6SVM

Crystal structure of human GFAT-1 in complex with Glucose-6-Phosphate, L-Glu, and UDP-GalNAc

Summary for 6SVM

• Entry DOI: 10.2210/pdb6svm/pdb
• Descriptor: Glutamine--fructose-6-phosphate aminotransferase [isomerizing] 1, GLUCOSE-6-PHOSPHATE, GLUTAMIC ACID, ... (6 entities in total)
• Functional Keywords: glutamine fructose-6-phosphate aminotransferase, gfat, ntn hydrolase, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 157322.73

Authors

Ruegenberg, S.,Horn, M.,Pichlo, C.,Allmeroth, K.,Baumann, U.,Denzel, M.S. (deposition date: 2019-09-18, release date: 2020-01-15, Last modification date: 2024-01-24)

Primary citation

Ruegenberg, S.,Horn, M.,Pichlo, C.,Allmeroth, K.,Baumann, U.,Denzel, M.S.
Loss of GFAT-1 feedback regulation activates the hexosamine pathway that modulates protein homeostasis.
Nat Commun, 11:687-687, 2020

PubMed 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.

PubMed: 32019926
DOI: 10.1038/s41467-020-14524-5

Experimental method

X-RAY DIFFRACTION (2.481 Å)