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Pyruvate kinase type M2: a crossroad in the tumor metabolome

S Mazurek1, H Grimm, C B Boschek

  • 1Institute for Biochemistry & Endocrinology, Veterinary Faculty, University of Giessen, Germany.

The British Journal of Nutrition
|March 16, 2002
PubMed

Insights

Pyruvate kinase M2 (M2-PK) regulates cell proliferation by controlling glucose metabolism. Tumor cells favor the dimeric M2-PK form, promoting biosynthesis and energy production for rapid growth.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Oncology

Background:

  • Cell proliferation requires significant energy, making nutrient supply critical.
  • Pyruvate kinase (PK) is a key enzyme regulating glucose metabolism for energy or biosynthesis.
  • Mammalian pyruvate kinase isoenzyme type M2 (M2-PK) plays a crucial role in adapting cell proliferation to nutrient availability.

Purpose of the Study:

  • To elucidate the regulatory mechanisms of M2-PK in cell proliferation.
  • To understand how M2-PK's activity influences glucose carbon channeling.
  • To investigate the role of M2-PK's dimeric and tetrameric forms in tumor cell metabolism.

Main Methods:

  • Analysis of M2-PK kinetic properties and its comparison to unicellular PK.
  • Investigation of M2-PK isoenzyme's conformational changes (dimeric vs. tetrameric forms).
  • Examination of factors regulating the tetramer-dimer ratio, including metabolites and oncoproteins.

Main Results:

  • M2-PK exists in dimeric (less active) and tetrameric (highly active) forms, controlling glucose channeling.
  • Tumor cells predominantly exhibit the dimeric M2-PK form, leading to glycolytic phosphometabolite accumulation.
  • The tetramer-dimer ratio is modulated by ATP, fructose-1,6-bisphosphate (FBP), serine, and oncoproteins like pp60v-src and HPV-16 E7.
  • In solid tumors, pyruvate is sourced from glutaminolysis and used for lactate, glutamate, and fatty acid synthesis.

Conclusions:

  • M2-PK's conformational state is a critical regulator of cellular metabolic fate, balancing proliferation and energy production.
  • The prevalence of the dimeric M2-PK form in tumors supports high biosynthetic demands.
  • M2-PK represents a potential therapeutic target for modulating tumor metabolism.

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