Affiliation: Department of Biochemistry and Molecular Biology, Holden Comprehensive Cancer Center, Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, University of Iowa 

Abstract: In many human cancers, both energy and biomass production are elevated to sustain rapid cell proliferation. For nucleotide supply, salvage synthesis alone is insufficient, and cancer cells rely heavily on de novo purine biosynthesis. Recent discoveries have revealed that sequential enzymes within this pathway assemble into dynamic biomolecular condensates known as purinosomes to meet the enhanced purine nucleotide demand. Super-resolution fluorescence microscopy has uncovered the spatial and temporal regulation of the purinosome, and these new findings have provided insights into how liquid-liquid phase separation organizes metabolic flux. 

Although the triggers that promote purinosome assembly are well characterized, the molecular events that facilitate its disassembly remain largely unexplored. Here, I will present an emerging model in which acetylation of purinosome enzymes initiates condensate disassembly and the release of key intermediates that function as signaling molecules to activate glycolysis to slow tumor progression. This mechanism underscores a role for post-translational modifications in coupling enzyme compartmentalization with broader cellular physiology. By elucidating the mechanisms of purinosome assembly and disassembly, our studies offer a more comprehensive picture of how condensates can control metabolic processes, and ultimately, generate insights into whether disrupting the “barrier” of the purinosome might provide a therapeutic strategy to curtail cancer metabolism.