Extended Data Fig. 6: Schematic model of how OGT-mediated nucleotides and NAD synthesis under metabolic stress regulate tumor growth and chemoradiotherapy resistance.
From: Direct stimulation of de novo nucleotide synthesis by O-GlcNAcylation
In the presence of sufficient nutrients, OGT catalyzes the transfer of UDP-GlcNAc to PRPS1, promoting its hexamer assembly and functional activity. This process enhances de novo nucleotide synthesis and NAD production, thereby accelerating tumor growth and resistance to chemoradiotherapy. A mutation associated with Arts Syndrome, PRPS1 R196W, exhibits decreased O-GlcNAcylation levels and activity of PRPS1. Under conditions of energy stress, such as glucose deprivation, AMPK phosphorylates PRPS1, leading to a reduction in its hexamer assembly and activity. The OGT-mediated O-GlcNAcylation of PRPS1 and AMPK-mediated phosphorylation antagonize each other. The O-GlcNAcylation of PRPS1 at S83 and T166 by OGT results in structural alteration, reducing the binding and phosphorylation capacity of AMPK. In contrast, AMPK-mediated phosphorylation of PRPS1 at S180 triggers a conformational change, inhibiting the PRPS1-OGT interaction and lowering PRPS1 O-GlcNAcylation. The intricate interplay between OGT and AMPK pathways, responding to distinct nutrient signals, establishes a complex regulatory network for PRPS1.
