ArticleNature communications2020
Loss of GFAT-1 feedback regulation activates the hexosamine pathway that modulates protein homeostasis.
Article in Nature communications, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 69 citations in OpenAlex.
- Hexosamine Biosynthetic Pathway and Fatty Acid β-Oxidative Imbalance: A Key Mechanism by Which Abnormal Macrophage Lipophagy Promotes Atherosclerosis in Diabetes.Cardiovascular drugs and therapy · 2026Review
- Review of Congenital Myasthenic Syndrome Caused by Pathogenic Variants in GFPT1.Muscle & nerve · 2026Review
- Glutamine: fructose-6-phosphate amidotransferase (GFAT) in the pathology of diseases: a review.Cell death discovery · 2025Review
- PFKFB2 Is Pivotal for Metabolic Flexibility and Differential Glucose Utilization.Journal of the American Heart Association · 2025Article
- Crystal structures of Salmonella enterica FraB deglycase reveal a conformational heterodimer with remarkable structural plasticity at the active site.Protein science : a publication of the Protein Society · 2025Article
- "Heptadecanol" a phytochemical multi-target inhibitor of SMYD3 & GFPT2 proteins in non-small cell lung cancer: an in-silico & in-vitro investigation.Journal of computer-aided molecular design · 2025Article
- Crosstalk between O-GlcNAcylation and phosphorylation in metabolism: regulation and mechanism.Cell death and differentiation · 2025Review
- Gfa1 (glutamine fructose-6-phosphate aminotransferase) is essential for Aspergillus fumigatus growth and virulence.BMC biology · 2025Article
- The role of protein O-GlcNAcylation in diabetic cardiomyopathy.Biochemical Society transactions · 2024Review
- An Optimized Marinopyrrole A Derivative Targets 6-Phosphoglucosamine Synthetase to Inhibit Methicillin-ResistantACS central science · 2024Article
- GFPT2: A novel biomarker in mesothelioma for diagnosis and prognosis and its molecular mechanism in malignant progression.British journal of cancer · 2024Article
- O-GlcNAcylation mediates Wnt-stimulated bone formation by rewiring aerobic glycolysis.EMBO reports · 2024Article
- Isocyanides inhibit bacterial pathogens by covalent targeting of essential metabolic enzymes.Chemical science · 2024Article
- Discovery of metal-binding proteins by thermal proteome profiling.Nature chemical biology · 2024Article
- Regulation of protein O-GlcNAcylation by circadian, metabolic, and cellular signals.The Journal of biological chemistry · 2024Review
- O-GlcNAcylation in ischemic diseases.Frontiers in pharmacology · 2024Review
- Splicing regulation of GFPT1 muscle-specific isoform and its roles in glucose metabolisms and neuromuscular junction.iScience · 2023Article
- Protective Effect and Mechanism of Xbp1s Regulating HBP/O-GlcNAcylation through GFAT1 on Brain Injury after SAH.Biomedicines · 2023Article
- Review
- The UDPase ENTPD5 regulates ER stress-associated renal injury by mediating protein N-glycosylation.Cell death & disease · 2023Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Glutamine fructose-6-phosphate amidotransferase (GFAT) is the key enzyme in the hexosamine pathway (HP) that produces uridine 5'-diphospho-N-acetyl-D-glucosamine (UDP-GlcNAc), linking energy metabolism with posttranslational protein glycosylation. In Caenorhabditis elegans, we previously identified gfat-1 gain-of-function mutations that elevate UDP-GlcNAc levels, improve protein homeostasis, and extend lifespan. GFAT is highly conserved, but the gain-of-function mechanism and its relevance in mammalian cells remained unclear. Here, we present the full-length crystal structure of human GFAT-1 in complex with various ligands and with important mutations. UDP-GlcNAc directly interacts with GFAT-1, inhibiting catalytic activity. The longevity-associated G451E variant shows drastically reduced sensitivity to UDP-GlcNAc inhibition in enzyme activity assays. Our structural and functional data point to a critical role of the interdomain linker in UDP-GlcNAc inhibition. In mammalian cells, the G451E variant potently activates the HP. Therefore, GFAT-1 gain-of-function through loss of feedback inhibition constitutes a potential target for the treatment of age-related proteinopathies.
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