A controls the hexosamine pathway by tuning the feedback inhibition of GFAT-1
| Autor: | Ilian Atanassov, Felix A.M.C. Mayr, Ulrich Baumann, S. Ruegenberg, Martin S. Denzel |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Glycosylation Science Protein domain Glycobiology General Physics and Astronomy Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Protein Domains Serine Animals Amino Acid Sequence Phosphorylation Caenorhabditis elegans Caenorhabditis elegans Proteins Protein kinase A X-ray crystallography Glutamine amidotransferase Feedback Physiological Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) chemistry.chemical_classification Uridine Diphosphate N-Acetylglucosamine Multidisciplinary Hexosamines General Chemistry Endoplasmic Reticulum Stress Cyclic AMP-Dependent Protein Kinases Uridine Cell biology Glutamine carbohydrates (lipids) Kinetics 030104 developmental biology Enzyme Amino Acid Substitution chemistry Mutagenesis Gain of Function Mutation Enzyme mechanisms ddc:500 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021) Nature Communications 12(1), 2176 (2021). doi:10.1038/s41467-021-22320-y Nat Commun Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Nature Communications 12(1), 2176 (2021). 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. Published by Nature Publishing Group UK, [London] |
| Databáze: | OpenAIRE |
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