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From Proteopedia
Crystal structure of human GFAT-1 R203H
Structural highlights
DiseaseGFPT1_HUMAN Defects in GFPT1 are the cause of myasthenia, congenital, with tubular aggregates, type 1 (CMSTA1) [MIM:610542. A congenital myasthenic syndrome characterized by onset of proximal muscle weakness in the first decade. Individuals with this condition have a recognizable pattern of weakness of shoulder and pelvic girdle muscles, and sparing of ocular or facial muscles. EMG classically shows a decremental response to repeated nerve stimulation, a sign of neuromuscular junction dysfunction. Affected individuals show a favorable response to acetylcholinesterase (AChE) inhibitors.[1] FunctionGFPT1_HUMAN Controls the flux of glucose into the hexosamine pathway. Most likely involved in regulating the availability of precursors for N- and O-linked glycosylation of proteins. Publication Abstract from PubMedThe 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. Protein kinase A controls the hexosamine pathway by tuning the feedback inhibition of GFAT-1.,Ruegenberg S, Mayr FAMC, Atanassov I, Baumann U, Denzel MS Nat Commun. 2021 Apr 12;12(1):2176. doi: 10.1038/s41467-021-22320-y. PMID:33846315[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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