Hexosamine signaling pathway - Homo sapiens (human)

Curator(s): Peter D'Adamo

The hexosamine biosynthetic pathway (HBP) results in the production of UDP-N-acetylglucosamine (UDP-GlcNAc) and other nucleotide hexosamines. UDP-GlcNAc, the major product, is the unique donor for the O-linkage of a single N-acetylglucosamine molecule (O-GlcNAc) to many cytoplasmic and nuclear proteins. Upon entering the cell glucose is rapidly phosphorylated to glucose-6-phosphate which can be oxidized via glycolysis or the pentose phosphate shunt or stored as glycogen. Approximately 2-5% of F6P, and for that matter glucose, is diverted to HBP. Gfpt1 (known as Gfat) catalyzes the formation of glucosamine-6-phosphate with glutamine as an amine donor and F6P as an acceptor substrate in the first and rate-limiting step of the pathway. Subsequently, the addition of an acetyl group yields N-acetyl glucosamine-6-phosphate which is rapidly modified to UDP-GlcNAc. The utilization of glucosamine and of acetyl in the first two steps potentially links amino acid and fatty acid metabolism with HBP. The reversible modification of proteins by the addition and removal of GlcNAc, analogous to addition and removal of phosphate, also has a complex interplay with the O-phosphate modification. Sites that are targets of O-GlcNAcylation are at or near sites of O-phosphorylation. The cycling of GlcNAc is carried out by two enzymes: Ogt that catalyzes the O-linkage to serine and threonine residues and Mgea5 (known as Oga) that removes the hexosamine moiety. The cycling of GlcNAc and the regulation of the two enzymes are subjects of intense research as the many targets of GlcNAcylation representing almost every functional class, including proteins involved in insulin synthesis and signaling, and in the expression of gluconeogenic enzymes.UDP-Glc has an important role in protein folding in the ER; glucose is added    
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Hexosamine signaling pathway - Homo sapiens (human) cluster_GOLGI GOLGI cluster_node28 NUCLEUS/ ER cluster_node29 !2 cluster_node30 !1 cluster_node31 CELL MEMBRANE Glycogen biosynthetic pathway node1 Glycolysis / Gluconeogenesis Pentose and glucuronate interconversions node2 17 Glucose Glucose->Glycogen biosynthetic pathway Glucose->Pentose and glucuronate interconversions Glucose->node2 Glucose GLUT Glucose->GLUT node3 Fru-6P node3->node1 node14 node3->node14 glutamine--fructose-6-phosphate transaminase 1 GFPT1 GFPT1->node14 node4 GlcN-6P node16 node4->node16 node6 Acetyl-CoA glucosamine-phosphate N-acetyltransferase 1 GNPNAT1 node6->GNPNAT1 UDP-N-acteylglucosamine pyrophosphorylase 1 UAP1 node18 UAP1->node18 UTP UTP->UAP1 node9 Glc-6P node15 node9->node15 O-linked N-acetylglucosamine (GlcNAc) transferase (UDP-N-acetylglucosamine:polypeptide-N-acetylglucosaminyl transferase) OGT node10 O-linked GlcNAc proteins OGT->node10 node11 Protein (GlcNAc removed) node12 3 node14->node4 node15->node3 node7 GlcNAc-6P node16->node7 node17 node8 GlcNAc-1P node17->node8 node19 UDP-GlcNAc node18->node19 node19->OGT node20 node19->node20 node23 N-Glycan biosynthesis - Homo sapiens (human) node19->node23 node21 UDP-GalNAc node20->node21 node22 node22->node11 node24 1 node25 17 node27 UDP-Glc Glycoprotein folding node27->Glycoprotein folding UDP UDP->node27 ectonucleoside triphosphate diphosphohydrolase 5 ENTPD5 UDP->ENTPD5 UMP UMP->UDP ATP->ADP phosphoglucomutase 3 PGM3 node7->PGM3 node13 node13->node9 node13->node12 node8->UAP1 GNPNAT1->node16 ENTPD5->UMP ENTPD5->Glycoprotein folding Glycoprotein folding->node23 ENTPD5 expression ENTPD5 expression->ENTPD5 GFR GFR->node24 GFR node26 PI3K/AKT GFR->node26 node26->node25 PI3K/AKT node26->ENTPD5 expression node26->GLUT GLUT->node27 GLUT->node13 PGM3->node17 meningioma expressed antigen 5 (hyaluronidase) MGEA5 MGEA5->node22 node10->MGEA5 node5 l-Glutamine node5->GFPT1 print "