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Cancer‐associated mutations in human pyruvate kinase M2 impair enzyme activity
Author(s) -
Liu Vivian M.,
Howell Andrea J.,
Hosios Aaron M.,
Li Zhaoqi,
Israelsen William J.,
Vander Heiden Matthew G.
Publication year - 2020
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.13648
Subject(s) - pkm2 , pyruvate kinase , allosteric regulation , glycolysis , mutant , enzyme , biochemistry , activator (genetics) , enzyme activator , biology , enzyme kinetics , isozyme , chemistry , gene , active site
Mammalian pyruvate kinase catalyzes the final step of glycolysis, and its M2 isoform (PKM2) is widely expressed in proliferative tissues. Mutations in PKM2 are found in some human cancers; however, the effects of these mutations on enzyme activity and regulation are unknown. Here, we characterized five cancer‐associated PKM2 mutations, occurring at various locations on the enzyme, with respect to substrate kinetics and activation by the allosteric activator fructose‐1,6‐bisphosphate (FBP). The mutants exhibit reduced maximal velocity, reduced substrate affinity, and/or altered activation by FBP. The kinetic parameters of five additional PKM2 mutants that have been used to study enzyme function or regulation also demonstrate the deleterious effects of mutations on PKM2 function. Our findings indicate that PKM2 is sensitive to many amino acid changes and support the hypothesis that decreased PKM2 activity is selected for in rapidly proliferating cells.