4g1n
From Proteopedia
PKM2 in complex with an activator
Structural highlights
Function[KPYM_HUMAN] Glycolytic enzyme that catalyzes the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP. Stimulates POU5F1-mediated transcriptional activation. Plays a general role in caspase independent cell death of tumor cells. The ratio betwween the highly active tetrameric form and nearly inactive dimeric form determines whether glucose carbons are channeled to biosynthetic processes or used for glycolytic ATP production. The transition between the 2 forms contributes to the control of glycolysis and is important for tumor cell proliferation and survival.[1] [2] [3] Publication Abstract from PubMedProliferating tumor cells use aerobic glycolysis to support their high metabolic demands. Paradoxically, increased glycolysis is often accompanied by expression of the lower activity PKM2 isoform, effectively constraining lower glycolysis. Here, we report the discovery of PKM2 activators with a unique allosteric binding mode. Characterization of how these compounds impact cancer cells revealed an unanticipated link between glucose and amino acid metabolism. PKM2 activation resulted in a metabolic rewiring of cancer cells manifested by a profound dependency on the nonessential amino acid serine for continued cell proliferation. Induction of serine auxotrophy by PKM2 activation was accompanied by reduced carbon flow into the serine biosynthetic pathway and increased expression of high affinity serine transporters. These data support the hypothesis that PKM2 expression confers metabolic flexibility to cancer cells that allows adaptation to nutrient stress. Small Molecule Activation of PKM2 in Cancer Cells Induces Serine Auxotrophy.,Kung C, Hixon J, Choe S, Marks K, Gross S, Murphy E, Delabarre B, Cianchetta G, Sethumadhavan S, Wang X, Yan S, Gao Y, Fang C, Wei W, Jiang F, Wang S, Qian K, Saunders J, Driggers E, Woo HK, Kunii K, Murray S, Yang H, Yen K, Liu W, Cantley LC, Vander Heiden MG, Su SM, Jin S, Salituro FG, Dang L Chem Biol. 2012 Sep 21;19(9):1187-98. doi: 10.1016/j.chembiol.2012.07.021. PMID:22999886[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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