Universität zu Köln

Ruegenberg, Sabine, Mayr, Felix A. M. C., Atanassov, Ilian, Baumann, Ulrich and Denzel, Martin S. (2021). Protein kinase A controls the hexosamine pathway by tuning the feedback inhibition of GFAT-1. Nat. Commun., 12 (1). BERLIN: NATURE PORTFOLIO. ISSN 2041-1723

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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. The glutamine fructose-6-phosphate amidotransferase 1 (GFAT-1) is the rate-limiting enzyme in the hexosamine pathway producing uridine 5'-diphospho-N-acetyl-D-glucosamine (UDP-GlcNAc), an essential glycosylation precursor. Here, the authors dissect the mechanisms of GFAT-1 regulation by protein kinase A (PKA)-mediated phosphorylation.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ruegenberg, Sabine UNSPECIFIED UNSPECIFIED UNSPECIFIED Mayr, Felix A. M. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Atanassov, Ilian UNSPECIFIED UNSPECIFIED UNSPECIFIED Baumann, Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Denzel, Martin S. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-570501
DOI:	10.1038/s41467-021-22320-y
Journal or Publication Title:	Nat. Commun.
Volume:	12
Number:	1
Date:	2021
Publisher:	NATURE PORTFOLIO
Place of Publication:	BERLIN
ISSN:	2041-1723
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HUMAN GLUTAMINE-FRUCTOSE-6-PHOSPHATE AMIDOTRANSFERASE; FRUCTOSE 6-PHOSPHATE AMIDOTRANSFERASE; GLUCOSAMINE-6-PHOSPHATE SYNTHASE; L-GLUTAMINE; MOLECULAR-DYNAMICS; O-GLCNACYLATION; PHOSPHORYLATION; AMMONIA; IDENTIFICATION; PURIFICATION Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/57050