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Impact of Cancer-Associated PKM2 Mutations on Enzyme Activity and Allosteric Regulation: Structural and Functional
Saurabh Upadhyay1, Mohit Bhardwaj1, Sivakumar Prasanth Kumar2
1Kusuma School of Biological Sciences, Indian Institute of Technology, New Delhi 110016, India.
Biochemistry
|March 13, 2025
Summary
Cancer-associated mutations in pyruvate kinase M2 (PKM2) disrupt its function and regulation. These PKM2 alterations impact glycolysis and may contribute to metabolic reprogramming in tumors.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Mammalian pyruvate kinase M2 (PKM2) is crucial for glycolysis and overexpressed in tumors.
- Cancer-associated PKM2 mutations are known, but their functional impact remains unclear.
Purpose of the Study:
- To investigate the structural and functional consequences of cancer-associated PKM2 mutations.
- To understand how these mutations affect enzyme kinetics, allosteric regulation, and oligomerization.
Main Methods:
- Computational modeling
- X-ray crystallography
- Biochemical assays
- Characterization of four specific PKM2 mutations (P403A, C474S, R516C, L144P)
Main Results:
- Mutations disrupt allosteric signaling, altering communication between regulatory and active sites.
- X-ray crystallography revealed conformational changes, favoring less active dimeric states for C474S and R516C mutants.
- Mutants showed reduced maximal velocity, lower substrate affinity, and impaired fructose-1,6-bisphosphate (FBP) activation.
- Alkaline pH conditions (tumor microenvironment) further destabilized PKM2 oligomeric states.
Conclusions:
- PKM2 is highly sensitive to cancer-associated mutations.
- These alterations impair PKM2 enzymatic regulation, potentially contributing to cancer cell metabolic reprogramming.
- Understanding these mutations offers insights into cancer metabolism and therapeutic strategies.
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