PKM encodes pyruvate kinase isoforms with fundamentally different metabolic properties - the M1/M2 switch is a hallmark of the Warburg effect in cancer.
| Isoform | UniProt ID | Synonym | Activity | Regulation | Expression |
|---|---|---|---|---|---|
| PKM1 | P14618-2 | M1-PK | HIGH constitutive | Not allosteric | ADULT muscle, brain, heart |
| PKM2 | P14618-1 | M2-PK | LOW basal, activatable | Allosteric (FBP) | EMBRYONIC, proliferating, CANCER |
Alternative splicing of mutually exclusive exons 9 and 10:
- Exon 9 → PKM1 (adult)
- Exon 10 → PKM2 (embryonic/cancer)
Controlled by hnRNP splicing factors (hnRNPA1, hnRNPA2, PTB).
PKM1 (isoform 2):
- Constitutively active homotetramer
- High pyruvate kinase activity
- Efficient ATP generation via glycolysis
- Normal oxidative metabolism
PKM2 (isoform 1):
- Allosterically regulated by fructose-1,6-bisphosphate (FBP)
- Can exist as inactive monomer/dimer or active tetramer
- LOW activity allows glycolytic intermediates to accumulate
- Supports biosynthetic pathways (nucleotides, amino acids, lipids)
- Nuclear translocation: Can act as transcription coactivator
Cancer cells switch from PKM1 to PKM2:
- LOW PKM2 activity → glycolytic intermediates diverted to biosynthesis
- Supports rapid proliferation
- PKM2 is nearly universal in cancer
PKM2 has functions ABSENT from PKM1:
- Protein kinase activity - phosphorylates histones (H3Y11)
- Transcription coactivation - interacts with HIF-1α
- Nuclear functions - regulates gene expression