Loss of GFAT-1 feedback regulation activates the hexosamine pathway that modulates protein homeostasis

Sabine Ruegenberg, Moritz Horn, Christian Pichlo, Kira Allmeroth, Ulrich Baumann () and Martin S. Denzel ()
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Sabine Ruegenberg: Max Planck Institute for Biology of Ageing
Moritz Horn: Max Planck Institute for Biology of Ageing
Christian Pichlo: Institute of Biochemistry
Kira Allmeroth: Max Planck Institute for Biology of Ageing
Ulrich Baumann: Institute of Biochemistry
Martin S. Denzel: Max Planck Institute for Biology of Ageing

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14524-5

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