The ubiquitous hexosamine pathway (HP) is essential for aminosugar biosynthesis (Fig. Thus, there is a clear need for the identification of druggable targets and respective drugs in gerontology. For example rapamycin, which targets mTOR, and metformin that acts through yet incompletely understood mechanisms, have entered clinical trials with the goal to slow aging and prevent age-related phenotypes 2, 3. While the plasticity of the aging process suggests that pathways could be targeted to prolong life and postpone age-related diseases in humans, few drug candidates have emerged.
Relevant pathways include insulin/IGF-1 signaling, mTOR, and the AMPK cascade 1. The aging process is modulated by specific signaling pathways and their manipulation can result in lifespan extension, suggesting that aging is a coordinated process. Therefore, GFAT-1 gain-of-function through loss of feedback inhibition constitutes a potential target for the treatment of age-related proteinopathies.Ī progressive decline of physiological functions limits healthspan and survival in most organisms. In mammalian cells, the G451E variant potently activates the HP. Our structural and functional data point to a critical role of the interdomain linker in UDP-GlcNAc inhibition. The longevity-associated G451E variant shows drastically reduced sensitivity to UDP-GlcNAc inhibition in enzyme activity assays. UDP-GlcNAc directly interacts with GFAT-1, inhibiting catalytic activity. Here, we present the full-length crystal structure of human GFAT-1 in complex with various ligands and with important mutations.
GFAT is highly conserved, but the gain-of-function mechanism and its relevance in mammalian cells remained unclear. In Caenorhabditis elegans, we previously identified gfat-1 gain-of-function mutations that elevate UDP-GlcNAc levels, improve protein homeostasis, and extend lifespan.
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.
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