Agm1/Pgm3-Mediated Sugar Nucleotide Synthesis Is Essential for Hematopoiesis and Development

Abstract

Carbohydrate modification of proteins includes N-linked and O-linked glycosylation, proteoglycan formation, glycosylphosphatidylinositol anchor synthesis, and O-GlcNAc modification. Each of these modifications requires the sugar nucleotide UDP-GlcNAc, which is produced via the hexosamine biosynthesis pathway. A key step in this pathway is the interconversion of GlcNAc-6-phosphate (GlcNAc-6-P) and GlcNAc-1-P, catalyzed by phosphoglucomutase 3 (Pgm3). In this paper, we describe two hypomorphic alleles of mouse Pgm3 and show there are specific physiological consequences of a graded reduction in Pgm3 activity and global UDP-GlcNAc levels. Whereas mice lacking Pgm3 die prior to implantation, animals with less severe reductions in enzyme activity are sterile, exhibit changes in pancreatic architecture, and are anemic, leukopenic, and thrombocytopenic. These phenotypes are accompanied by specific rather than wholesale changes in protein glycosylation, suggesting that while universally required, the functions of certain proteins and, as a consequence, certain cell types are especially sensitive to reductions in Pgm3 activity.

The roles ofO-linked β-N-acetylglucosamine in cardiovascular physiology and disease

“…Consistent with the OGT knockout, disrupting flux through the HBP and thus concentrations of UDP-GlcNAc has severe consequences (5,49). Deletion of glucosamine-phosphate Nacetyltransferase 1 (EMeg32; Gnpnat1; Fig.…”

“…More recently, the activity of phosphoglucomutase 3 (Pgm3), also known as phosphoacetylglucosamine mutase 1, which catalyzes the penultimate step of the HBP (Fig. 1), has been manipulated genetically (49). Similar to deleting OGT and glucosamine-phosphate N-acetyltransferase 1, deletion of Pgm3 results in embryonic lethality between E3.5 and E6.5, again highlighting the importance of O-GlcNAcylation and other glycoconjugates (49).…”

“…1), has been manipulated genetically (49). Similar to deleting OGT and glucosamine-phosphate N-acetyltransferase 1, deletion of Pgm3 results in embryonic lethality between E3.5 and E6.5, again highlighting the importance of O-GlcNAcylation and other glycoconjugates (49). Notably, the authors also generated a number of hypomorphic mutations in Pgm3, which allowed them to study the effects of incremental changes in UDP-GlcNAc levels (49).…”

Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis

“…Interestingly, free radicals promote GFAT activity suggesting one mechanism by which cellular stress and high glucose can lead to upregulation of UDP-GlcNAc pools (Du et al 2000). Mutations in genes encoding enzymes that significantly lower O-GlcNAc levels, such as emeg32 (glucosamine-6-phosphate acetyltransferase) and pgm3 (Nacetylglucosamine-phosphate mutase), are embryonic lethal highlighting the importance of O-GlcNAc and other forms of protein glycosylation that rely on UDP-GlcNAc (Boehmelt et al 2000a, b;Greig et al 2007). …”

“…1). Highlighting the importance of O-GlcNAc in cellular homeostasis, deletion of OGT, OGlcNAcase, and other key enzymes in the hexosamine biosynthetic pathway (HBP) is lethal in mammals (Mio et al 1999;Greig et al 2007;Boehmelt et al 2000a, b;Shafi et al 2000;Forsythe et al 2006;Yang et al 2012).…”