6ZMK

Crystal structure of human GFAT-1 L405R

Summary for 6ZMK

• Entry DOI: 10.2210/pdb6zmk/pdb
• Descriptor: Glutamine--fructose-6-phosphate aminotransferase [isomerizing] 1, GLUCOSE-6-PHOSPHATE, GLUTAMIC ACID, ... (5 entities in total)
• Functional Keywords: glutamine fructose-6-phosphate amidotransferase, gfat, ntn hydrolase, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 156227.47

Authors

Ruegenberg, S.,Mayr, F.,Miethe, S.,Atanassov, I.,Baumann, U.,Denzel, M.S. (deposition date: 2020-07-02, release date: 2020-08-05, Last modification date: 2024-11-13)

Primary citation

Ruegenberg, S.,Mayr, F.A.M.C.,Atanassov, I.,Baumann, U.,Denzel, M.S.
Protein kinase A controls the hexosamine pathway by tuning the feedback inhibition of GFAT-1.
Nat Commun, 12:2176-2176, 2021

PubMed Abstract: The hexosamine pathway (HP) is a key anabolic pathway whose product uridine 5'-diphospho-N-acetyl-D-glucosamine (UDP-GlcNAc) is an essential precursor for glycosylation processes in mammals. It modulates the ER stress response and HP activation extends lifespan in Caenorhabditis elegans. The highly conserved glutamine fructose-6-phosphate amidotransferase 1 (GFAT-1) is the rate-limiting HP enzyme. GFAT-1 activity is modulated by UDP-GlcNAc feedback inhibition and via phosphorylation by protein kinase A (PKA). Molecular consequences of GFAT-1 phosphorylation, however, remain poorly understood. Here, we identify the GFAT-1 R203H substitution that elevates UDP-GlcNAc levels in C. elegans. In human GFAT-1, the R203H substitution interferes with UDP-GlcNAc inhibition and with PKA-mediated Ser205 phosphorylation. Our data indicate that phosphorylation affects the interactions of the two GFAT-1 domains to control catalytic activity. Notably, Ser205 phosphorylation has two discernible effects: it lowers baseline GFAT-1 activity and abolishes UDP-GlcNAc feedback inhibition. PKA controls the HP by uncoupling the metabolic feedback loop of GFAT-1.

PubMed: 33846315
DOI: 10.1038/s41467-021-22320-y

Experimental method

X-RAY DIFFRACTION (2.382 Å)