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Cancer-associated mutations in human pyruvate kinase M2 impair enzyme activity

Vivian M Liu1,2, Andrea J Howell1, Aaron M Hosios1

  • 1David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.

FEBS Letters
|October 24, 2019
PubMed

Insights

Cancer-associated mutations in pyruvate kinase M2 (PKM2) reduce its activity and alter regulation. These findings suggest decreased PKM2 function is favored in rapidly proliferating cancer cells.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Pyruvate kinase M2 (PKM2) is a key enzyme in glycolysis, crucial for energy production in proliferating cells.
  • Mutations in PKM2 are observed in human cancers, but their functional impact remains unclear.

Purpose of the Study:

  • To investigate the effects of cancer-associated mutations on PKM2 enzyme activity and allosteric regulation.
  • To understand how these mutations influence substrate kinetics and fructose-1,6-bisphosphate (FBP) activation.

Main Methods:

  • Characterization of five cancer-associated PKM2 mutations.
  • Analysis of enzyme kinetics, including maximal velocity and substrate affinity.
  • Assessment of activation by the allosteric activator FBP.

Main Results:

  • Mutated PKM2 enzymes exhibited reduced maximal velocity and/or substrate affinity.
  • PKM2 mutants displayed altered sensitivity to FBP activation.
  • Additional studied mutants also showed impaired enzymatic function.

Conclusions:

  • PKM2 is highly sensitive to amino acid substitutions, with many cancer-associated mutations impairing its function.
  • The data support the hypothesis that reduced PKM2 activity is advantageous for rapidly proliferating cancer cells.
Keywords:
allosterycancerenzymologymutation

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