Pyruvate kinase muscle isozyme M1 (PKM1)

Pyruvate kinase muscle isozyme M1 (PKM1) is a constitutively active isoform of the glycolytic enzyme pyruvate kinase, produced by the alternative splicing of the PKM gene through the inclusion of exon 9. Unlike the M2 isoform (PKM2), which is allosterically regulated and typically upregulated in cancer cells to support the Warburg effect, PKM1 is predominantly expressed in differentiated, high-energy-demand tissues such as the heart, brain, and skeletal muscle. PKM1 promotes efficient ATP production through oxidative phosphorylation and is essential for maintaining metabolic homeostasis and cellular growth in these tissues. In many cancers, PKM1 acts as a tumor suppressor, and its downregulation is a hallmark of metabolic reprogramming; however, it has been found to be upregulated and required for proliferation in specific subtypes like small-cell lung cancer and certain neuroendocrine tumors. Therapeutic interest in PKM1 involves either its inhibition in PKM1-dependent cancers or its restoration/activation in other cancers to reverse aerobic glycolysis. Additionally, PKM1 is a target for treating cardiovascular diseases, as its loss is associated with heart failure and impaired cardiac remodeling.

Other names

Pyruvate kinase muscle isozymePKMPK2PK3Opa-interacting protein 3Cytosolic thyroid hormone-binding proteinCTHBPOIP-3

Allosteric inhibition, splicing modulation to increase PKM1 expression, and catalytic activation to mimic PKM1-like high activity states.