Thursday, January 17, 2013
Metabolic pathways regulated by pyruvate kinase. To block the cancer metabolism pathway driven by the
pyruvate kinase M2 isozyme (PKM2) dimer, researchers are working to develop
small molecules that either inhibit the enzyme or keep the enzyme in its
high-activity tetramer state. However, results from Cortés-Cros et al.
suggest that blocking PKM2 may not be enough to prevent tumor proliferation.
PKM1 is expressed in most normal cells as a
constitutively active tetramer, whereas PKM2 is expressed in cancer cells
either as a high-activity tetramer or a low-activity dimer.
In normal cells with the PKM1 tetramer or cancer cells with the PKM2 tetramer,
the kinase catalyzes the transfer of phosphate from phosphoenolpyruvate (PEP)
to ADP, generating ATP and pyruvate. Pyruvate then is shuttled into the
tricarboxylic acid cycle to produce acetyl-CoA and citrate. The process is balanced to allow the production of
both ATP and the biosynthesis of cellular macromolecules to sustain growing
In cancer cells with the PKM2 dimer, the low-activity kinase also catalyzes the
transfer of phosphate from PEP to ADP, generating ATP and pyruvate. The PKM2
dimer does so at a much slower rate than the PKM2 tetramer or PKM1 tetramer,
leading to a bottleneck in the metabolic pathway. The buildup of intermediate
metabolites of glycolysis feed other biosynthetic pathways to produce large
quantities of cellular macromolecules. In addition, the decreased generation of
pyruvate leads to lactate production.