Filament formation drives catalysis by glutaminase enzymes important in cancer progression

Area of Science:

• Biochemistry
• Structural Biology
• Cancer Biology

Background:

• Glutaminase enzymes (GAC and GLS2) are vital for cancer cell metabolism by converting glutamine to glutamate.
• The precise mechanisms governing glutaminase activation and catalysis remained largely undefined.
• These enzymes are recognized as promising targets for anti-cancer drug development.

Approach:

• Cryo-electron microscopy (cryo-EM) was employed to determine the structures of GAC and GLS2.
• The study investigated the direct correlation between filament formation and catalytic activity.
• Conformational changes associated with enzyme activation were analyzed.

Key Points:

• Filament formation in GAC and GLS2 is intrinsically linked to their catalytic function.
• Cryo-EM structures reveal critical conformational states essential for catalysis.
• An 'activation loop' and 'lid' mechanism, regulated by filament formation, facilitate substrate binding and catalysis.
• Ankyrin repeats on GLS2 play a role in regulating enzymatic activity.

Conclusions:

• Filament formation is a prerequisite for glutaminase catalytic activity and glutaminolysis.
• Allosteric activators promote filament stabilization, enhancing enzyme function.
• Clinically relevant inhibitors impede filament formation, thereby blocking glutaminase activity.
• Targeting glutaminase filamentation represents a promising strategy for cancer therapy.