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Review
. 2015 Jul:43:43-51.
doi: 10.1016/j.semcdb.2015.08.004. Epub 2015 Aug 13.

Pyruvate kinase: Function, regulation and role in cancer

William J Israelsen  1 , Matthew G Vander Heiden  2
Affiliations
Review

Pyruvate kinase: Function, regulation and role in cancer

William J Israelsen et al. Semin Cell Dev Biol. 2015 Jul.

Abstract

Pyruvate kinase is an enzyme that catalyzes the conversion of phosphoenolpyruvate and ADP to pyruvate and ATP in glycolysis and plays a role in regulating cell metabolism. There are four mammalian pyruvate kinase isoforms with unique tissue expression patterns and regulatory properties. The M2 isoform of pyruvate kinase (PKM2) supports anabolic metabolism and is expressed both in cancer and normal tissue. The enzymatic activity of PKM2 is allosterically regulated by both intracellular signaling pathways and metabolites; PKM2 thus integrates signaling and metabolic inputs to modulate glucose metabolism according to the needs of the cell. Recent advances have increased our understanding of metabolic regulation by pyruvate kinase, raised new questions, and suggested the possibility of non-canonical PKM2 functions to regulate gene expression and cell cycle progression via protein-protein interactions and protein kinase activity. Here we review the structure, function, and regulation of pyruvate kinase and discuss how these properties enable regulation of PKM2 for cell proliferation and tumor growth.

Keywords: Cancer metabolism; PKM2; Pyruvate kinase.

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Figures

Figure 1
Figure 1. Generation of PKM1 and PKM2 by alternative splicing
PKM1 and PKM2 are produced by alternative splicing from the PKM gene. PKM exon 9 is included in mature PKM1 mRNA, and exon 10 is included in mature PKM2 mRNA. Production of the M2 isoform of pyruvate kinase requires both repression of exon 9 and inclusion of exon 10. The splicing factors PTB, hnRNPA1, and hnRNPA2 repress inclusion of exon 9, while SRSF3 promotes inclusion of exon 10.
Figure 2
Figure 2. Crystal structure of tetrameric PKM2 with bound ligands
The ribbon structure of tetrameric PKM2 (PDB 3BJF [8]) is shown, with a single subunit colored to represent individual domains. The A, B, C, and N-terminal domains are depicted in green, magenta, cyan, and yellow, respectively. Bound ligands are shown as gray spheres. In this structure, the catalytic site is occupied by K+, Mg2+, and oxalate (a PEP mimetic), and FBP is bound at its allosteric pocket. The binding site for phenylalanine, alanine, and serine is empty; but this site of amino acid binding between the A and C domains is indicated. The binding site for small molecule activators is also indicated. The endogenous ligand binding in the “activator” site, if any, is unknown.
Figure 3
Figure 3. The isoform-specific portion of a PKM2 tetramer
A ribbon structure of a PKM2 tetramer is shown in green. The parts of each subunit that are encoded by exon 10, and are therefore PKM2 isoform-specific, are highlighted in magenta. The PKM2-specific region of the protein forms the bulk of the interface between the dimer of dimers and also forms part of the FBP binding site. Ligands bound in the catalytic and FBP binding sites are shown as black spheres.
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