Filamentation modulates allosteric regulation of PRPS

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Biology

Background:

• Phosphoribosyl pyrophosphate (PRPP) is crucial for nucleotide and cofactor biosynthesis.
• PRPP synthase (PRPS) dysregulation links to human diseases like gout and Arts syndrome.
• PRPS filament formation (cytoophidia) observed in eukaryotes suggests a regulatory role.

Purpose of the Study:

• To investigate PRPS filamentation in prokaryotes.
• To determine the structural basis of PRPS filament formation and regulation.
• To explore the implications of PRPS filamentation in cellular metabolism.

Main Methods:

• In vitro and in vivo studies of *E. coli* PRPS.
• Cryo-electron microscopy (Cryo-EM) to solve filament structures at near-atomic resolution.
• Ligand binding analysis to understand filament formation control.

Main Results:

• PRPS forms distinct cytoophidia filaments in prokaryotes.
• Two unique filament structures of *E. coli* PRPS were determined by Cryo-EM.
• Filament formation is ligand-dependent, with one type resistant to allosteric inhibition.
• Structural analysis revealed conformational changes in a regulatory loop and identified a noncanonical AMP/ADP binding site.

Conclusions:

• PRPS filamentation represents a novel regulatory mechanism in prokaryotes.
• Structural insights elucidate ligand-controlled filament formation and allosteric inhibition.
• PRPS filamentation adds a new layer to cellular metabolic regulation.