Loss of GFAT-1 feedback regulation activates the hexosamine pathway that modulates protein homeostasis.
Nat Commun
; 11(1): 687, 2020 02 04.
Article
em En
| MEDLINE
| ID: mdl-32019926
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Glutamina-Frutose-6-Fosfato Transaminase (Isomerizante)
/
Hexosaminas
Limite:
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article