Dataset Information

Protein kinase A controls the hexosamine pathway by tuning feedback inhibition of GFAT-1

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 all glycosylation processes in mammals. It modulates the ER stress response, is implicated in cancer and diabetes, and HP activation extends lifespan in Caenorhabditis elegans. The highly conserved glutamine fructose-6-phosphate amidotransferase 1 (GFAT 1) is the first and rate-limiting HP enzyme. GFAT 1 activity is modulated through UDP-GlcNAc feedback inhibition and by kinase signaling, including Ser205 phosphorylation by protein kinase A (PKA). The consequence and molecular mechanism of GFAT 1 PKA phosphorylation, however, remains poorly understood. Here, we identify the GFAT 1 R203H substitution that elevates UDP-GlcNAc levels in C. elegans, leading to ER stress resistance. In human GFAT-1, the R203H substitution interfered with UDP-GlcNAc inhibition and with PKA-mediated Ser205 phosphorylation. Of note, Ser205 phosphorylation had two discernible effects: It lowered baseline GFAT 1 activity while abolishing UDP-GlcNAc feedback inhibition. Thus, GFAT-1 phosphorylation by PKA uncoupled the feedback loop of the HP and depending on UDP-GlcNAc availability, phosphorylation by PKA lowers or enhances GFAT 1 activity in vivo. Mechanistically, our data indicate that the relative positioning of the two GFAT 1 domains might be affected by phosphorylation and we propose a model how Ser205 phosphorylation modulates the activity and feedback inhibition of GFAT 1.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Ilian Atanassov

LAB HEAD: Martin S. Denzel

PROVIDER: PXD020451 | Pride | 2020-07-23

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	190220_FS1_IA_MD_SR_pept_1_7nmol_6_60.raw	Raw
	190220_FS1_IA_MD_SR_pept_2_7nmol_6_60.raw	Raw
	190529_FS1_IA_MD_SR_01.raw	Raw
	190529_FS1_IA_MD_SR_02.raw	Raw
	190529_FS1_IA_MD_SR_03.raw	Raw

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Protein kinase A controls the hexosamine pathway by tuning the feedback inhibition of GFAT-1.

Ruegenberg Sabine S Mayr Felix A M C FAMC Atanassov Ilian I Baumann Ulrich U Denzel Martin S MS

Nature communications 20210412 1

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 k ...[more]

PMID: 33846315

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