Abstract
N-acetylphosphoglucosamine mutase (AGM1) is a key component of the hexosamine biosynthetic pathway that produces UDP-GlcNAc, an essential precursor for a wide range of glycans in eukaryotes. AGM belongs to the α-d-phosphohexomutase metalloenzyme superfamily and catalyzes the interconversion of N-acetylglucosamine-6-phosphate (GlcNAc-6P) to N-acetylglucosamine-1-phosphate (GlcNAc-1P) through N-acetylglucosamine-1,6-bisphosphate (GlcNAc-1,6-bisP) as the catalytic intermediate. Although there is an understanding of the phosphoserine-dependent catalytic mechanism at enzymatic and structural level, the identity of the requisite catalytic base in AGM1/phosphoglucomutases is as yet unknown. Here, we present crystal structures of a Michaelis complex of AGM1 with GlcNAc-6P and Mg2+, and a complex of the inactive Ser69Ala mutant together with glucose-1,6-bisphosphate (Glc-1,6-bisP) that represents key snapshots along the reaction co-ordinate. Together with mutagenesis, these structures reveal that the phosphate group of the hexose-1,6-bisP intermediate may act as the catalytic base.
Highlights
N-acetylphosphoglucosamine mutase (AGM1) catalyzes the interconversion of N-acetylglucosamine-6-phosphate (GlcNAc-6P) to N-acetylglucosamine-1-phosphate (GlcNAc-1P) in eukaryotes [1]
The enzyme catalyzes the interconversion of GlcNAc-6P to GlcNAc-1P, which is subsequently converted to UDP-GlcNAc by UDP-GlcNAc pyrophosphorylase, the last enzyme in the pathway
UDP-GlcNAc is the direct precursor for many cellular processes, for instance, in fungi, it is used in the synthesis of chitin that forms the major component of the fungi cell wall and it is believed that enzymes involved in its synthesis are potential drug targets [3,34,35]
Summary
N-acetylphosphoglucosamine mutase (AGM1) catalyzes the interconversion of N-acetylglucosamine-6-phosphate (GlcNAc-6P) to N-acetylglucosamine-1-phosphate (GlcNAc-1P) in eukaryotes [1]. UDP-GlcNAc is an important metabolite for many cellular processes In bacteria, it is the precursor of outer membrane lipopolysaccharide [4,5] and cell wall peptidoglycan [6]. It is the precursor of outer membrane lipopolysaccharide [4,5] and cell wall peptidoglycan [6] In eukaryotes, it is the precursor of GPI anchors [7] together with its role as sugar donor in many glycosylation reactions including N-glycosylation and O-glycosylation [8,9]. There are no mechanism-inspired inhibitors of this family of enzymes due to a limited understanding of their catalytic mechanisms
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