Overview

Metabolons, or transient protein assemblies of sequential metabolic enzymes within a given pathway, have emerged as a new level of metabolic control in cancer cells. Purine nucleotides are essential for maintaining cellular homeostasis and supporting cell growth. In highly aggressive cancers, purine demand is markedly increased and is met through activation of the de novo purine biosynthetic pathway. To enhance pathway efficiency, enzymes catalyzing this pathway assemble into dynamic, functional protein condensates known as purinosomes. While additional cytoplasmic assemblies containing purine biosynthetic enzymes have been observed, these structures often differ in their biophysical properties or do not correlate with increased pathway activity.

These observations raise fundamental questions about what molecular features uniquely define the purinosome and how these features are regulated to support elevated metabolic flux.

Research Strategy

This project focuses on defining how regulation of individual purinosome enzymes facilitates condensate formation and spatial organization. We hypothesize that purinosome assembly is not driven by uniform behavior across pathway enzymes, but instead arises from enzyme-specific regulatory features—including folding state, interaction networks, and post-translational control—that collectively promote condensate nucleation, maturation, and localization.

Outstanding Questions

• What molecular features distinguish functional purinosomes from other purine enzyme assemblies?
• How is enzyme composition regulated to maximize metabolic flux through the pathway?
• Do changes in enzyme properties contribute to condensate formation and function?
• How does purinosome assembly enhance pathway efficiency in high-demand cellular states?