GPCRs regulate the assembly of a multienzyme complex for purine biosynthesis

Area of Science:

• Cellular Biology
• Molecular Biology
• Biochemistry

Background:

• G protein-coupled receptors (GPCRs) are crucial for signal transduction, impacting various cellular processes in both healthy and diseased states.
• The role of GPCR signaling in regulating cytosolic metabolic pathways remains largely unexplored.
• Purine biosynthesis, facilitated by the purinosome complex, is essential for cellular growth and proliferation.

Purpose of the Study:

• To investigate the association between GPCR-mediated signaling and purine metabolism.
• To determine if GPCR activation influences the assembly and disassembly of the purinosome.
• To explore the potential role of purinosome dynamics as a downstream event in GPCR signaling pathways relevant to cancer.

Main Methods:

• Fluorescent live-cell imaging was employed to visualize the purinosome, a key complex in de novo purine biosynthesis.
• Label-free dynamic mass redistribution assays were utilized to monitor cellular responses to GPCR activation.
• A library screen of GPCR ligands was performed in conjunction with metabolic imaging.

Main Results:

• The study demonstrated a correlation between the activation of endogenous Gα(i)-coupled receptors and the dynamic assembly/disassembly of the purinosome in HeLa cells.
• GPCR activation was shown to directly impact the purinosome, a critical metabolic complex.

Conclusions:

• GPCR signaling is linked to the regulation of purine metabolism through modulation of purinosome dynamics.
• The findings suggest that purinosome assembly and disassembly may represent downstream events of mitogenic GPCR signaling.
• This connection holds potential implications for understanding and targeting metabolic pathways in human cancer cells.