Regulation and pathophysiological implications of UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) as the key enzyme of sialic acid biosynthesis.

Abstract

The key enzyme for the biosynthesis of N-acetylneuraminic acid, from which all other sialic acids are formed, is the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). GNE is a highly conserved protein found throughout the animal kingdom. Its highest expression is seen in the liver and placenta. GNE is regulated by a variety of biochemical means, including tetramerization promoted by the substrate UDP-GlcNAc, phosphorylation by protein kinase C and feedback inhibition by CMP-Neu5Ac, which is defect in the human disease sialuria. GNE knock-out in mice leads to embryonic lethality, emphasizing the crucial role of this key enzyme for sialic acid biosynthesis. The metabolic capacity to synthesize sialic acid and CMP-sialic acid upon ManNAc loads is amazingly high. An additional characteristic of GNE is its interaction with proteins involved in the regulation of development, which might play a crucial role in the hereditary inclusion body myopathy. Due to the importance of increased concentrations of tumor-surface sialic acid, first attempts to find inhibitors of GNE have been successful.

• Authors: Stefan O Reinke, Gerhard Lehmer, Stephan Hinderlich, Werner Reutter
• Journal: Biological chemistry (Biol Chem) Vol. 390 Issue 7 Pg. 591-9 (Jul 2009) ISSN: 1431-6730 [Print] Germany
• PMID: 19426133 (Publication Type: Journal Article, Review)

Chemical References

• Enzyme Inhibitors
• Phosphotransferases (Alcohol Group Acceptor)
• N-acylmannosamine kinase
• Carbohydrate Epimerases
• UDP acetylglucosamine-2-epimerase
• N-Acetylneuraminic Acid

Topics

• Animals
• Carbohydrate Epimerases (antagonists & inhibitors, genetics, metabolism)
• Disease
• Enzyme Inhibitors (pharmacology)
• Humans
• N-Acetylneuraminic Acid (biosynthesis)
• Phosphotransferases (Alcohol Group Acceptor) (antagonists & inhibitors, genetics, metabolism)