Dimerization of PHGDH via the catalytic unit is essential for its enzymatic function

Area of Science:

• Biochemistry
• Enzymology
• Cancer Biology

Background:

• Human D-3-phosphoglycerate dehydrogenase (PHGDH) is crucial for serine biosynthesis and is amplified in cancers.
• Understanding PHGDH's oligomeric states is key for developing anticancer drugs targeting this enzyme.

Purpose of the Study:

• To investigate the relationship between PHGDH's oligomeric states and its enzymatic activity.
• To identify key residues involved in PHGDH dimerization for potential drug design.

Main Methods:

• Studied PHGDH enzymatic activity in relation to its monomer-dimer-tetramer equilibrium.
• Utilized computational methods to identify dimer interface residues.
• Performed site-directed mutagenesis and molecular dynamics simulations.
• Assessed the impact of mutations on full-length PHGDH oligomerization and activity.

Main Results:

• PHGDH exists as a dynamic mixture of monomers, dimers, and tetramers, with activity dependent on dimer content.
• Specific hotspot residues at the dimer interface were identified; mutations abolished activity.
• Dimer formation was shown to be essential for substrate binding and maintaining catalytic conformation.
• Mutations disrupting the catalytic subunit dimer also affected full-length PHGDH tetramer formation and activity.

Conclusions:

• PHGDH enzymatic activity is intrinsically linked to its oligomeric structure.
• Disrupting PHGDH oligomerization is a viable strategy for anticancer drug development.
• Identified hotspot residues provide targets for designing PHGDH inhibitors.